Endocrine Pathophysiology: A Concise Guide To The Physical Exam Andrea Manni Akuffo Quarde

Endocrine
Pathophysiology
A Concise Guide to the Physical

Exam
Andrea Manni
Akuffo Quarde
123
Endocrine Pathophysiology
Andrea Manni • Akuffo Quarde
Endocrine
Pathophysiology
A Concise Guide to the Physical Exam
Andrea Manni Akuffo Quarde
Division of Endocrinology Sanford Health Clinic
Diabetes and Metabolism Bemidji, MN
Penn State Milton S. Hershey USA
Medical Center
Hershey, PA
USA
ISBN 978-3-030-49871-9 ISBN 978-3-030-49872-6 (eBook)

https://doi.org/10.1007/978-3-030-49872-6
© Springer Nature Switzerland AG 2020

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To my colleagues and trainees, who enriched
my academic life.
To my wife, Rosemary, for her support

throughout my career. – Andrea
To my beloved parents, for being inspiring

forces in my life.
To my wife Anisa and children Stephanie

and Nathan. – Akuffo
Preface
The physical exam is a dying art in modern medicine. In some instances, diagnostic
tests and imaging procedures are significantly relied on at the expense of the physi-
cal examination. Hormone science (endocrinology) involves the study of perturba-
tions in complex hormonal systems, which can present with a myriad of clinical
signs. By bringing the pathophysiologic basis of clinical signs to the fore, we hope
physicians in training can develop a better appreciation of the importance of the
clinical exam.
Although modern medicine has improved our understanding of disease, the
foundations laid by observant clinicians of a bygone era should be recognized by
present-day clinicians. We have sought to highlight the contributions of various cli-
nicians who have been pivotal in the development of this exciting field of clinical
endocrinology.
We have strived to provide a concise approach to exploring endocrine patho-
physiology through the physical exam and hope trainees and clinicians alike find the
book an excellent addition to their library.
Hershey, PA, USA Andrea Manni

Bemidji, MN, USA Akuffo Quarde
vii
Acknowledgments
We are grateful for the helpful suggestions and worthy contributions of various
persons during the development of this book.
We appreciate the contributions of Dr. Alan Sacerdote (Retired Professor of
Medicine, New York University School of Medicine), Dr. Chris Fan (Endocrinology
Fellowship Director, Penn State University), Dr. Kanthi Bangalore Krishna
(Assistant Professor of Medicine, Pediatric Endocrinology and Diabetes Division,
Penn State University), Dr. Ariana Pichardo-Lowden (Associate Professor of
Medicine, Endocrinology Division, Penn State University), and Dr. Shyam Narayana
(Assistant Professor of Medicine, Endocrinology Division, Penn State University).
We sincerely appreciate the efforts of Dr. Avinindita Nura Lestari (Bachelor of
Medicine, Universitas Islam Bandung, Indonesia) for designing and editing the
illustrations. Her creative input and dedication to this project were commendable.
We want to thank Lisa Doster (Endocrinology Division, Penn State University)
for her assistance during the writing of the manuscript.
We are also grateful to our publishing team at Springer and would like to say a
special thank you to Kristopher Spring, Keerthana Gnanasekeran and Karthik
Rajasekar.
Hershey, PA, USA Andrea Manni

Bemidji, MN, USA Akuffo Quarde
ix
Contents
1 Pituitary Gland Signs�� 1

1.1 Cushing’s Disease �� 1
1.1.1 Proximal Myopathy�� 1
1.1.2 Fat Maldistribution�� 3
1.1.3 Striae and Skin Atrophy�� 4
1.1.4 Facial Plethora�� 4
1.1.5 Hirsutism�� 5
1.1.6 Hypertension �� 6
1.1.7 Fragility Fractures�� 6
1.1.8 Hyperpigmentation �� 7
1.2 Acromegaly�� 8
1.2.1 Acanthosis Nigricans�� 8
1.2.2 Frontal Bossing and Prognathism �� 9
1.2.3 Acrochordons and Other Skin Manifestations�� 9
1.2.4 Colonic Polyps�� 10
1.2.5 Tinel’s Sign (Carpal Tunnel Syndrome) �� 11
1.3 Prolactinoma �� 12
1.3.1 Hypogonadism�� 12
1.3.2 Gynecomastia and Galactorrhea �� 12
1.3.3 Bitemporal Hemianopsia�� 13
1.4 Adult Growth Hormone Deficiency�� 14
1.4.1 Abnormal Body Composition�� 14
1.5 Growth Hormone Insensitivity (Laron-Type Dwarfism)�� 16
1.5.1 Short Stature�� 16
1.5.2 Obesity�� 16
1.5.3 Small Genitalia�� 17
1.6 Central Diabetes Insipidus�� 18
1.6.1 Dehydration due to Polyuria and Polydipsia�� 18
References�� 21
2 Thyroid Gland Signs�� 27
2.1 Hashimoto’s Thyroiditis�� 27
2.1.1 Queen Anne’s Sign�� 27
xi
xii Contents
2.1.2 Bradycardia �� 28

2.1.3 Pericardial and Pleural Effusions�� 28
2.1.4 Dry Skin�� 29
2.1.5 Macroglossia �� 29
2.1.6 Hyporeflexia�� 30
2.1.7 Proximal Myopathy�� 30
2.1.8 Galactorrhea�� 30
2.2 Graves’ Disease�� 32
2.2.1 Thyroid Eye Disease �� 32
2.2.2 Pretibial Myxedema�� 34
2.2.3 Thyroid Acropachy �� 34
2.2.4 Onycholysis�� 35
2.2.5 Periodic Paralysis�� 35
2.2.6 Thyroid Bruit and Thrill�� 36
2.2.7 Tachycardia �� 36
2.2.8 Gynecomastia�� 37
2.2.9 Lymphadenopathy�� 37
2.2.10 Change in Body Composition (Weight Loss) �� 38
2.3 Euthyroid Goiter with Thoracic Outlet Syndrome�� 39
2.3.1 Pemberton’s Sign�� 39
2.3.2 Other Compressive Signs (Superior Vena Cava Syndrome,
Phrenic Nerve Paralysis)�� 40
2.4 Resistance to Thyroid Hormone �� 42
2.4.1 Goiter�� 42
2.5 Medullary Thyroid Cancer�� 44
2.5.1 Facial Flushing and Other Clinical Features of
Neuroendocrine Origin �� 44
2.5.2 Cervical Mass�� 44
References�� 45
3 Adrenal Gland Signs�� 51
3.1 Primary Adrenal Insufficiency�� 51
3.1.1 Postural Hypotension�� 51
3.2 Primary Hyperaldosteronism�� 55
3.2.2 Muscle Weakness�� 57
3.2.3 Atrial Fibrillation�� 57
3.2.4 Dehydration�� 57
3.3 Pseudohypoaldosteronism�� 60
3.3.1 Cardiac Arrest due to Life-Threatening Hyperkalemia�� 60
3.3.2 Cutaneous Manifestations (Folliculitis and
Atopic Dermatitis)�� 60
Contents xiii
3.4 Familial Glucocorticoid Deficiency�� 61

3.4.2 Hypoglycemia �� 61
3.5 Pheochromocytomas and Other Paraganglioma Syndromes�� 63
3.5.2 Hypotension�� 65
3.5.3 Generalized Hyperhidrosis�� 66
3.5.4 Cardiogenic Shock�� 66
3.6 Nonclassic Congenital Adrenal Hyperplasia (NCCAH)�� 67
3.6.1 Clinical Hyperandrogenism (Acne and Hirsutism)�� 67
3.6.2 Testicular Adrenal Rest Tumors�� 68
3.6.3 Signs of Insulin Resistance (Skin Tags and
Acanthosis Nigricans)�� 68
References�� 71
4 Pancreatic Gland Signs�� 77
4.1 Diabetes Mellitus�� 77
4.1.2 Diabetic Dermopathy�� 78
4.1.3 Acrochordons (Skin Tags)�� 78
4.1.4 Necrobiosis Lipoidica Diabeticorum�� 78
4.1.5 Lipodystrophy Due to Insulin Injections�� 79
4.1.6 Diabetic Retinopathy on Direct Ophthalmoscopy�� 81
4.1.7 The Diabetic Foot �� 83
4.2 Rabson-Mendenhall Syndrome (Type A Insulin Resistance) �� 86
4.3 Glucagonoma�� 88
4.3.1 Necrolytic Migratory Erythema�� 88
4.4 Carcinoid Syndrome �� 89
4.4.1 Cutaneous Flushing�� 89
4.4.2 Diarrhea�� 90
4.4.3 Bronchospasm�� 91
4.4.4 Cardiac Valvular Lesions�� 92
4.4.5 Other Cutaneous Manifestations (Pellagra)�� 92
4.5 VIPoma �� 94
4.5.1 Dehydration Due to Extrarenal Losses �� 94
References�� 97
5 Parathyroid Gland and Musculoskeletal Signs �� 103
5.1 Hyperparathyroidism�� 103
5.1.1 Acute Abdomen�� 103
5.1.3 Band Keratopathy/Cataracts �� 104
xiv Contents
5.2 Hypoparathyroidism �� 109

5.2.1 Trousseau’s Sign and Chvostek Sign in the
Setting of Hypocalcemia�� 109
5.2.2 Seizures �� 109
5.2.3 Hypotension�� 110
5.2.4 Papilledema�� 110
5.3 Pseudohypoparathyroidism�� 111
5.3.2 Obesity�� 112
5.3.3 Brachydactyly �� 112
5.3.4 Dental Manifestations �� 113
5.4 Paget’s Disease of Bone�� 114
5.4.1 Fractures and Bone Deformity�� 114
5.4.2 Congestive Heart Failure�� 115
5.4.3 Sensorineural Hearing Loss�� 115
5.5 Hereditary Vitamin D-Resistant Rickets Type 2 (HVDRR-II) �� 116
5.5.1 Rickets�� 116
5.6 X-Linked Hypophosphatemic Rickets�� 117
5.6.2 Dental Abscess�� 119
References�� 120
6 Reproductive Organ Signs�� 127
6.1 Turner’s Syndrome�� 127
6.1.2 Webbed Neck and Lymphedema�� 129
6.1.4 Melanocytic Nevi�� 130
6.1.5 Sexual Infantilism �� 130
6.2 Polycystic Ovarian Syndrome�� 131
6.2.1 Hirsutism�� 131
6.2.3 Acne�� 132
6.2.4 Obesity�� 132
6.3 Male Hypogonadism�� 134
6.3.1 Decreased Testicular Volume�� 134
6.3.2 Gynecomastia�� 135
6.3.3 Loss of Height or Fragility Fractures�� 137
6.3.4 Change in Body Composition�� 138
6.4 Menopause�� 139
6.4.1 Vaginal Dryness�� 139
6.4.3 Change in Body Composition�� 140
6.5 Estrogen Resistance�� 141
6.5.1 Tall Stature�� 141
Contents xv
6.6 Complete Androgen Insensitivity�� 142

6.6.1 Abnormalities of the External and Internal Genitalia �� 142
6.6.2 Normal Breast Tissue Development �� 142
7 Signs in Disorders of Lipid Metabolism and Obesity �� 151
7.1 Signs in Disorders of Lipid Metabolism�� 151
7.1.1 Corneal Arcus�� 151
7.1.2 Xanthomas and Xanthelasma�� 152
7.1.3 Skin Crease (Frank’s Sign) �� 153
7.1.4 Lipemia Retinalis�� 153
7.2 Congenital Leptin Deficiency �� 160
7.2.1 Obesity�� 160
7.3 Proopiomelanocortin (POMC) Deficiency �� 161
7.3.1 Triad of Obesity, Adrenal Insufficiency, and
Reddish Hair �� 161
7.4 Lipodystrophy Syndromes�� 163
7.4.1 Atrophy of Adipose Tissue�� 163
7.4.2 Hepatomegaly �� 163
8 Eponymous Terms and Selected Historical
Figures in Endocrinology�� 171
8.1 Eponyms Related to the Pituitary Gland�� 171
8.1.1 Wolfram Syndrome (DIDMOAD)�� 171
8.1.2 Histiocytosis X�� 172
8.2 Eponyms Related to the Thyroid Gland�� 172
8.2.1 Pendred’s Syndrome �� 172
8.3 Eponyms Related to the Adrenal Glands�� 174
8.3.1 Carney Dyad or Carney-Stratakis Syndrome�� 174
8.3.2 Allgrove Syndrome �� 175
8.4 Eponyms Related to the Pancreas �� 175
8.4.1 Kussmaul’s Breathing (Diabetic Ketoacidosis)�� 175
8.4.2 Somogyi Effect �� 175
8.5 Eponyms Related to the Parathyroid Glands and
Bone Metabolism�� 176
8.5.1 Albers-Schönberg Disease�� 176
8.5.2 McCune-Albright Syndrome�� 177
8.6 Miscellaneous Eponyms �� 177
8.7 A Brief Account of Selected Historical
Figures in Endocrinology�� 177
8.7.1 Harvey Cushing (1869–1939)�� 177
8.7.2 Hakaru Hashimoto (1881–1934)�� 178
8.7.3 Thomas Addison (1793–1860)�� 179
8.7.4 Fuller Albright (1900–1969) �� 179
8.7.5 Jerome W. Conn (1907–1994)�� 180
xvi Contents
8.7.6 Frederick Banting (1891–1941)�� 180

8.7.7 Robert Graves (1797–1853)�� 181
8.7.8 Edward Kendall (1888–1972)�� 181
Appendix �� 187
Index�� 193
About the Authors
Andrea Manni MD – Professor of Medicine, Chief of the Division of

Endocrinology, Diabetes and Metabolism, College of Medicine, The Pennsylvania
State University, Hershey PA, USA. Email: amanni@pennstatehealth.psu.edu
Akuffo Quarde MD, PgD (Clinical Trials) – Endocrinologist, Sanford Health

Clinic, Bemidji MN, USA. Email: akuffo.quarde@sanfordhealth.org
xvii
Pituitary Gland Signs
1
Learning Objectives
At the end of this chapter, you will be able to:
1. Understand the metabolic effects of growth hormone in both hormone

excess and hormone-deficient states
2. Understand the role of growth hormone and other related hormones in the
development of the growth plate
3. Identify the multiple effects of cortisol excess on the skin and integument
4. Recognize the concept of physiological cortisol resistance and its impor-
tance in specific endocrine conditions
5. Understand the effects of hyperprolactinemia on the hypothalamic-

pituitary-gonadal axis
6. Recognize the pathophysiologic basis for the clinical presentation of cen-
tral diabetes insipidus
1.1 Cushing’s Disease
1.1.1 Proximal Myopathy
Clinical Features
Harvey Cushing reported muscle weakness as a cardinal finding in his original
description of Cushing’s disease [1, 2]. Proximal myopathy is an essential clinical
clue in patients with overt hypercortisolism, with variable rates of prevalence rang-
ing from 40 to 70% in retrospective studies [3, 4].
Proximal muscle weakness associated with Cushing’s disease presents as an
inability to either climb stairs or get up from a seated position without assistance.
Loss of handgrip strength is also a known physical manifestation of Cushing’s
© Springer Nature Switzerland AG 2020 1

A. Manni, A. Quarde, Endocrine Pathophysiology,
https://doi.org/10.1007/978-3-030-49872-6_1
2 1 Pituitary Gland Signs
disease, although pelvic girdle muscles are more likely to be involved than pectoral
girdle and upper limb muscles [5, 6].
Pathophysiology
1. Glucocorticoids cause an increase in muscle protein catabolism resulting in a
loss of lean body mass [7].
2. A reduction in postabsorptive and post-prandial muscle protein synthesis con-
tributes to a loss of lean body mass as well [8].
3. Supraphysiologic levels of glucocorticoids activate the mineralocorticoid recep-
tor at the level of the kidney, which results in hypokalemia (see Fig. 1.1).
Hypokalemia-mediated muscle weakness contributes to the myopathy observed
in endogenous hypercortisolism [9].
4. In Cushing’s disease, aldosterone secretion is further augmented by adrenocorti-
cotrophic hormone (ACTH) excess [10].
Pathophysiology Pearl
Physiologic “Cortisol Resistance”
Cortisol can bind both glucocorticoid and mineralocorticoid receptors, and
indeed under normal physiological conditions, plasma levels of cortisol are up to
1000-fold higher than that of aldosterone. 11Beta-hydroxysteroid dehydrogenase
type 2 (11β-HSD2) inactivates physiological concentrations of cortisol and thus
protects the mineralocorticoid receptor from direct activation by cortisol [11].
Cortisol
Cortisol
Binds to the hepatic GCR
11β -HSD1 11β -HSD2
Cortisone
Cortisone Cannot bind to the renal MCR
Fig. 1.1 The cortisol-to-cortisone shunt – the role of 11beta-hydroxysteroid dehydrogenases in

mediating tissue-specific levels of cortisol. The two isoforms of 11beta-hydroxysteroid dehydro-
genase play essential roles in the cortisol-to-cortisone shunt. 11Beta-hydroxysteroid dehydroge-
nase type 1 (11β HSD1) converts inactive cortisone to active cortisol in the liver, which subsequently
binds its cognate hepatic glucocorticoid receptor (GCR)(dark arrows) [11]. 11Beta-hydroxysteroid
dehydrogenase type 2 (11β HSD2) converts active cortisol to inactive cortisone at the level of the
kidney, thus protecting the mineralocorticoid receptor (MCR) from activation by cortisol (white
arrows) [12] (Redrawn and modified from Gomez-Sanchez et al. [11])
1.1 Cushing’s Disease 3
Table 1.1 Comparison of the isoforms of 11β HSD

11β HSD1 11β HSD2
Increases circulating levels of cortisol [15, 16] Promotes physiological cortisol resistance [15]
Absent from the kidney [17] Present in the kidney [17]
Absent from sweat and salivary glands [17] Present in sweat and salivary glands [17]
Present in the liver [17] Absent from the liver [17]
Present in osteoblasts and osteocytes [17] Absent from the bone [17]
Present in adipose tissue [17] Absent from adipose tissue [17]
11β HSD1 11beta-hydroxysteroid dehydrogenase type 1
11β HSD2 11beta-hydroxysteroid dehydrogenase type 2
Adapted from references [15–17]
In both ACTH-dependent and ACTH-independent Cushing’s syndrome, there is

an impaired activity of 11β HSD2, which leads to reduced deactivation of cortisol to
cortisone in the kidney [9]. This defect results in a state of cortisol excess, akin to
apparent mineralocorticoid excess (AME), or even licorice ingestion [13].
The excess cortisol thus stimulates the mineralocorticoid receptor. Increased
mineralocorticoid action accounts for the hypokalemia observed in patients with
hypercortisolemia [14] (Table 1.1).
Clinical Pearl
Patients with adrenal crises because of Addison’s disease do not require
concomitant fludrocortisone (mineralocorticoid) administration if their total
daily dose of steroids is greater than or equal to 50 mg of hydrocortisone, or
steroid equivalent. Supraphysiologic doses of hydrocortisone, given during
an emergency, will activate the mineralocorticoid receptor and thus provide
additional mineralocorticoid coverage. Patients managed with methylpred-
nisolone may and those taking dexamethasone will require mineralocorti-
coid due to limited binding of the former and zero binding of the latter to
mineralocorticoid receptors [18].
1.1.2 Fat Maldistribution
Clinical Features
Visceral adiposity in the setting of endogenous hypercortisolism has been referred
to as “Cushing’s disease of the omentum” [19]. Abnormal fat distribution can also
be disproportionately higher over the dorsocervical, supraclavicular, or temporal
regions compared to the extremities [20].
Pathophysiology
1. Glucocorticoids inhibit a regulatory kinase involved in the sensing of

cellular energy status. Under physiologic conditions, activation of adenosine
5’-monophosphate-activated protein kinase (AMPK) switches off fatty acid
synthesis. Excess glucocorticoids inhibit AMPK and, by so doing, increase
fatty acid synthesis. This is a novel mechanism underlying the distribution of

fat in Cushing’s disease [21, 22].
2. There is overexpression of 11β HSD1 in visceral adipose tissue, which accounts
for the excessive conversion of cortisone to cortisol in patients with Cushing’s
disease [23, 24] (see Fig. 1.1). Supraphysiologic levels of cortisol act in a para-
crine fashion to increase fat storage in adipocytes, ultimately resulting in the
accumulation of visceral fat [19]. The reasons for the preferential distribution of
excess fat in the abdomen, head, and neck area, however, remain unclear.
1.1.3 Striae and Skin Atrophy
Clinical Features
Striae observed in Cushing’s disease tend to be broad and violaceous, in contrast to
the pale-colored thin striae associated with obesity. In darker-skinned individuals,
striae may, however, not appear purple. Striae are typically distributed over the
flanks, lower abdomen, upper thighs, and buttocks [25].
Skin atrophy can be assessed clinically by measuring skinfold thickness with a
skin caliper [26]. Bedside assessment of skinfold thickness has been validated as an
essential clinical tool in the evaluation of hypercortisolism. An improvised simple
electrocardiographic caliper with its sharp edges blunted can be used to assess skin-
fold thickness over the proximal phalanx of the middle finger of the nondominant
hand [27].
A skinfold thickness of 1.5 mm or lower is predictive of hypercortisolemia when
comparing patients with Cushing’s disease to controls without endogenous hyper-
cortisolism [28].
In a recent paper, a skin thickness threshold of <2 mm was reported as being
consistent with clinically significant thin skin. The positive likelihood ratio (+LR)
for predicting endogenous hypercortisolism in patients with skin thickness less than
2 mm was estimated as 116 [27].
Pathophysiology
There are glucocorticoid receptors in the epidermis of the skin, located mainly on
basal and Langerhans cells [29]. Activation of the glucocorticoid receptors present
on these epidermal cells impairs collagen formation by reducing type 1 collagen
gene expression; this leads to impaired skin growth and thinning of the epidermal
layer [30].
1.1.4 Facial Plethora
Clinical Features
Facial plethora is a common clinical finding in patients with hypercortisolism [25]
and is highly predictive of Cushing’s disease. Of note, the other positive discrimina-
tory findings of endogenous hypercortisolism include easy bruising, proximal
myopathy, and purplish striae >1 cm [31].
Pathophysiology
Investigators at the National Institutes of Health (NIH) quantified vascular flow
rates in patients with Cushing’s syndrome, pre- and post-surgery. Patients with per-
sistent facial plethora in the post-surgery period were noted to have cortisol levels
above 3 mcg/dL, which was predictive of a lack of surgical cure. These subjects had
a high facial blood volume fraction, measured by near-infrared multispectral imag-
ing. Increased blood flow in the facial skin is the cause of plethora observed in the
setting of endogenous hypercortisolism [32].
1.1.5 Hirsutism
Clinical Features
Hirsutism, a sign of androgen excess, is more common in the setting of adrenal
carcinoma compared to Cushing’s disease. Nonetheless, hirsutism in the right clini-
cal context can be suggestive of endogenous hypercortisolemia [33]. Hirsutism
presents in females as excessive terminal, pigmented hair growth, distributed in a
classic male pattern [34].
Pathophysiology
ACTH-dependent Cushing’s syndrome causes a mild form of hirsutism in women,
through the trophic effect of corticotropin (ACTH) on the adrenal cortex. ACTH
stimulates the zona reticularis resulting in increased biosynthesis of adrenal sex
steroids [35] (Fig. 1.2).
Pigmented hair
External root sheath

Internal root sheath
Melanocyte
Follicular Unit
Extracellular matrix
Keratinocyte
Basement membrane
Dermal papilla cells
Blood capillary with

circulating androgens
Fig. 1.2 Mechanism of androgen action in hair follicles. Circulating androgens access the dermal
papilla cells via dermal capillaries. Androgens (testosterone or dihydrotestosterone) bind to spe-
cific target nuclear receptors in dermal papilla cells. Direct stimulation of keratinocytes and mela-
nocytes occurs through androgen-mediated release of regulatory and growth-promoting factors
from the dermal papilla cells [36]. (Based on Thornton et al. [36])
Associated Endocrinopathies/Differentials of Hirsutism

Congenital adrenal hyperplasia (CAH, both classical and nonclassical); poly-
cystic ovarian syndrome (PCOS); Cushing’s disease; acromegaly; insulin
resistance; hyperandrogenism, insulin resistance, and acanthosis nigricans
(HAIR-AN syndrome); and virilizing adrenal, ovarian, or ectopic tumors [34].
1.1.6 Hypertension
Clinical Features
80% of patients with Cushing’s syndrome have hypertension. Of note, Cushing’s-
specific hypertension and primary hypertension may coexist in the same patient [37].
Pathophysiology
1. Supraphysiologic levels of cortisol overwhelm 11β-HSD2, an essential enzyme
that protects the renal mineralocorticoid receptor from direct activation by glu-
cocorticoids (see Fig. 1.1). Mineralocorticoid receptor activation eventually
leads to excessive renal sodium and water conservation [14].
2. Glucocorticoids increase the plasma concentration of angiotensinogen and thus
directly stimulate increased activity of the renin-angiotensin-aldosterone system
(RAAS) [38].
3. Glucocorticoids increase the vasopressor effect of angiotensin II by stimulating
messenger RNA expression of the angiotensin 1 (AT-1) receptor, the vascular
receptor for angiotensin II [39].
4. Increased systemic vascular resistance due to glucocorticoid-mediated inhibition
of vasodilatory pathways such as the nitric oxide system, kallikrein, and prosta-
cyclin plays a contributory role as well [40].
1.1.7 Fragility Fractures
Clinical Features
Endogenous hypercortisolism increases the risk of low bone mineral density in a
manner akin to exogenous glucocorticoid-induced osteoporosis (GIOP). Unlike
exogenous GIOP, there is very little published literature on the prevalence of osteo-
porosis related-fractures in patients with Cushing’s syndrome [41].
Pathophysiology
Endogenous hypercortisolism through various processes outlined below results in a
low bone mineral density and predisposes patients to fragility fractures.
1. Decreased bone formation occurs because of increased glucocorticoid-mediated

apoptosis of osteoblasts. There is also evidence that glucocorticoids directly
inhibit the function of osteoblast as well [41].
2. Osteocytes which act as mechanoreceptors are also subject to apoptosis in the

setting of high levels of glucocorticoids.
3. Glucocorticoids increase the expression of receptor activator of nuclear factor
κ-B ligand (RANK-L) on the surface of osteoblasts with a concomitant reduction
in osteoprotegerin (decoy-receptor for RANK-L) expression. The absence of the
decoy receptor for RANK-L further potentiates osteoclastic activity, which ulti-
mately promotes increased bone resorption and loss of bone mineral density (see
Sect. 5.1.2) [41].
1.1.8 Hyperpigmentation
Clinical Features
Hyperpigmentation of the skin can occur in Cushing’s disease, although it is more
common in patients with ectopic ACTH production [42]. For patients with Cushing’s
disease, hyperpigmentation is common in those with persistent pituitary disease
after bilateral adrenalectomy, i.e., Nelson’s syndrome. Hyperpigmentation is usu-
ally evident in scars, buccal mucosa, conjunctivae, and sun-exposed areas [43, 44].
Pathophysiology
ACTH-induced hyperpigmentation has been described in detail (see Sect. 3.1.2).
Clinical Pearl
Summary of the Clinical Features of Cushing’s Disease (Fig. 1.3)
Fig. 1.3 Clinical features

Depression
of Cushing’s disease. The
physical examination Facial plethora
Dorsocervical fat pad
findings that are highly
suggestive of Cushing’s Hypertension
Hyperglycemia
include proximal muscle
weakness (myopathy), easy
bruising, thick violaceous
striae, and facial plethora Muscle atrophy Central adiposity
[31]. (Based on Nieman
et al. [31]) Thick violaceous striae
Osteoporosis
Easy bruisability
Skin atrophy
Questions You Might Be Asked on Clinical Rounds

Why would a patient with pituitary-dependent Cushing’s develop adrenal
insufficiency after adenomectomy?
A long duration of exposure of normal corticotrophs to supraphysiologic
levels of cortisol results in suppression of their function through sustained
negative feedback inhibition. Removal of the abnormal ACTH-producing
cells contributes to loss of trophic stimulation of the zona fasciculata (cortisol
producing layer of the adrenal gland). The remaining normal ACTH-producing
cells are unable to sense low cortisol levels due to their chronic suppression
by negative feedback inhibition; this explains the development of secondary
adrenal insufficiency in patients during the postoperative period [45].
What is Nelson’s syndrome?
Nelson’s syndrome occurs after bilateral adrenalectomy to correct hyper-
cortisolism in patients with Cushing’s disease who have typically failed trans-
sphenoidal surgery. It occurs as a result of the aggressive growth of the
ACTH-producing adenoma following a loss of negative feedback inhibition
by cortisol [46, 47].
Increased ACTH production and the mass effect of an expanding pituitary
tumor contribute to the clinical features of this condition. These include
hyperpigmentation, headaches, and visual field defects [48].
1.2 Acromegaly
1.2.1 Acanthosis Nigricans
Clinical Features
Patients with acromegaly exhibit some signs of insulin resistance. Acanthosis nigri-
cans (AN) is a cardinal dermatologic feature of insulin resistance [49] and appears
as a hyperpigmented, velvety skin lesion that has a predilection for flexural areas
such as the neck, groin, and antecubital fossa [50, 51].
Pathophysiology
Growth hormone (GH) inhibits the phosphorylation of the insulin receptor in
response to insulin-to-receptor binding, a process that contributes to the develop-
ment of hyperinsulinemia [49].
The skin has several cells that express insulin-like growth factor 1 (IGF-1) recep-
tors, including the stratum granulosum of the epidermis and dermal fibroblasts [52].
Excess insulin activates IGF-1 receptors in the skin and initiates the proliferation of
dermal fibroblasts [53].
1.2 Acromegaly 9
Associated Endocrinopathies/Differentials
Cushing’s syndrome, acromegaly, PCOS, CAH, HAIR-AN syndrome, diabe-
tes mellitus, paraneoplastic, and other hormonal causes of peripheral insulin
resistance [51].
1.2.2 Frontal Bossing and Prognathism
Clinical Features
Frontal bossing and prognathism are cardinal craniofacial manifestations of acro-
megaly. Other signs include dental malocclusion and nasal bone hypertrophy [54].
In a study involving 29 acromegalics, the investigators assessed for any improve-
ment in craniofacial skeletal deformities after curative tumor resection. Prespecified
skull measurements did not differ significantly when the pre- and postsurgical
dimensions were compared on serial magnetic resonance images (MRIs) [55].
These physical findings, unfortunately, will persist even after curative operative
management of acromegaly, based on the results of this study.
Pathophysiology
Excess growth hormone and IGF-1 stimulate periosteal new bone formation result-
ing in the characteristic craniofacial features of acromegaly [54].
Clinical Pearl
The Role of the “Photograph Biopsy”
Acromegaly is a rare disease, which usually presents with a slow and pro-
gressive change in a patient’s facial features. The diagnosis of acromegaly can
be delayed by up to 10 years in most cases due to the subtle craniofacial
changes seen in patients. In a recent study comparing over 500 acromegalic
patients with an equivalent number of controls, the investigators used machine
learning algorithms to predict the diagnosis of acromegaly in subjects with a
high positive predictive value. Artificial intelligence software using facial rec-
ognition of serial photographs performed very well with both positive and
negative predictive values well above 95% [56].
1.2.3 Acrochordons and Other Skin Manifestations
Clinical Features
Various cutaneous changes occur in acromegaly, including acrochordons (skin tags)
and psoriasis [53]. Acrochordons, a sign of excessive soft tissue proliferation, may also
point to the presence of synchronous colonic polyposis [54, 57]. Three or more skin
tags in patients with a disease duration of 10 years are associated with a high pre-test
probability for concomitant colonic polyposis [58]. Other skin and soft tissue manifes-
tations include large lips or noses, oily skin, and hyperhidrosis (see Table 1.2) [59].
Table 1.2 Mechanisms underlying other manifestations of acromegaly

Physical
sign Mechanism
Skin Deposition of glycosaminoglycans in the skin [58]
thickening
Sweaty or IGF-1-mediated hypertrophy of sebaceous and sweat glands [58]
oily skin
Hirsutism GH causes reduced production of sex hormone-binding globulin (SHBG), most
likely because of GH-induced hyperinsulinemia. This leads to excess circulating
free androgens due to the reduced fraction of SHBG (see Sect. 1.1.5) [68]
Excess circulating IGF-1 causes insulin resistance and consequent
hyperinsulinemia. Hyperinsulinemia potentiates the production of androgens
from the ovaries [68]
Goiter GH and IGF-1 have growth stimulatory effects on thyroid follicular cells [69]
Adapted from references [58, 68, 69]
Pathophysiology
1. The action of IGF-1 on skin cells causes an accumulation of dermal glycosami-
noglycans, which accounts for the characteristic soft tissue changes noted on the
face, hands, and feet [53].
2. The mechanism underlying skin tag formation is unclear. It may be due to IGF-1
acting on its receptors present on skin cells, which ultimately leads to a prolifera-
tion of dermal fibroblasts. An alternative explanation is growth hormone excess,
contributing to an insulin-resistant state, which promotes hyperinsulinemia-
mediated skin tag formation (see Sect. 4.1.3) [59, 60].
1.2.4 Colonic Polyps
Clinical Features
There is a reported excess risk of premalignant colonic adenomas in patients with
acromegaly compared to the general population [61].
Pathophysiology
IGF-1, through its potentiation effects on colonic epithelial cell proliferation,
increases the risk of colonic polyp formation [61].
Clinical Pearl
The Endocrine Society recommends a baseline colonoscopy screen at the
time of diagnosis and every 5 years if there is persistently elevated IGF-1 or
the presence of a colonic polyp at the initial screening colonoscopy. In the
absence of colonic polyps or persistent elevation of IGF-1, the recommenda-
tion is to screen every 10 years [62].
1.2 Acromegaly 11
1.2.5 Tinel’s Sign (Carpal Tunnel Syndrome)
Clinical Features
Nerve entrapment syndromes like carpal tunnel syndrome (CTS) and ulnar nerve
neuropathy occur in acromegalics. CTS has a prevalence of 20 to 64% in patients
with acromegaly [63]. Positive Tinel’s sign is the presence of reproducible median
nerve compressive symptoms (tingling sensation involving the first three and a half
digits) upon tapping the location of the median nerve, just proximal to the wrist
joint. Tinel’s sign has positive and negative predictive values of 88% and 76%,
respectively [64].
Pathophysiology
This compressive neuropathy based on clinical studies involving an imaging modal-
ity has been attributed to edema of the perineural sheath and not mere soft tissue
proliferation in the wrist joint [63]. In a paper published in the Annals of Internal
Medicine, researchers investigated the reason for CTS seen in acromegaly [65].
Magnetic resonance images (MRIs) of the wrists, at baseline, were compared to
repeat images at 6 months post-treatment. The dimensions of soft tissue in the wrist
were no different between acromegalics with and without CTS. There was, how-
ever, an improvement in perineural edema, making it the underlying cause of the
neuropathic complaints, and not soft tissue swelling [65].
1.2.6 Hypertension
Clinical Features
Hypertension increases the risk of cardiovascular mortality in patients with acro-
megaly [66], with an estimated prevalence of 33–46% [62].
Pathophysiology
1. Increased plasma volume because of the activation of the renin-angiotensin-
aldosterone axis by excess growth hormone [66].
2. Excess IGF-1 also promotes the growth of cardiomyocytes (cardiac remodel-
ing) [66].
3. Insulin resistance in the setting of acromegaly contributes to vascular smooth
muscle proliferation and vasculopathy [66].
4. Increased cardiac inotropy occurs because of IGF-1-mediated potentiation of
calcium effects in the contractile units of the heart [66].
5. Obstructive sleep apnea due to soft tissue proliferation in the head and neck
region contributes to hypertension [67].
Clinical Pearl
Acromegaly is associated with other physical manifestations, including
hyperhidrosis, hirsutism, goiter, and skin thickening.

Approximately 30% of patients with acromegaly have hyperprolactinemia.
What are the reasons for this [70]?
1. Co-secretion of growth hormone and prolactin by the tumor may occur in

patients with acromegaly due to the common embryologic origin of mam-
mosomatotroph cells.
2. Compression of the pituitary stalk by a macroadenoma impairs dopamine-
mediated tonic inhibition of prolactin secretion (stalk effect) [70].
What are the familial syndromes associated with growth hormone hyperse-
cretion [58]?
Carney complex, multiple endocrine neoplasia (MEN) type 1, McCune-
Albright syndrome, and familial isolated acromegaly [58]
1.3 Prolactinoma
1.3.1 Hypogonadism
Clinical Features
Prolactinomas usually present with hypogonadal symptoms in men. These include
erectile dysfunction, infertility, and decreased libido [71]. Premenopausal women
may have either oligomenorrhea or amenorrhea [72].
Pathophysiology
1. Hyperprolactinemia reduces the pulse frequency and amplitude of luteinizing
hormone (LH) and follicle-stimulating hormone (FSH) through its inhibitory
action on gonadotrophin-releasing hormone (GnRH) neurons in the hypothala-
mus [73].
2. Prolactin directly inhibits the synthesis of gonadal steroids leading to hypogo-
nadism [74]. Interestingly, prolactin stimulates adrenal androgen synthesis by
potentiating the effect of ACTH on the zona reticularis, although this contribu-
tory effect of prolactin on steroidogenesis is not very significant [75].
1.3.2 Gynecomastia and Galactorrhea
Clinical Features
Galactorrhea is defined as the secretion of a milky fluid from the breast either spon-
taneously or with manual expression, in the absence of gestation [76]. Galactorrhea
occurs in both men and women, although it tends to be more prevalent in the latter.
Gynecomastia is the benign growth of male breast glandular tissue [31].
1.3 Prolactinoma 13
Pathophysiology
Prolactin binds to its receptors on mammary epithelial cells, which happen to be
embryologic derivatives of keratinocytes. This stimulates glandular tissue prolifera-
tion resulting in gynecomastia (men) and galactorrhea (both men and women)
[77, 78].
Galactorrhea is less common in men compared to women because of the lack of
estrogen and progesterone primed glandular breast tissue in the former compared to
the latter [77].
1.3.3 Bitemporal Hemianopsia
Clinical Features
Bitemporal hemianopsia presents as a loss of peripheral vision. The presence of this
peripheral scotoma may impact a patient’s functional status negatively, including
the ability to drive a motor vehicle [79]. It is best measured by conventional perim-
etry [79], although a simple bedside visual field confrontation test can be helpful in
the initial assessment [80].
The classic presentation of bitemporal hemianopsia is rare in patients with visual
field defects due to a pituitary macroadenoma [81–83]. In a recent retrospective
study comparing pituitary MRI findings with formal visual field records, the authors
reported other visual field defects as being more likely even in the presence of sig-
nificant optic chiasmal compression, defined as a chiasmal displacement greater
than 3 mm. Interestingly, a single patient out of a cohort of 115 had the classic
presentation of bitemporal hemianopsia, despite the evidence of chiasmal compres-
sion. These findings are indeed inconsistent with the long-held view of bitemporal
hemianopsia being the likely visual field defect in the setting of chiasmal compres-
sion [84].
Pathophysiology
The classic presentation of bitemporal hemianopsia occurs because of the unique
anatomic position of the optic chiasm with relation to the pituitary gland and the
intricate neuronal innervation of both the temporal and nasal visual fields by the
optic nerve [83].

What are the mechanisms underlying the increased risk of fragility fractures
in patients with prolactinomas?
Hypogonadism is the cardinal reason for low bone mineral density in
patients with prolactinomas. Also, prolactin impairs the proliferation of osteo-
blasts and may, in some instances, contribute to apoptosis of these cells [85].
How does hyperprolactinemia cause hirsutism?
• Prolactin receptors are present on dermal papilla cells and keratinocytes.

Prolactin-to-prolactin receptor binding induces active hair growth through
stimulation of dermal papilla cells, a process that results in the prolifera-
tion of keratinocytes [78].
• Prolactin directly induces adrenal androgen synthesis [75].
1.4 Adult Growth Hormone Deficiency
1.4.1 Abnormal Body Composition
Clinical Features
Adult growth hormone deficiency (AGHD) is characterized by increased visceral
adiposity (abdominal obesity) and a low lean body mass [86, 87].
Pathophysiology
1. Growth hormone (GH) plays an essential role in lipolysis by modulating the
activity of both lipoprotein and hormone-sensitive lipases. GH inhibits the activ-
ity of lipoprotein lipase (LPL) in adipose tissue (GH deficiency promotes fat
storage). Also, the inhibitory role of insulin on hormone-sensitive lipase (HSL)
activity is further enhanced by GH action (GH deficiency inhibits fat mobiliza-
tion) [88, 89] (see Fig. 1.4). The exact mechanism underlying the excessive stor-
age of fat in adipose tissue as occurs in AGHD, however, remains unclear. What
is known is that patients with AGHD have a higher fat cell volume, but a rela-
tively lower fat cell number, when compared to matched controls without growth
hormone deficiency. In summary, growth hormone deficiency causes a net effect
of increased lipid storage in adipose tissue [90].
2. GH increases protein synthesis; it, however, remains unclear if GH stimulates
protein synthesis in all tissues. Impaired GH-mediated protein synthesis explains,
in part, the loss of lean body mass in patients with AGHD [91].
Clinical Pearl
Management of Hypertriglyceridemia-Induced Pancreatitis
A continuous intravenous insulin infusion is used in treating significant
hypertriglyceridemia-induced acute pancreatitis. Insulin augments the action
of LPL, which facilitates the transfer of TAG-rich lipoproteins such as chylo-
microns and VLDL from the circulation into fat stores in adipose tissue (see
Fig. 1.4) [92].
1.4 Adult Growth Hormone Deficiency 15
Does adult growth hormone deficiency lead to low bone mineral density [93]?
AGHD does not cause low bone mineral density. There is a paucity of ran-
domized controlled trials (RCTs) investigating the effects of growth hormone
replacement therapy on fragility fracture risk in AGHD [93].
Do quality of life (QoL) scores improve after growth hormone replacement
therapy in patients with AGHD?
There is a variable response in QoL scores across a heterogeneous patient
population with AGHD. Patients either develop worse scores, remain the
same, or improve [93].
Triglyceride-rich White adipose tissue

lipoproteins
(Chylomicrons, VLDL)
TAG
LPL
+ INS Esterification
FFAs TAG
+ INS
+ INS Lipogenesis
- INS HSL
CH2OH
FFAs FFAs
GLUT4 +
Glucose Glucose Glycerol Glycerol
+ INS
Prandial period (storage of fat) Fasting period (mobilization of fat)
+ INS = Facilitated by insulin - INS = Inhibited by insulin
Fig. 1.4 Schematic diagram of the role of LPL and HSL in fat storage and mobilization. LPL is
synthesized in adipocyte tissue and is then transported to its site of action, which is the luminal
surface of the capillary endothelium. LPL is involved in the uptake of fatty acids into adipose
tissue by mediating the hydrolysis of triacylglycerol (TAG) laden lipoproteins into free fatty
acids (FFAs) (thin arrow). Glucose transporter 4 (GLUT4) mobilizes glucose from the periph-
eral circulation for lipogenesis in adipose tissue. This occurs in the fed state and is facilitated by
insulin (dotted arrows). The esterification of FFAs into TAG is potentiated by insulin (wavy
arrow). Hormone-sensitive lipase (HSL) mediates the conversion of TAG into glycerol and FFAs
(thick arrow) for subsequent release into the bloodstream (dashed arrows). This process of fat
mobilization occurs in the fasting state and is inhibited by insulin [89]. (Redrawn and modified
from Frayn et al. [89])
1.5 Growth Hormone Insensitivity (Laron-Type Dwarfism)
1.5.1 Short Stature
Clinical Features
Laron-type dwarfism is the most severe form of growth hormone insensitivity and
was first described in 1966. Children born with Laron dwarfism have a growth
velocity of less than 50% of their predicted rate [94]. Patients are of short stature
with a final height being −4 to −8 standard deviations below the normal for their
age and gender [95].
Pathophysiology
Mutation of the growth hormone receptor (GHR) gene results in resistance to the
systemic effects of growth hormone. Patients with GH insensitivity have high circu-
lating levels of GH with very low IGF-1 levels [94, 96].
1. The role of growth hormone in stimulating chondrocytes in the proliferative zone

of the growth plate is impaired in growth hormone insensitivity [97, 98].
2. Local IGF-1 production in the growth plate is impaired because of an absence of
the stimulating effects of growth hormone in the setting of a mutation of the
GHR [97]. Disruption of the stimulatory paracrine effects of IGF-1 on growth
plate chondrocytes results in impaired linear growth [98, 99].
Growth Plate Physiology and the Hormonal Milieu
Growth hormone (GH) secretion from the anterior pituitary somatotrophs
is under trophic stimulation by hypothalamic-derived growth hormone-releas-
ing hormone (GHRH). GH binds to receptors in the liver, leading to hepatic
production of IGF-1, which mediates the peripheral effects of GH. GH acts
locally in the growth plate of the bone to stimulate local IGF-1 production,
which, through its paracrine effects, plays a vital role in linear growth [97, 99]
(Fig. 1.5).
1.5.2 Obesity
Clinical Features
Obesity in subjects with Laron dwarfism worsens progressively with age [96].
Patients have a higher proportion of body fat compared to age- and gender-matched
healthy controls [103]. Dr. Zvi Laron and colleagues reported severe obesity as a
cardinal clinical sign in both children and adults with Laron dwarfism [104].
1.5 Growth Hormone Insensitivity (Laron-Type Dwarfism) 17
Metaphyseal end of the bone
Resting zone
Proliferative
(IGF-1 action potentiated
by T3)
Physis (Growth Plate)
Hypertrophic zone
Epiphyseal end of the bone
Fig. 1.5 Physiologic zones of the growth plate. The growth plate is composed of three zones, the
resting, proliferative, and hypertrophic zones. Bone formation is a gradual process of differentia-
tion and maturation of chondrocytes in the growth plate, with a progressive transition from the
epiphyseal (articular end of the bone) to the metaphyseal end (main shaft of the bone) [100].
Progenitor cells in the resting zone are destined to become more matured chondrocytes in the
proliferative zone under the influence of hormonal signals, including thyroid hormone, androgens,
estrogens, GH, and IGF-1 [101].Chondrocytes in the hypertrophic zone are terminally differenti-
ated and, in due time, undergo apoptosis. Eventually, chondrocytes are no longer able to lay down
the matrix needed for new bone formation, leading to complete fusion of the epiphyses [102]. The
role of thyroid hormone and estrogens has been described elsewhere (see Sects. 2.4.2 and 6.5.1,
respectively). (Redrawn and modified from Long et al [100])
Pathophysiology
1. The reasons for the increased incidence of obesity in subjects with Laron dwarf-
ism remains unclear [104]. However, since GH increases lean body mass and the
muscle/fat ratio, it is plausible that a lack of GH effect would cause the opposite
effect, i.e., a low muscle to fat ratio [105].
2. A study by Dr. Laron and his group discounted the reasons for obesity as being
due to either hyperphagia or reduced metabolism. They also measured the rest-
ing energy expenditure in patients with growth hormone insensitivity and found
it be unexpectedly higher than was predicted based on the lean body mass of
subjects [103].
1.5.3 Small Genitalia
Clinical Features
There is a delayed but eventual achievement of full sexual maturity. The male testis
reaches a final adult size of 5-9 ml, which is lower than that of healthy subjects
[104]; nonetheless, both sexes can still achieve fertility in adulthood [104, 106].
Pathophysiology
Testicular growth and development are influenced by endocrine and paracrine
effects of IGF-1, although the exact mechanisms are yet to be elucidated. There are
indeed IGF-1 receptors present on Sertoli cells of the testis [107]. The importance
of trophic stimulation of the Sertoli cells in determining the final testicular volume
has been described in Sect. 6.3.1.

What is the reason for a low risk of cancers seen in patients with congenital
growth hormone receptor deficiency (GHRD)?
In a prospective cohort study of 99 subjects with growth hormone receptor
deficiency (Laron dwarfism) followed up for more than two decades, cancer-
related deaths did not occur. The authors tested in vitro human mammary
epithelial cells and were able to demonstrate that reduced IGF-1 signaling
resulted in programmed cell death of epithelial cells whose DNA had been
damaged by pretreatment with hydrogen peroxide. IGF-1 signaling prevents
apoptosis of damaged DNA and therefore increases the risk of carcinogenesis
[108]. Interestingly, clinical trials investigating the use of monoclonal anti-
bodies directed against the IGF-1 signaling pathway have not been consis-
tently successful in cancer therapy [109].
What is the reason for the low risk of diabetes mellitus seen in patients with
congenital GHRD?
In another prospective cohort of patients with congenital growth receptor
deficiency followed up for more than two decades, despite having dispropor-
tionately high body fat, subjects demonstrated increased insulin sensitivity.
None of the subjects had diabetes mellitus. Interestingly, other measures of
insulin resistance, such as the homeostatic model assessment of insulin resis-
tance (HOMA-IR), triglycerides, and glucose levels, were all lower than age-
and sex-matched controls. GHRD impairs the counterregulatory effects of
GH on glucose metabolism; this may explain the absence of diabetes in these
patients [110]. Might an anti-IGF-1 monoclonal antibody be a potential future
diabetes therapy?
1.6 Central Diabetes Insipidus
1.6.1 Dehydration due to Polyuria and Polydipsia
Clinical Features
Patients with central diabetes insipidus present with hypotonic polyuria and poly-
dipsia. Excessive free water loss leads to clinical signs suggestive of dehydra-
tion [111].
1.6 Central Diabetes Insipidus 19
Pathophysiology
1. Downregulation of vasopressin V2 receptors in the principal cell of the collect-
ing tubule occurs due to the absence of trophic stimulation by arginine vasopres-
sin (AVP), in the setting of complete central diabetes insipidus. Also, a loss of
AVP stimulation causes internalization of aquaporin-2 (AQP2) water channels
into cytosolic vesicles, which ultimately leads to free water loss (see Fig. 1.6)
[112, 113].
2. Additionally, AVP in high concentrations, as might occur during periods of
shock, binds to V1 receptors in vascular smooth muscle. V1 receptor activation
causes smooth muscle contraction and maintenance of blood pressure [115].
Tubular fluid Interstitial fluid Peritubular capillary
Principal cell of the collecting duct

AVP
V2 receptor coupled
to G protein 1
5 3 2
4
Adenylate cyclase
PKA mediated cAMP production
AQP2
AQP3
6
AQP4
H2O H2O
AM BM
Fig. 1.6 The role AVP in renal water conservation at the renal collecting duct cell. AVP binds to
the G-protein-coupled V2 receptor on the basolateral membrane of the principal cell (step 1). This
is followed by the activation of cytosolic adenylate cyclase, which subsequently increases cyclic
AMP (cAMP) production (step 2). Increased intracellular cAMP activates Protein Kinase A (PKA)
(step 3), which then facilitates the phosphorylation of AQP2 in its endocytic vesicles (step 4).
AQP2 liberated from endocytic vesicles are translocated to the apical membrane (AM) of the prin-
cipal cell (step 5). AQP3 and AQP4 are constitutively expressed (not released from endocytic
vesicles) on the basolateral membrane, independent of PKA action. AQP2 moves free water from
the collecting tubule into the cytosol of the ductal cell, while AQP3 and AQP4 water channels
mediate the movement of free water across the basolateral membrane into the peritubular capillar-
ies (step 6) [114]. (Redrawn and modified from Moritz et al [114])
Clinical Pearl
The Triphasic Response of Central Diabetes Insipidus
Complete transection of the pituitary stalk, as might occur in traumatic
brain injury or transsphenoidal surgery, results in the classic “triphasic
response” of central diabetes insipidus.
• There is an initial phase of transient central diabetes insipidus, which

occurs due to axonal shock.
• The first phase is followed within 24 to 48 hours by a second phase of
syndrome of inappropriate antidiuretic hormone (SIADH), due to axonal
injury and rapid release of preformed AVP into circulation.
• The third phase of recurrence of central diabetes insipidus occurs after the
complete depletion of neuronal reserves of AVP.
The challenge in managing this condition is realizing the clinical timeline

of the triphasic response and altering fluid management promptly to prevent
acute sodium imbalance [116].

With regard to desmopressin supplementation in the management of central
diabetes insipidus, what precautions should be taken in patients on concomi-
tant nonsteroidal anti-inflammatory drugs (NSAIDs)?
Patients should be informed of suitable alternatives to NSAIDs when on
long-term stable doses of desmopressin therapy. Clinicians taking care of
patients should also be aware of the risk of water intoxication and severe
hyponatremia when patients on desmopressin receive NSAIDs [117].
How do prostaglandins impact water conservation in the kidney?
Prostaglandin E2 (PGE2) plays a critical role in inhibiting the effects of
AVP in the collecting ducts. NSAIDs inhibit prostaglandin synthesis, which
results in an exaggeration of AVP effects in the renal collecting system, a
process that promotes water intoxication and hyponatremia [118].
It is worthy to note that up to 85% of glomerular filtrate reabsorption is
AVP-independent and occurs in the proximal tubules and descending limbs of
the loop of Henle. AVP-dependent mechanisms, although accounting for only
15% of water reabsorption at the level of the collecting ducts, contribute sig-
nificantly to sodium balance [112, 119].
References 21
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Thyroid Gland Signs
2
Learning Objectives
1. Understand the metabolic effects of active thyroid hormone in various tis-

sues in the human body
2. Understand the pathophysiologic basis for the classic clinical signs of
Graves’ disease
3. Recognize how the anatomical relations of the thyroid gland explains com-
pressive clinical signs in the setting of goiters
4. Understand the pathophysiologic basis of thyroid hormone resistance.
2.1 Hashimoto’s Thyroiditis
2.1.1 Queen Anne’s Sign
Clinical Features
This eponymous medical sign is named after Anne of Denmark, due to her truncated
lateral eyebrows, which was depicted in a portrait by Paul Van Somer [1]. Facial and
body hair tends to be dry, thin, and brittle in hypothyroidism. Loss of hair over the
lateral third of the eyebrow is a recognized sign of hypothyroidism [2].
Pathophysiology
1. Triiodothyronine (T3) and tetraiodothyronine (T4) have direct effects on the
human scalp. T3 and T4 both play essential roles in hair follicle growth, apopto-
sis, and keratin expression. T4 prolongs the growth phase of the hair follicle
(anagen). This, in part, explains the reason for telogen effluvium in hypothyroid
patients [3].

https://doi.org/10.1007/978-3-030-49872-6_2
28 2 Thyroid Gland Signs
2. Lack of expression of keratin due to low T4 levels accounts for the thin and
brittle hair follicles in hypothyroid patients [3].
Conditions which May Present with Queen Anne’s Sign

Queen Anne’s sign is also known as Hertoghe’s sign. It may be seen in a
myriad of other medical conditions, including syphilis [4], leprosy, atopic
dermatitis, seborrheic dermatitis, psoriasis, and biotin deficiency, to name a
few [5].
2.1.2 Bradycardia
Clinical Features
Hypothyroidism is a known cause of bradycardia and significant bradyarrhythmias
such as high-grade atrioventricular (AV) block. A recent retrospective study involv-
ing 668 subjects reported the need for permanent pacemaker insertions in some
patients who presented with high-grade AV block, even after resolution of hypothy-
roidism [6].
Pathophysiology
T3 increases atrial myocyte pacemaker current frequency by improving the function
of the sodium-calcium exchanger. This has been demonstrated in animal models.
The mechanism underlying the cause of bradycardia has, however, not been eluci-
dated in humans [7, 8].
2.1.3 Pericardial and Pleural Effusions
Clinical Features
The incidence of pericardial effusions ranges between 3 and 6%, in mainly advanced
stages of hypothyroidism. Pericardial effusions in mild hypothyroidism are, how-
ever, rare [9, 10]. Pleural effusion can be diagnosed by eliciting a “stony dull” per-
cussion note and reduced tactile vocal fremitus over the lung zones [11]. Distant
heart sounds, hypotension [12], pulsus paradoxus, and jugular venous distension
may be observed in significant pericardial effusions [13].
Pathophysiology
There is a substantial increase in the extravascular content of albumin due to the
transcapillary escape of albumin [14, 15]. Compensatory fractional return of extrava-
sated fluid via the lymphatic system, in response to “albumin leak,” is impaired in
hypothyroidism due to the accumulation of mucopolysaccharide protein complexes
in the interstitial space. The response to this based on Starling’s forces is the retention
of extravascular fluid, which can manifest as pleural and pericardial effusions [14].
2.1 Hashimoto’s Thyroiditis 29
2.1.4 Dry Skin
Clinical Features
Dry skin (xerosis) is a cardinal skin manifestation of hypothyroidism [16]. Xerosis
is the most frequent cutaneous manifestation of hypothyroidism, with a prevalence
greater than 65% [17]. In a small study designed to assess the predictive value of the
physical examination in suggesting a diagnosis of hypothyroidism, rough, dry skin
had a reported positive likelihood ratio (+LR) of +2.3 in diagnosing hypothyroid-
ism [18].
Pathophysiology
There are thyroid hormone receptors present in the skin and its appendages; as such,
perturbations in thyroid hormone levels result in various skin manifestations
[16, 19].
1. Diminished sebaceous gland units reduce the extent of dermal secretions [19].
Sweat glands in significant hypothyroidism are atrophic due to a yet to be eluci-
dated mechanism [16].
2. Reduced epidermal sterol synthesis produces dryness of the hypothyroid

skin [19].
Other cutaneous changes seen in clinically significant hypothyroidism include

lymphedema and myxedema (Table 2.1).
2.1.5 Macroglossia
Clinical Features
Macroglossia is a rare sign of hypothyroidism [21] and is described as protrusion of
the tongue beyond the teeth during a state of normal relaxation of the tongue mus-
culature [22].
Pathophysiology
Dysregulation in the formation of hydrophilic glycosaminoglycans leads to their
accumulation in the interstitium [23]. As was previously described for hypothyroid-
ism induced-pericardial effusions, there is an accumulation of extravascular fluid in
various tissues, including those of the tongue [14, 23] (see Sect. 2.1.3).
Table 2.1 Other skin manifestations of hypothyroidism

Lesion Pathophysiology
Lymphedema (hands, face, Accumulation of hydrophilic mucopolysaccharides in the
and eyelids) interstitial space impairs lymphatic drainage [20]
Myxedema Deposition of mucopolysaccharides in the skin [20]
Adapted from Ai et al. [20]
2.1.6 Hyporeflexia
Clinical Features
Hyporeflexia in hypothyroidism classically presents as a delayed relaxation phase
of deep tendon reflexes (DTRs) [24]. This has been eponymously labeled as the
“Woltman’s sign of myxedema” [25]. It is best elicited at the ankle joint with the
patient in a seated position and the lower extremities in a dependent position. This
allows an accurate assessment of the relaxation phase of the reflex since relaxation
will be occurring against gravity [26].
Pathophysiology
Decreased myosin calcium-ATPase activity, with a concomitantly reduced rate of
sequestration of calcium in the sarcoplasmic reticulum of the skeletal muscle,
accounts for Woltman’s sign [27]. T3 plays a critical role in muscle metabolism
through its effects on the sarcoplasmic reticulum Calcium-ATPase function.
Prolonged skeletal muscle contraction occurs due to impaired sequestration of cal-
cium by the sarcoplasmic reticulum in the setting of low T3. This increases the
duration of the relaxation phase of DTRs [28].
2.1.7 Proximal Myopathy
Clinical Features
Myopathy presents with proximal muscle weakness involving the pelvic or shoulder
girdle musculature [29]. Clinically identifiable neuromuscular dysfunction had a
prevalence of approximately 40% in a prospective cohort study assessing neuro-
muscular dysfunction in patients with hypothyroidism [30].
Hoffman syndrome, a form of hypothyroid-related muscular dysfunction, is
described as a triad of muscle weakness, hyporeflexia, and muscular hypertro-
phy [31].
Pathophysiology
Low levels of T4 impair glycogen breakdown in skeletal muscle and contributes to
selective atrophy of fast-twitch type 2 skeletal muscle fibers [29]. This leads to a
state of a predominance of slow-twitch type 1 skeletal muscle fibers, which results
in the weakness observed in subjects with hypothyroidism [32, 33].
2.1.8 Galactorrhea
Clinical Features
Patients may present with galactorrhea, although spontaneous or expressible galac-
torrhea is a rare finding in primary hypothyroidism [34].
2.1 Hashimoto’s Thyroiditis 31
Pathophysiology
• Low circulating levels of free T3, as occurs in primary hypothyroidism, results in
a loss of feedback inhibition of T3 on TRH producing cells of the hypothalamus.
This is followed by the release of TRH, which has a stimulatory effect on pitu-
itary lactotrophs, resulting in increased production of prolactin from the anterior
pituitary. Prolactin stimulates glandular breast tissue proliferation, leading to
galactorrhea.
• Additionally, there is also a loss of negative feedback inhibition of lactotrophs by
T3. This compounds the state of excess prolactin secretion.
• Reduced metabolic clearance of prolactin (PRL) due to hypothyroidism contrib-
utes to high circulating levels of prolactin.
• Finally, TRH stimulation of both thyrotropes and lactotrophs promotes pituitary
hyperplasia. Enlargement of the pituitary gland causes a “stalk effect,” which
blocks the dopaminergic tracts involved in reducing lactotroph production of
PRL [35] (see Fig. 2.1).
2 Loss of T3 inhibition of
TRH stimulates pituitary TSH 1
and prolactin secretion TRH and TSH secretion
–
Low T3
(loss of negative feedback inhibition)
High Prolactin +
Thyroid gland
Galactorrhea 3
Fig. 2.1 Schematic diagram depicting the pathophysiologic basis of hyperprolactinemia in pri-
mary hypothyroidism. Low circulating levels of active thyroid hormone (T3) results in a loss of
negative feedback inhibition of both hypothalamic and pituitary thyrotropin-releasing hormone
(TRH) and thyroid-stimulating hormone (TSH) release, respectively (step 1). Increased TRH
secretion, in turn, stimulates both pituitary lactotrophs and thyrotrophs (step 2). Also, inadequate
clearance of prolactin due to hypothyroidism-induced hypometabolism contributes to hyperprolac-
tinemia and galactorrhea (step 3) [35]. (Based on Ansari et al. [35])
Clinical Pearl
Pituitary Pseudotumor
Thyrotrope hyperplasia (pituitary pseudotumor) can occur in patients with
a long-standing history of primary hypothyroidism. It is a condition that is
entirely reversible with timely initiation of thyroid hormone replacement [36].
The diagnosis of primary hypothyroidism should be considered in patients
with diffuse enlargement of the pituitary gland, without an obvious adenoma,
in the setting of hyperprolactinemia [37].
Questions You Might Be Asked on Rounds

What is the reason for yellowing of the skin in some hypothyroid patients?
Yellowing of the skin is due to hypercarotenemia, and it tends to involve
the palms, soles of the feet, and nasolabial folds. A reduction in hepatic
metabolism of β-carotene accounts for its excess circulating levels. β-Carotene
is subsequently deposited in the skin, and this results in the characteristic yel-
lowish hue of the skin [20].
Why would a patient with Hashimoto’s thyroiditis develop eye and skin
changes somewhat like Graves’ disease?
Cross-reactivity between circulating anti-thyroid peroxidase antibodies
and fibroblasts present in the orbit and skin [20].
Besides, some patients with Hashimoto’s thyroiditis have increased
thyroid-stimulating immunoglobulins (TSI) as well, which may contribute to
eye and dermal manifestations similar to Graves’ disease. Autoimmune thy-
roid disease is a balance between thyroid hormone-blocking and stimulating
antibodies. The antibody which predominates determines the disorder, i.e.,
Hashimoto’s thyroiditis or Graves’ disease. At any point in the disorder, the
balance may change [38].
2.2 Graves’ Disease
2.2.1 Thyroid Eye Disease
Clinical Features
Thyroid eye disease (TED) is the most common extra-thyroidal manifestation of
Graves’ disease [39]. TED can present with a myriad of ocular signs, including
photophobia, proptosis, or conjunctival injection [40]. Other signs suggestive of
TED include lid lag, globe lag, lid retraction, and even, in some severe cases, evi-
dence of optic neuropathy [41].
2.2 Graves’ Disease 33
Table 2.2 Selected eponymous thyroid eye signs in Graves’ disease

Eye sign Clinical findings
Dalrymple’s sign Lid retraction involving the upper eyelid [45]
Von Grafe’s sign Lagging of the upper eyelid upon downward gaze [45]
Collier’s sign Lid retraction involving the lower eyelid [45]
Stellwag’s sign Infrequent blinking of the eyelids [45, 46]
Rosenbach’s sign Tremors of the eyelids upon closure [46]
Gifford sign A difficulty with eversion of the upper eyelids [46]
Jellinek sign Hyperpigmentation of the upper eyelids [46]
Sainton sign Nystagmus on the voluntary horizontal movement of the
eyes [46]
Ballet sign Paresis of extraocular muscles [46]
Enroth sign Periorbital edema [46]
Griffith’s sign Lid lag involving the lower eyelid on upward gaze [46]
Adapted from references Mallika [45] and Urrets-Zavalia [46]
Pathophysiology
• Orbital fibroblasts have TSH and IGF-1 receptors, which are directly stimu-
lated by thyroid-stimulating immunoglobulins (TSIs). There is an enhanced
proliferation of orbital fibroblasts as a consequence, which eventually causes
extensive fibrosis in the orbit [42]. Teprotumumab, a monoclonal antibody that
targets the IGF-1 receptor, was recently approved for the management of
TED. Teprotumumab resulted in a significant reduction in proptosis, clinical
activity score, and diplopia when compared to placebo [43].
• TSI also mediates the differentiation of orbital fibroblasts into adipocytes and
myofibroblasts. A state of hyperproliferation of adipocytes and myofibroblasts
increases periorbital soft tissue volume [44].
• Also, orbital fibroblasts exhibit an exaggerated inflammatory response in the set-
ting of TSI-TSH receptor interaction. There is an accumulation of extracellular
matrix in the setting of this pro-inflammatory milieu, which leads to soft tissue
edema and proptosis [40, 41].
There are a host of thyroid eye signs named after the clinicians who first described
them. A few have been outlined in Table 2.2.
Why do patients with Graves’ disease have upper eyelid retraction?
• Muller’s muscle (superior tarsal muscle) under the sympathetic stimula-

tion of excess circulating thyroid hormones contracts and contributes to lid
retraction [47].
• Due to extensive orbital inflammation, the levator palpebrae superioris is
infiltrated by inflammatory cells, which leads to fibrosis and contraction of
the muscle [47].
• Although lid retraction occurs in Graves’ disease, it is not pathognomonic
for this condition and can occur in other forms of hyperthyroidism [48].
2.2.2 Pretibial Myxedema
Clinical Features
Pretibial myxedema (PM) is a cutaneous manifestation of Graves’ disease and
can appear as non-pitting edema, plaque-like, or nodular lesions. In severe cases,
it may appear like the lymphedema associated with elephantiasis. The nodular
variant occurs in fewer than 10% of subjects and has been reported to mimic the
characteristic lesions of erythema nodosum [49]. PM can recur several years
after definitive treatment of Graves’ disease, i.e., surgery or radioactive iodine
ablation [50].
Pathophysiology
The exact mechanism has not been elucidated at this time, although the lesions are
noted to be present at sites of repetitive trauma. The influx of inflammatory cells and
fibroblast proliferation have been proposed as possible reasons for pretibial myx-
edema. Histologically, there is an accumulation of mucopolysaccharides in the der-
mis of the skin [49], and the process is believed to be mediated by circulating TSI
acting on TSH receptors present on fibroblasts in the skin [51, 52].
Other cutaneous manifestations of hyperthyroidism include urticaria, telangiec-
tasia, erythema, and warm skin (Table 2.3).
2.2.3 Thyroid Acropachy
Clinical Features
Thyroid acropachy (TA) is characterized by digital clubbing involving the upper
and lower extremity digits. It has a strong association with thyroid eye disease [58,
59] and may, in some instances, herald a diagnosis of Graves’ disease [60].
Pathophysiology
Accumulation of glycosaminoglycans and concomitant fibroblast proliferation have
also been proposed as the underlying mechanisms of thyroid acropachy [59].
Table 2.3 Other skin manifestations of hyperthyroidism

Lesion Pathophysiology
Warm and moist Vasodilation of cutaneous vessels [53]
skin
Palmar erythema Vasodilation of cutaneous vessels [54, 55]
Urticaria Binding of anti-TPO immunoglobulin E antibodies to receptors on the
surface of mast cells leads to their activation and degranulation [56]
Telangiectasia Increased dermal blood flow and a possible immune-mediated process have
been proposed [57]
TPO thyroid peroxidase
Clinical Pearl
What might be seen on a plain radiograph of an involved extremity, for
patients with TA?
A periosteal reaction involving bones of the hand or feet might be seen on
a plain radiograph. TA presents with a clinical triad of periosteal reaction,
swelling of the hands or feet, and clubbing of the digits [60].
2.2.4 Onycholysis
Clinical Features
Onycholysis has eponymously been referred to as “Plummer’s nails.” Dr. Henry
Plummer of Mayo Clinic described various characteristic features of dystrophic
nails in hyperthyroidism, including the unique “scoop shovel” appearance and flat-
tening of the fingernails [61]. Plummer’s nails present as a separation of the distal
aspect of the nail from its underlying nail bed. It is an inconsistent physical finding
and occurs in approximately 5% of patients with hyperthyroidism [62].
Pathophysiology
The cause of onycholysis remains unclear, although hyperthyroidism-induced
catabolism and rapid growth of the underlying nail bed are possible reasons for
separation of the nail from the nail bed [63].
2.2.5 Periodic Paralysis
Clinical Features
A form of periodic paralysis known as thyrotoxic periodic paralysis (TPP) occurs in
patients with Graves’ disease and may present with either mild muscle weakness or
overt flaccid paresis [64]. TPP presents most often in people of East Asian descent
but has been described in other ethnicities [65].
Pathophysiology
• T3 enters the mitochondria of skeletal muscle cells and increases metabolism
with subsequent generation of ATP. ATP increases the activity of sodium-
potassium ATPase present in skeletal muscle [66] and promotes an increase in
the transcellular shift of potassium, which results in hyperpolarization of the
skeletal cell membrane. Hyperpolarized skeletal muscle tissue has reduced excit-
ability, and this accounts for reduced muscular contraction and paralysis [67].
• T3 also increases gene expression and subsequent translation of the sodium-
potassium ATPase. The increased presence and subsequent enhanced activation
of the sodium-potassium ATPase in skeletal muscle contributes to TPP [67].
2.2.6 Thyroid Bruit and Thrill
Clinical Features
Bruits auscultated over the superior thyroid arteries are detectable in up to 85% of
patients with symptomatic hyperthyroidism. They are continuous (throughout the
cardiac cycle) and are accentuated in the systolic phase of the cardiac cycle [68].
The auscultatory findings of a thyroid bruit are different from those of carotid bruits
or radiating cardiac murmurs to the neck. The bruit associated with carotid artery
disease, for example, tends to occur only in the systolic phase of the cardiac
cycle [69].
It is worthy to note that the presence of a thyroid bruit on the clinical exam is
pathognomonic for an autonomously hyperfunctioning gland (Graves’ disease).
This clinical finding effectively rules out thyroiditis in patients with biochemical
hyperthyroidism [70].
Pathophysiology
Hyperthyroidism-mediated accelerated blood flow accounts for the continuous bruit
heard over the superior thyroid arteries [68].
2.2.7 Tachycardia
Clinical Features
Patients with hyperthyroidism classically have tachycardia, with more than 90%
having a resting heart rate higher than 90 beats per minute [71]. Atrial fibrillation, a
cause of tachycardia, is, however, less frequent in Graves’ disease. Indeed, elderly
patients with “apathetic hyperthyroidism” are more likely to have atrial fibrillation
than younger patients [53]. An irregularly irregular peripheral pulse is a hallmark of
atrial fibrillation on the clinical exam [72].
Pathophysiology
• Triiodothyronine (T3) increases the duration of activation of myocardial sodium
channels, which leads to increased intracellular sodium. An increased intracel-
lular sodium concentration then stimulates the sodium-calcium antiport system,
which is critical in maintaining intramyocardial calcium concentrations.
Accentuated sodium-calcium antiport activity increases intramyocardial calcium
and promotes myocardial contractility [73].
• T3 upregulates the β1 adrenergic receptor expression not only in the myocar-
dium but also in the Juxtaglomerular cells (JGCs) of the kidney. Catecholamine
activation of β1 receptors of the JGCs is responsible for the release of renin and
eventual activation of the renin-angiotensin-aldosterone system (RAAS)(see
Fig. 3.1). Sodium and fluid retention increases cardiac preload and contractility
(Frank-Starling law of the heart) [73].
• T3 binds to intracellular thyroid hormone response elements involved in the tran-

scription and translation of calcium adenosine triphosphatase (Ca-ATPase) in
the myocardial sarcoplasmic reticulum. Ca-ATPase is essential in regulating
intramuscular calcium concentration. An increase in myocardial calcium con-
centration accounts for the exaggerated inotropic effects of excess T3 [7].
• T3 increases myocardial calcium uptake through direct activation of the myocar-
dial L-type calcium channels. This contributes to the inotropic effect of thyroid
hormone excess [71].
• The upregulation of a myocardial gap junction protein critical in the transmission
of electrical impulses has been proposed as a mechanism of hyperthyroidism-
induced atrial fibrillation [74].
• The effects of T3 include a blunting of cardiac parasympathetic tone and an
increase in tissue sensitivity to the effects of normal circulating catechol-
amines [75].
2.2.8 Gynecomastia
Clinical Features
Gynecomastia is a known clinical manifestation of thyrotoxicosis but is seldom a
presenting feature of the disease. Gynecomastia is usually reversible after the con-
trol of hyperthyroidism [76]. It presents as palpable subareolar tissue and should be
differentiated from pseudogynecomastia (lipomastia), which is a generalized accu-
mulation of fat in male breasts [77, 78].
Pathophysiology
• Thyroid hormone increases the synthesis of sex hormone-binding globulin
(SHBG) by the liver. SHBG binds to testosterone and reduces the circulating
level of free testosterone (active or unbound testosterone). A significant lowering
of the androgen/estrogen ratio promotes mammary gland proliferation due to the
effects of estrogen [78].
• Increased peripheral aromatization of androgens into estrogens [78].
2.2.9 Lymphadenopathy
Clinical Features
Perithyroidal lymphadenopathy is a reported finding in benign thyroid disease. Up
to a third of patients with Graves’ disease in a recent cross-sectional study were
noted to have clinically discernible perithyroidal lymph node enlargement [79].
Pathophysiology
Reactive lymphocyte proliferation (lymphoid hyperplasia) in the setting of autoim-
mune thyroiditis [80]
2.2.10 Change in Body Composition (Weight Loss)
Clinical Features
Patients with uncontrolled thyrotoxicosis present with unintentional weight loss in
the setting of hyperphagia. Loss of body fat and muscle bulk may be discernible on
the routine clinical examination [81].
Pathophysiology
• Resting energy expenditure (REE) is a critical determinant of weight and is
dependent on brown adipose tissue (BAT) mitochondrial activity. In stark con-
trast to the role of mitochondria in other tissues, BAT mitochondria are not pri-
marily involved in ATP generation. They possess an uncoupling protein that
interrupts the electron transport chain and allows the transduction of mitochon-
drial membrane potential energy directly into heat energy [82]. T3 increases
thermogenesis in brown adipose tissue by potentiating the effects of the uncou-
pling protein involved in the BAT mitochondrial electron transport chain [81].
• Type 2 deiodinase enzyme activity (involved in the peripheral conversion of free
T4 into free T3) is also upregulated in BAT. This increases the local concentra-
tion of T3, further compounding the effects of T3 on the mitochondrial uncou-
pling protein [81].
Thyroid hormone synthesis (Fig. 2.2)

What is the mechanism underlying cutaneous hyperpigmentation seen in
Graves’ disease?
Hyperthyroxinemia leads to accelerated metabolism of cortisol. Low
serum cortisol causes a compensatory increase in adrenocorticotrophic hor-
mone (ACTH) due to the loss of negative feedback inhibition of cortisol on
ACTH production. ACTH mediates hyperpigmentation of the skin (see Sect.
3.1.2) [20]. This proposed mechanism of increased cortisol metabolism may
explain a rare report of adrenal crisis in a hyperthyroid patient with cryptic,
non-classic 21-hydroxylase deficiency [84].
Why may pretibial myxedema not improve after treatment of Graves’
disease?
Treatment of Graves’ disease with thyroidectomy or radioactive iodine
ablation does not prevent the production of thyroid-stimulating immunoglob-
ulins (TSIs). Circulating TSIs can still stimulate TSH receptors present on
dermal fibroblasts long after the cure of hyperthyroidism [85].
2.3 Euthyroid Goiter with Thoracic Outlet Syndrome 39
FC
PC
PC C
1a NIS
TPO 2
I2 I- I-
H2O2
Tyrosine
3 1b
Tg ER + Golgi
Iodination of Tg Complex
TPO
4
PROTEOLYSIS
T4 + T3
5
MIT DIT T3 T4
Fig. 2.2 Synthesis of T3 and T4 by the thyroid follicular unit. Iodide(I−) is transported from the
perifollicular capillary (PC) into the thyroid follicular cell (FC) by the basal sodium-iodide sym-
porter (NIS), under a sodium electrochemical gradient facilitated by the sodium-potassium pump
(step 1a). Thyroglobulin (Tg) is synthesized from tyrosine residues, a process that occurs in the
rough endoplasmic reticulum (step 1b). Tg undergoes further posttranslational modification in the
Golgi apparatus of the follicular cell. It is then secreted into the follicular lumen (site of colloid
storage) through a process of exocytosis. Iodide is transported to the apical membrane of the thy-
roid follicular cell, where thyroid peroxidase (TPO) enzyme catalyzes the oxidation of iodide to
iodine. This oxidation step requires hydrogen peroxide(H2O2)(step 2). Tyrosyl residues on the
thyroglobulin molecule undergo iodination by the previously oxidized iodine molecule. This pro-
cess of “organification” is facilitated by TPO and results in the formation of monoiodothyronine
(MIT) and diiodiothyronine (DIT) residues (step 3). Triiodothyronine (T3) and tetraiodothyronine
(T4) are then formed in a final coupling reaction which involves the formation of ester linkages
between “donor” and “acceptor” iodothyronine (MIT or DIT) residues (step 4). The thyroid fol-
licular cell ingests colloid (C) by pinocytosis through the apical membrane. Proteolysis of the
colloidal substrate in the thyroid follicular cell yields thyroglobulin, MIT, DIT, T3, and T4 (step 5).
Deiodinases present in the follicular cell convert some T4 into active thyroid hormone (T3).
Thyroid hormones (T3 and T4) are then actively transported across the basolateral plasma mem-
brane of the thyroid epithelial cell into capillary [83]. (Based on Carvalho et al. [83])
2.3 Euthyroid Goiter with Thoracic Outlet Syndrome
2.3.1 Pemberton’s Sign
Clinical Features
This sign is eponymously named after Dr. Hugh Pemberton, who described this
classic physical finding in a letter published in Lancet in 1946 titled “sign of a sub-
merged goitre.” He explained the method of eliciting the sign, expected clinical
findings, and also proposed a mechanism for the physical finding [86].
The sign is elicited by instructing the patient to lift their arms such that the arms
touch both sides of the head. The patient is then instructed to hold their arms in that
position until facial congestion or erythema is noticed [86].
Pathophysiology
In a recent case report, magnetic resonance imaging (MRI) of the neck was used to
elucidate the mechanism underlying Pemberton’s sign. In this report of a patient
with a retrosternal goiter, there was no demonstrable craniocaudal change in the
position of the thyroid gland during the maneuver to elicit the sign. The widely
accepted “cork effect” initially proposed by Pemberton was not consistent with the
MRI findings noted in the study. The authors objectively confirmed compression of
the external jugular and subclavian veins by the clavicles during the clinical maneu-
ver. The thoracic inlet, however, remained relatively fixed in size, thus discounting
the “cork effect” as a plausible explanation of Pemberton’s sign [87].
2.3.2 O
ther Compressive Signs (Superior Vena Cava Syndrome,
Phrenic Nerve Paralysis)
Clinical Features
Superior vena cava (SVC) syndrome can occur in patients with large goiters. There
are multiple case reports of mediastinal goiters leading to SVC syndrome. A goiter
may sometimes not be palpable on the physical exam due to its ectopic position in
the mediastinum [88–90].
Clinically significant dyspnea due to either unilateral or bilateral phrenic nerve
compression by large retrosternal goiters has been reported [91, 92]. In a recent
large series of 50 retrosternal goiters, nerve compression syndromes were second
only to tracheal compression in terms of clinically significant complications [93].
Pathophysiology
The compression of the brachiocephalic vessels by an extrinsic retrosternal thyroi-
dal mass causes SVC syndrome. Ipsilateral distension of the subclavian, axillary,
and jugular veins occurs as a consequence of impaired drainage of the brachioce-
phalic veins [90].
The phrenic nerve supplies motor innervation to the diaphragm and is derived
from the 3rd, 4th, and 5th cervical nerves and passes in front of the anterior scalene
muscle on its descent from the neck into the thoracic cavity [94, 95]. Extrinsic com-
pression of the phrenic nerve during either its intrathoracic or cervical course results
in dyspnea [92] (Table 2.4).
Table 2.4 Modified World Health Organization (WHO) classification for the clinical evaluation
of a goiter
Grade Examination findings
Grade 0 Goiter not visible or palpable [96, 97]
Grade 1 Goiter not visible in the normal position of the neck but is palpable. The thyroidal
mass should be palpable on deglutition [96, 97]
Grade 2 Visible and palpable goiter [96, 97]
Adapted from references Lewinski [96] and Abuye [97]
2.3 Euthyroid Goiter with Thoracic Outlet Syndrome 41
Pathogenesis of nodular goiter formation [98]
• There is an initial insult to the thyroid in the form of nutritional iodine

deficiency, goitrogens, or even autoimmune thyroid disease, which results
in reduced thyroid hormone synthesis.
• As an adaptation to decreased active thyroid hormone, there is a reduction
in negative feedback inhibition of the central thyrotropes, causing an
increase in TSH stimulation of thyroid follicular cells. Thyroid hyperplasia
and hydrogen peroxide generated as a result of hypermetabolism increase
the risk of genetic mutations. This high replication rate reduces the time for
the repair of possible mutations, leading to persistent errors in transcription
and translation of deoxyribonucleic acid (DNA).
• Some of the mistakes (gain-of-function mutations) involve the constitutive
intrathyroidal cyclic adenosine monophosphate pathways (TSH receptor),
which further promotes excessive clonal proliferation.
• Continuous clonal expansion contributes to additional mutations, which
may result in the formation of “hot” or “cold” nodules [98].

What is Riedel’s thyroiditis?
It is a rare fibrosclerosing condition of the thyroid, characterized by a
“stony hard” thyroid consistency. Involvement of thyrocervical tissues
leads to a change in voice (recurrent laryngeal nerve infiltration) and other
compressive symptoms such as dysphagia and dyspnea [99]. Riedel’s thy-
roiditis is now appreciated as a thyroidal manifestation of IgG4-related
systemic disease (IgG4-RSD) [100]. IgG4-RSD has an unclear etiology,
although a predominant lymphoplasmacytic infiltrate and elevated serum
IgG4 (immunoglobulin G4) are hallmarks of this disease. Extra-thyroidal
involvement of sialolacrimal glands, hepatobiliary system, and retroperito-
neum have been reported [101].
How does thyromegaly result in Horner’s syndrome? (Fig. 2.3).
Higher order neurons

Nerve to the Muller Enophthalmos
from the hypothalamus
muscle (upper Oculosympathetic
eyelid) paresis
Ptosis
Carotid
Miosis sympathetic
plexus
Nerve to the dilator
pupillae muscle
Anhydrosis
Nerve to the sebaceous
glands SCG
THYROMEGALY
compression of the SCG Thoracic sympathetic
ganglion
Fig. 2.3 Pathogenesis of thyromegaly induced Horner’s syndrome. Horner’s syndrome classically
presents with ptosis, miosis, and enophthalmos. The superior cervical ganglion (SCG) serves as a
relay center for higher-order neurons and has projecting from it, postganglionic neurons, which
will eventually terminate in the orbit, skin of the head and neck region [102, 103]. The SCG lies
near the thyroid and is subject to extrinsic compression in the setting of significant thyromegaly
[104]. Distal innervation of Muller’s muscle, dilator pupillae muscle, and sebaceous glands in the
skin can be impaired by clinically significant thyromegaly (compression of the SCG). Motor neu-
rons supplying Muller’s muscle are involved, accounting for ptosis. The involvement of sympa-
thetic innervation of the dilator pupillae muscle accounts for miosis. Enophthalmos occurs because
of oculosympathetic paresis [102]. (Redrawn and modified from Kanagalingam et al. [103])
2.4 Resistance to Thyroid Hormone
2.4.1 Goiter
Clinical Features
Goiter is quite frequent in patients with thyroid hormone resistance syndromes, a
state of differential tissue insensitivity to circulating thyroid hormone, with a
reported prevalence of 66–95% [105].
Pathophysiology
Impaired negative feedback inhibition of central thyrotropes in the setting of thyroid
hormone resistance promotes TSH-mediated thyromegaly [106].
2.4.2 Short Stature
Clinical Features
In a prospective study at the National Institutes of Health, including 104 patients
with thyroid hormone resistance, 18% had short stature [107].
2.4 Resistance to Thyroid Hormone 43
Pathophysiology
• T3 acts on thyroid hormone receptors present on chondrocytes in the growth
plate and plays a critical role in their differentiation and maturation [108].
Reduced levels of T3, as occurs in hypothyroidism, leads to thinning of both the
proliferative and hypertrophic zones of the growth plate [109].
• T3 potentiates the local production of IGF-1 in the growth plate [108] (see Sect.
1.5.1). Hypothyroid subjects have impaired longitudinal growth due to the
blunted effects of T3 on the GH-IGF1 axis [109].
Thyroid hormone resistance
Thyroid hormone resistance (THR) states occur as a result of mutations in
the genes responsible for the various subtypes of the thyroid hormone recep-
tor [105, 110, 111]. The thyroid hormone receptor alpha (THRA) and thyroid
hormone receptor beta (THRB) genes code for TRɑ and TRβ subtypes of the
thyroid hormone receptor, respectively [111–113].
There is a variable expression of these receptors in different tissues,
accounting for the lack of consistent clinical findings in patients with THR
[113, 114].
Pituitary or central thyroid hormone resistance occurs due to impaired
negative feedback of the circulating thyroid hormone on the pituitary thyro-
tropes. Patients are usually clinically hyperthyroid [115]. In contrast, patients
with generalized thyroid hormone resistance may be euthyroid, hypothyroid,
or hyperthyroid, depending on the predominant tissue-specific thyroid hor-
mone receptor subtype affected [112].

Does TSH hypersecretion due to thyroid hormone resistance lead to thyroid
adenomas or cancer?
TSH hypersecretion causes mild enlargement of the thyroid gland, but
there is no evidence that it increases the risk of either adenoma or malig-
nancy [116].
What is the eponymous name for thyroid hormone resistance syndromes?
The first case of thyroid hormone resistance was described in 1967 by Dr.
Samuel Refetoff and his colleagues [106]. “Refetoff syndrome” was first used
in a published case report from Japan [117]. Subsequent case reports have
since used this eponymous term [118–120].
2.5 Medullary Thyroid Cancer
2.5.1 F
acial Flushing and Other Clinical Features
of Neuroendocrine Origin
Clinical Features
Patients with medullary thyroid cancer can present with facial flushing. It is
described as a “dry flush” due to the absence of associated cutaneous sweating
[121], in contrast to the “wet flush” of menopause [122].
Pathophysiology
The parafollicular cells of the thyroid gland are derived from cells of neural crest
origin, which have been aptly named APUD (amine precursor uptake decarboxyl-
ation) cells. These neuroendocrine cells can release various amines, including sero-
tonin, histamine, prostaglandins, and ACTH [123]. Cutaneous flushing and diarrhea
due to these amines are discussed in Sects. 4.4.1 and 4.4.2, respectively.
2.5.2 Cervical Mass
Clinical Features
The most frequent clinical finding in MTC is the presence of a mass or nodule in the
cervical region, with a reported prevalence of 35% to 50%. Neck findings could be
due to cervical lymph node involvement or compressive neck symptoms due to an
enlarged thyroid nodule [124].
Pathophysiology
MTC occurs due to malignant transformation of parafollicular cells [125], which
are of neural crest origin [124]. A mutation of the rearranged during transfection
(RET) proto-oncogene results in the clonal proliferation of parafollicular cells [125].

Which endocrine conditions present with MTC? [126].
• Multiple endocrine neoplasia type 2A and 2B.

• Familial medullary thyroid carcinoma (FMTC).
• Sporadic MTC occurs much later in life between 40 and 60 years of age.
Hereditary MTC encompasses MEN type 2 syndromes and FMTC and
tends to occur much earlier in life compared to sporadic MTC [127].
At what age and in which specific inherited endocrinopathies should pro-

phylactic total thyroidectomy be performed? [128].
Patients should have a total thyroidectomy by 5 years of age if they have
MEN2A with germline mutation involving the RET codon at position 634
or MEN2B.
References 45
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Adrenal Gland Signs
3
Learning Objectives
1. Understand the renin-angiotensin-aldosterone (RAA) axis and the factors

involved in both positive and negative feedback regulation
2. Appreciate the target effects of aldosterone and how perturbations in the
RAA hormonal milieu result in specific clinical signs
3. Understand the role of cortisol in catecholamine metabolism
4. Understand the cardiovascular effects of catecholamines
5. Recognize the genetic basis for glucocorticoid-resistant states and appreci-
ate the pathophysiologic basis of their clinical manifestations
3.1 Primary Adrenal Insufficiency
3.1.1 Postural Hypotension
Clinical Features
Arterial blood pressure decreases in patients with primary adrenocortical insuffi-
ciency [1]. Orthostatic hypotension can be elicited at the bedside by confirming a
postural drop in blood pressure in changing from a supine to a semi-recumbent
position or standing position [2].
Pathophysiology
1. Autoimmune-mediated destruction of the adrenal cortex results in reduced pro-
duction of mineralocorticoids needed to maintain sodium and water balance [3]
(see Fig. 3.1).

https://doi.org/10.1007/978-3-030-49872-6_3
52 3 Adrenal Gland Signs
Renal Nerve
Afferent Arteriole
Bowman’s Space
Macula Densa Cells

lining the DCT
Proximal Tubule
JGCs
Efferent Arteriole
Glomerulus
Components of the Juxtaglomerular Apparatus
Fig. 3.1 The components of the juxtaglomerular apparatus. Triggers of renin secretion include a
low sodium load presented to macula densa cells (located in the DCT), adrenergic stimulation from
renal nerves innervating JGCs in the afferent arteriole, and a reduced tensile stretch of the afferent
arteriole of the glomerulus. Renin, the rate-limiting enzyme in the renin-angiotensin-aldosterone
system (RAAS), is critical in maintaining intravascular volume and blood pressure [7]. Renin
release is also controlled by long and short negative feedback loops mediated by the effect of ATII
on the collecting tubule and JGCs, respectively [9]. (Redrawn and modified from Alessandro
et al. [9])
2. There is a single study to date, exploring the role of adrenomedullin in Addison’s

disease. Adrenomedullin (AM), a novel hypotensive peptide, was found to be
high in patients with proven Addison’s disease. There was, however, a weak cor-
relation (r = 0.458; P value = 0.048) between systolic blood pressure and plasma
AM levels in subjects with adrenocortical insufficiency. The authors were unable
to explain the exact mechanism accounting for the high levels of AM in patients
with Addison’s disease [4].
3. Cortisol is critical in maintaining vascular tone through several mechanisms.
Glucocorticoids potentiate the vasoconstrictive effect of catecholamines on vas-
cular ɑ1-receptors. An increase in vascular adrenergic receptor density is induced
by glucocorticoids [5].
4. Similar to the effects of glucocorticoids on adrenergic receptors, vascular recep-
tors of angiotensin II are upregulated by glucocorticoids [5].
5. Glucocorticoids increase the transcription of angiotensinogen, a precursor of
angiotensin II [5].
3.1 Primary Adrenal Insufficiency 53
Mechanisms of Renin Release
The juxtaglomerular apparatus is composed of the macula densa cells pres-
ent in the distal convoluted tubule (DCT), juxtaglomerular cells (present in
the entire glomerular vasculature but more prominent in the afferent arteri-
ole), and the glomerular afferent arteriole (AT) [6]. See Fig. 3.1.
Renin, an enzyme released from juxtaglomerular cells, initiates a cas-
cade of reactions, which leads to the eventual formation of angiotensin II
(ATII) [7].
• Change in sodium chloride load presented to the macula densa cells (a

group of 15–20 cells in the distal convoluted tubule) influences the
eventual release of renin from the juxtaglomerular cells (JGCs), through
some signaling mediators. A high sodium load inhibits renin release
from the juxtaglomerular cells, whereas a low sodium load does the
opposite [8].
• A change in blood pressure at the afferent arteriole controls renin release
from the JGCs. Low tension in the afferent arteriolar wall increases renin
release, which ultimately enhances sodium conservation and maintenance
of intravascular volume [8].
• Activation of beta-adrenergic sympathetic nerves terminating in the juxta-
glomerular cells promotes renin release [8].
Clinical Pearl
Biochemical Monitoring of Mineralocorticoid Replacement Therapy
Management of patients with primary adrenal insufficiency requires moni-
toring of mineralocorticoid replacement therapy to prevent hypertension,
edema, and hypokalemia. The goal is to maintain plasma renin activity close
to the upper limit of normal [10].
Clinical Features
Addison’s disease presents with a classic dermatologic feature of hyperpigmenta-
tion involving sun-exposed areas, areas of prior trauma, palmar creases, oral
mucosa, conjunctivae, and the nails (dark longitudinal ridges referred to as melano-
nychia) [11].
Pathophysiology
1. Melanogenesis is induced by α-melanocyte-stimulating hormone (MSH) acting
on type 1 melanocortin receptors (MC1-R), present on melanocytes [12].
2. ACTH also binds to MC1-R receptors present on melanocytes [12]. Elevated
levels of ACTH, as occurs in Addison’s disease, contribute to hyperpigmentation
of the skin.
3. Interestingly, all POMC-derived peptides have receptors on melanocytes, fibro-
blasts, and keratinocytes [12].
Mediators of Melanin Formation (Fig. 3.2)
CRH: from the hypothalamus
POMC
Active ACTH β-lipoprotein
β-endorphin MSH
Skin Melanin (pigmentation)
Melanocyte
(stimulated by POMC derivatives)
MC1-R
Fig. 3.2 Melanogenesis – the role of POMC derivatives in melanocyte activation. Corticotropin-
releasing hormone (CRH) from the hypothalamus has a stimulating effect on the production of
proopiomelanocortin (POMC) and its downstream products in the anterior pituitary gland.
Adrenocorticotrophic hormone (ACTH) and beta-lipotropin are derived from POMC. Beta-
lipotropin is subsequently cleaved to form beta-endorphin and melanocyte-stimulating hormone
(MSH). MSH binds its cognate melanocyte 1 receptor (MC1-R) on the melanocyte to activate
melanogenesis (solid line). Also, both POMC and ACTH can bind the MC1-R receptor and aug-
ment melanin production (dashed line) [12]. (Based on Yamamoto et al [12])
3.2 Primary Hyperaldosteronism 55
Clinical Pearl
The Houssay Phenomenon
Houssay phenomenon is an eponymous termed named after the Nobel
Prize Laureate Dr. Bernardo Houssay. It is defined as significant hypoglyce-
mia due to cortisol deficiency in the setting of panhypopituitarism. Patients
with pre-existing diabetes may experience either resolution of diabetes or
new-onset recurrent hypoglycemia due to the loss of the metabolic effects of
crucial counterregulatory glucocorticoids [13].
Questions on Clinical Rounds

What about the vascular supply of the adrenal gland that predisposes it to
hemorrhage in the setting of coagulopathy?
Each adrenal gland is drained by a single adrenal vein, which makes it
susceptible to veno-occlusive disease in the setting of coagulopathy. The left
adrenal vein forms a confluence with the inferior phrenic vein and finally
drains into the left renal vein. The right adrenal vein, however, drains directly
into the inferior vena cava [14, 15].
What are the other clinical features of Addison’s disease (Table 3.1)?
3.2 Primary Hyperaldosteronism
3.2.1 Hypertension
Clinical Features
Primary hyperaldosteronism happens to be the most common cause of secondary
hypertension, with a reported prevalence of 5–10% among all hypertensive patients
and as high as 20% in those with resistant hypertension [19].
Table 3.1 Clinical features grouped by the underlying mechanism

Clinical features Underlying mechanism
Postural dizziness, hypotension, salt craving, and Mineralocorticoid insufficiency [16]
weight loss
Confusion, pallor, and diaphoresis Hypocortisolemia-induced hypoglycemia
[16]
Nausea, vomiting, and abdominal discomfort The pathophysiology is uncertain [17]
Loss of androgen-dependent hair (adolescents, Androgen deficiency [18]
females) and reduced libido Autoimmune-mediated destruction of
Vitiligo melanocytes [18]
Adapted from Park [16] Mandadi [17] and Auron [18]
Pathophysiology
Aldosterone promotes nuclear transcription and translation of the amiloride-
sensitive epithelial sodium channels, which increases sodium and water conserva-
tion (see Fig. 3.3) [20].
There are mineralocorticoid receptors on vascular endothelial cells. Aldosterone
plays an active role in both vasoconstriction and vasodilation; the circumstances
under which it performs these roles are, however, yet to be elucidated [20].
Nonetheless, aldosterone excess induces mineralocorticoid receptor overactivation,
inflammation of the vascular endothelium, and myocardial remodeling, which are
all critical contributory factors to the development of hypertension [20].
Aldosterone-Mediated Sodium and Water Conservation
Aldosterone
Distal renal tubular cell
4
MCR
1
Na+
ENaC 2
HRE
us
cle
3Na+ (Net Na+ gain)

Nu
(Net K+ loss) K+ 5
3 2K+
ROMK
Increased expression of ENaC
and Na-K+ ATPase
Apical side Basolateral side
(tubular lumen) (interstitial fluid)
Fig. 3.3 Aldosterone-mediated sodium and water conservation at the distal renal tubule.
Aldosterone, a lipid-soluble steroid hormone, diffuses through the cell membrane of the ductal
epithelial cell and binds to the cytosolic mineralocorticoid receptor (MCR) (step 1). The
aldosterone-MCR complex is then translocated into the nucleus where it attaches to the hormone
response element (HRE) (step 2) required for transcription and translation of the epithelial sodium
chloride (ENaC) channel and sodium-potassium adenosine triphosphatase (Na-K+ ATPase) pump
(step 3). ENaC and Na-K+ ATPase both play an active role in sodium reabsorption from the filtered
renal sodium load present in the collecting duct and distal convoluted tubule. The net effect is the
transfer of sodium from the apical to the basolateral side of the renal tubular cell (steps 4 and 5)
[19, 20]. Aldosterone also promotes the expression of renal outer medullary potassium (ROMK)
channels. The insertion of ROMK channels on the apical membrane facilitates potassium and
hydrogen ion loss [21]. (Redrawn and modified from Byrd et al. [19])
3.2.2 Muscle Weakness
Clinical Features
Significant muscle weakness can occur in patients with primary hyperaldosteron-
ism. There are a few case reports of myopathy as the presenting feature of Conn’s
syndrome [22–24].
Pathophysiology
Aldosterone plays an active role in the upregulation of potassium (K+) channels
present on the apical surface of the ductal cell. These K+ channels are involved in the
extrusion of K+ from the ductal cell into the lumen of the renal tubule (see Fig. 3.3).
This accounts for the hypokalemia-induced muscle weakness seen in patients with
primary hyperaldosteronism (see Fig. 3.3) [20].
3.2.3 Atrial Fibrillation
Clinical Features
An association of atrial fibrillation with hyperaldosteronism is widely accepted;
there is, however, a paucity of prospective study data on the prevalence of atrial
fibrillation in subjects with hyperaldosteronism [25]. Patients with primary aldoste-
ronism are at a 12-fold risk of developing atrial fibrillation compared to patients
with essential hypertension [26]. An irregularly irregular pulse rate and rhythm is
the classic clinical finding in atrial fibrillation [27].
Pathophysiology
1. Mineralocorticoid receptors present on cardiac myocytes are activated by excess
aldosterone, which results in myocyte hypertrophy. Left ventricular hypertrophy
causes significant diastolic dysfunction and predisposes patients to atrial fibrilla-
tion [25].
2. Mineralocorticoid-mediated inflammation induces fibrosis of the myocardium.
Multiple foci of fibrosis induce re-entry circuits in the heart, which increases the
risk of atrial fibrillation [25].
3. Hyperaldosteronism-induced hypokalemia causes prolongation of the PR inter-
val (extends the period of ventricular diastolic filling), which impairs diastolic
function and, as mentioned in (1) above, predisposes the myocardium to arrhyth-
mias [25].
3.2.4 Dehydration
Clinical Features
Patients with primary hyperaldosteronism can present with hypotonic polyuria and
polydipsia [28].
Pathophysiology
Hyperaldosteronism increases potassium wasting at the distal renal tubules [28].
Hypokalemia subsequently promotes a downregulation of aquaporin-2 (AQP-2)
channels on both cortical and inner medullary ductal cells, which results in renal
free water loss [29].
Hypokalemia reduces intracellular cyclic adenosine monophosphate (cAMP)
activity, a critical second messenger that mediates the effects of antidiuretic hor-
mone (ADH) at the ductal cell. ADH is, therefore, unable to promote the insertion
of AQP-2 water channels on the renal tubular apical membrane. This results in an
acquired form of nephrogenic diabetes insipidus (see also Fig. 1.6) [28].
Clinical Pearl
Screening for Hyperaldosteronism
1. Hypokalemia inhibits aldosterone production; as such, potassium levels

should be maintained at a level ≥ 4 mmol/L before screening for hyperal-
dosteronism with the aldosterone to renin ratio (ARR) [19].
2. Medications that interfere with ARR testing, such as mineralocorticoid
antagonists and angiotensin-converting enzyme (ACE) inhibitors, may not
need to be held before initial hyperaldosteronism screening. Indeed, if
renin is suppressed in the setting of mineralocorticoid antagonist or ACE
inhibitor therapy, then the ARR is interpretable. It is essential to bear this
caveat in mind since the discontinuation of antihypertensives comes with
risks such as poorly controlled hypertension or, worse still, hypertensive
crises [19].
Why do patients with primary hyperaldosteronism seldom develop peripheral
edema despite the sodium and water-conserving effects of excess aldosterone?
1. An increase in sodium and water conservation elevates the cardiac preload

and leads to stretching of the atrial cardiomyocytes. Atrial natriuretic fac-
tor is then released by the atrial cardiomyocytes, which promotes natriure-
sis (renal sodium loss) in the medullary collecting ducts of the nephron [30].
2. Increased renal perfusion pressures due to plasma volume expansion leads
to “pressure natriuresis.” The proximal tubule is unable to reabsorb enough
sodium due to an increased filtered load in the setting of increased intra-
glomerular filtration pressures. This results in the delivery of a high renal
tubular sodium load to the distal nephrons, which subsequently over-
whelms the sodium-conserving effects of aldosterone (see Fig. 3.3) [30].

What clinical features should prompt a clinician to screen a patient for pri-
mary hyperaldosteronism (Table 3.2)?
What are the causes of pseudohyperaldosteronism?
These are endocrine conditions that present with some of the clinical fea-
tures of primary hyperaldosteronism (hypertension and hypokalemia) but do
not exhibit the expected increase in plasma aldosterone to plasma renin ratio.
Patients with pseudohyperaldosteronism have low levels of both aldosterone
and renin [32] (Table 3.3).
Table 3.2 Screening recommendations for hyperaldosteronism

Endocrine Society screening recommendations:
Blood pressure above 150/100 mmHg; should be measured on three occasions on separate
days [31]
Uncontrolled blood pressure on three or more antihypertensives, including a diuretic ∆ [31]
Controlled blood pressure requiring four or more antihypertensive agents ∆ [31]
Hypertension in the setting of sleep apnea or adrenal incidentaloma [31]
Hypertension with a family history of early-onset hypertension or stroke at <40 years of age
[31]
First-degree hypertensive relatives of patients with primary hyperaldosteronism [31]
∆ Suggestive of resistant hypertension
Adapted from Funder et al. [31]
Table 3.3 Mechanisms underlying the various causes of pseudohyperaldosteronism

Condition Mechanism
Liddle’s syndrome A gain-of-function mutation of the gene encoding the amiloride-
sensitive epithelial sodium chloride transporter [33]
Gordon syndrome A gain-of-function mutation of the thiazide-sensitive sodium
chloride cotransporter in the distal nephron. Unlike other causes of
pseudohyperaldosteronism, Gordon syndrome is associated with
hyperkalemia instead of hypokalemia [34]
Defects in adrenal Deficiency of 11beta-hydroxylase enzyme results in a buildup of
steroidogenesis 11-deoxycorticosterone (which has intrinsic mineralocorticoid
activity) [35]
Cushing’s syndrome Excess cortisol binds to the mineralocorticoid receptor due to
saturation of the 11beta-hydroxysteroid dehydrogenase 2 enzyme
(see the cortisol-to-cortisone shunt, Section 1.1.1) [36]
Apparent An autosomal recessive condition characterized by an inactivating
mineralocorticoid excess mutation of the 11beta-hydroxysteroid dehydrogenase 2 enzyme
(see the cortisol-to-cortisone shunt, Section 1.1.1) [37]
Excessive intake of Inhibition of 11beta-hydroxysteroid dehydrogenase 2 (see the
licorice, grapefruits, or cortisol-to-cortisone shunt, Section 1.1.1) [36]
carbenoxolone
Medication-induced Corticosteroids and contraceptives [36]
3.3 Pseudohypoaldosteronism
3.3.1 Cardiac Arrest due to Life-Threatening Hyperkalemia
Clinical Features
Infants born with this condition present with sudden cardiac death [38, 39].
Pathophysiology
Pseudohypoaldosteronism type 1 (PHA1) can be inherited in either an autosomal
dominant or recessive pattern. Loss-of-function mutations in either the mineralocor-
ticoid receptor (MCR) or the amiloride-sensitive epithelial sodium chloride channel
(ENaC) gene reduce the target organ effects of aldosterone. Refractory hyperkalemia
can lead to peaked T waves, wide QRS complex, eventual ventricular arrhythmia,
and asystole [38, 39]. Impaired action of aldosterone results in not only hyperkale-
mia but hyponatremia and metabolic acidosis as well [40] (see Sect. 3.2.1).
Clinical Manifestation of Hypoaldosteronism

Dehydration, seizures (hyponatremia induced), and failure to thrive [40]
3.3.2 C
utaneous Manifestations (Folliculitis
and Atopic Dermatitis)
Clinical Features
Patients with PHA1 can present with multiple cutaneous manifestations, including
folliculitis and atopic dermatitis [41, 42].
Pathophysiology
Epithelial sodium chloride channels are present in multiple tissues outside the kid-
ney, including the human skin [43]. A recent study has elucidated the role of ENaC
in mediating secretions from the sebaceous glands and other eccrine glands of the
skin. The inability of ENaC to mediate salt reabsorption in the sweat gland results in
the accumulation of inspissated secretions in the ducts of sweat glands. This creates
a suitable environment for bacterial overgrowth and inflammation (folliculitis) [41].

What endocrine condition can PHA type 1 be misdiagnosed as?
PHA type 1 mimics an acute adrenocortical crisis in the neonatal period.
Neonates will, however, not improve with glucocorticoid replacement as
would be expected in patients with an adrenocortical crisis [39].
How can renal (mineralocorticoid receptor gene mutation) type of PHA
type 1 be differentiated from the systemic (ENaC) variant?
Genetic testing and sweat gland tests [39]
3.4 Familial Glucocorticoid Deficiency 61
3.4 Familial Glucocorticoid Deficiency
Clinical Features
Hyperpigmentation is a characteristic cutaneous sign in patients with familial glu-
cocorticoid deficiency (FGD) [44–47], which improves with treatment [44].
Pathophysiology
ACTH stimulates melanocortin-1 receptors present on melanocytes of the skin. In
response to this, melanocytes increase melanogenesis (hyperpigmentation) (see
Sect. 3.1.2) [46].
Pathophysiologic basis of FGD:
• FGD occurs as a result of peripheral target tissue resistance to the trophic

effects of ACTH [46], due to mutations in the gene locus responsible for
the translation of the melanocortin-2 receptor (MC2R) [44].
• ACTH is unable to bind its cognate receptor (MC2R) in the adrenal cortex,
which leads to atrophy of the glucocorticoid and androgen-producing
regions of the adrenal cortex. The loss of negative feedback suppression of
ACTH production in the setting of hypocortisolemia promotes excess
ACTH production [45].
• Mineralocorticoid action is preserved in FGD since the zone glomerulosa
mediates the renin-angiotensin-aldosterone system and is not directly
influenced by circulating ACTH levels [45, 46].
3.4.2 Hypoglycemia
Clinical Features
Patients with FGD can present with recurrent hypoglycemia [45, 48]. Possible
hypoglycemia-related seizures have been reported [49] and can predispose
patients to significant intellectual impairment [46]. Hypoglycemia should be con-
firmed objectively via Whipple’s triad, i.e., biochemically confirmed hypoglyce-
mia, hyperadrenergic, or neurologic symptomatology suggestive of hypoglycemia
and prompt resolution of symptoms after administration of glucose (orally or par-
enterally) [50].
Pathophysiology
Cortisol, an essential counterregulatory hormone in glucose metabolism, is absent
and predisposes patients to clinically significant hypoglycemia [44].

What is generalized glucocorticoid resistance (GGR)?
GGR is due to a mutation in the glucocorticoid receptor gene, which results
in reduced target tissue responsiveness to circulating cortisol [51]. It is indeed
characterized by partial tissue resistance to the effects of cortisol [52].
What are the clinical effects of generalized glucocorticoid resistance
(Chrousos syndrome)?
Due to partial pituitary insensitivity to circulating cortisol levels, there is
impaired negative feedback inhibition of adrenocorticotrophic hormone
(ACTH) production. Excess ACTH enhances the stimulation of the zona fas-
ciculata and reticularis, which results in excess glucocorticoid and androgen
production, respectively [53]. Excess deoxycorticosterone and corticosterone
through their mineralocorticoid effects account for hypertension and hypoka-
lemia observed in patients with this disorder. This occurs in the setting of
normal circulating aldosterone. Excess androgens lead to virilization in
women [52]. In boys, androgen excess may lead to early accelerated growth
and muscle development followed by early epiphyseal closure and a reduced
height [54] (Fig. 3.4).
Normal pituitary sensitivity Partial pituitary sensitivity B

A to cortisol feedback to cortisol feedback
ATCH
– ACTH – +
+
Cortisol
Cortisol
Corticosterone
11-Deoxycorticosterone
Androgens
Corticosterone
11-Deoxycorticosterone Androgens
Fig. 3.4 Partial tissue insensitivity to cortisol (Chrousos syndrome). Pituitary ACTH secretion is
under negative feedback control from adrenal-derived cortisol in normal physiology (a) [51].
Partial pituitary insensitivity to circulating cortisol levels results in increased ACTH production
and eventual adrenocortical hyperplasia [52]. This accounts for the increased production of andro-
gens, cortisol, and mineralocorticoids (11-deoxycorticosterone and corticosterone) [53, 54](b).
(Redrawn and modified from Chrousos et al. [54])
3.5 Pheochromocytomas and Other Paraganglioma Syndromes 63
3.5 Pheochromocytomas and Other

Paraganglioma Syndromes
3.5.1 Hypertension
Clinical Features
Hypertension is the most frequent physical manifestation of pheochromocy-
toma, accounting for a prevalence of 80–90% in this patient population.
Hypertension may be either paroxysmal or sustained, although normotension
may be a presenting future in a small subset of patients [55]. Recent evidence
suggests that pheochromocytomas and paraganglioma syndromes (PPGLs)
account for 0.2 to 0.6% of all hypertensive cases seen in outpatient prac-
tices [56].
Pathophysiology
Direct effects of catecholamines on adrenergic and dopaminergic receptors present
on cardiovascular target sites account for hypertension in patients with PPGLs [55].
See Table 3.4 for the various cardiac effects of catecholamines.
Table 3.4 Review of the location and cardiac effects of catecholamines

Adrenergic receptor (location) Cardiac-specific effects
α1 adrenergic receptor (smooth Increases systemic blood pressure through
muscle of arteries and veins) vasoconstriction
Positive inotropic effects [55]
α2 adrenergic receptor (presynaptic Arterial vasodilation [55]
surface of sympathetic ganglia and
on smooth muscles)
β1 adrenergic receptors in Positive inotropic effects under direct stimulation by
cardiomyocytes epinephrine and norepinephrine [55]
Positive chronotropic effects through stimulation of the
cardiac pacemaker cells [55]
Receptors present in the juxtaglomerular cells of the
kidney under stimulation by catecholamines release renin
leading to activation of the renin-angiotensin-aldosterone
axis [55]
β2 adrenergic receptors (smooth Vasodilation of muscular arteries
muscles and sympathetic ganglia) Induces increased norepinephrine release from
sympathetic ganglia [55]
D1 dopaminergic receptor (kidney Stimulation results in vasodilation of renal arteries [55]
vasculature) ⦽
D2 dopaminergic receptor Negative inotropic effect by inhibiting norepinephrine
(presynaptic) ⦽ secretion from sympathetic nerve terminals [55]
⦽At high concentrations of dopamine, as might occur with PPGLs, dopamine stimulates α1 and
β1 adrenergic receptors, which leads to vasoconstriction and an increased heart rate, respectively
Adapted from Zuber et al. [55]
Catecholamine-Induced Hyperglycemia
1. Hyperglycemia in the setting of PPGLs occurs because of the inhibitory

effect of catecholamines on insulin secretion. Binding of catecholamines,
especially epinephrine to the α2 adrenergic receptor present on pancreatic
beta-cells, is a widely reported mechanism [57, 58].
2. Other adrenergic effects include the induction of both hepatic gluconeo-
genesis and lipolysis [57].
Catecholamine Synthesis (Fig. 3.5)
L-Tyrosine
Tyrosine hydroxylase
DOPA
Adrenal medulla
DOPA decarboxylase
Dopamine
Dopamine hydroxylase
COMT
Normetanephrine Norepinephrine
PNMT
COMT
Metanephrine Epinephrine
A Cortisol-induced enzyme
Fig. 3.5 Schematic diagram of catecholamine synthesis. The rate-limiting step in the synthesis of
catecholamine occurs at the initial conversion of L-tyrosine into L-3,4-dihydroxyphenylalanine
(DOPA) via the tyrosine hydroxylase enzyme. DOPA is subsequently converted to dopamine.
Dopamine is hydroxylated into L-norepinephrine, which is then converted into epinephrine. The
conversion of norepinephrine to epinephrine requires the cortisol-induced enzyme,
phenylethanolamine-N-methyl transferase (PNMT) (dashed arrow) [55]. This is the reason why
epinephrine and its metabolite (metanephrine) are only produced by PNMT-containing organs
such as chromaffin cells in the adrenal gland and the organ of Zuckerkandl (located at the aortic
bifurcation). Norepinephrine and epinephrine are converted into their metabolites, i.e., normeta-
nephrine and metanephrine, respectively, by catechol-O-methyltransferase (COMT) (dotted arrow)
[59]. (Based on Grouzmann et al. [59])
3.5 Pheochromocytomas and Other Paraganglioma Syndromes 65
Clinical Pearl
Catecholamines and Fractionated Metanephrines (Understanding Terminology)
1. Continuous intratumoral conversion of catecholamines (epinephrine and

norepinephrine) into their metabolites (metanephrine and normetaneph-
rine, respectively) by COMT makes fractionated metanephrines either in
plasma or urine a valuable screening tool. Catecholamines are, however,
released intermittently; as such, screening tests involving the use of only
catecholamines might miss a PPGL [60].
2. The term fractionated metanephrines refers to the metabolites of epineph-
rine and norepinephrine; these are metanephrine and normetanephrine,
respectively [61].
3. Clinically significant elevation of epinephrine or metanephrine (its metab-
olite) almost always implies the presence of adrenal pheochromocytoma.
PNMT, a cortisol-induced enzyme, although present in extra-adrenal tis-
sues like paraganglia, is not under paracrine stimulation by cortisol in
these tissues and, therefore, does not convert norepinephrine into epineph-
rine [62].
3.5.2 Hypotension
Clinical Features
Hypotension is usually an unexpected finding in patients with pheochromocy-
toma. Clinicians should, however, be aware of the possibility of a paradoxical
decrease in blood pressure in patients with PPGLs [63]. Interestingly there are
even reports of hypotension and hypertension rarely coexisting in rapid cycling
paroxysms [64].
Pathophysiology
1. Prolonged activation of adrenergic receptors causes profound arterial and
venous vasoconstriction. This process results in a reduction in cardiac output
(hypotension), which is sensed by baroreceptors, leading to a compensatory
increase in catecholamine release. This catecholamine surge causes sustained
hypertension, which invariably activates the baroreceptor reflex arc again,
leading to hypotension [65].
2. Sustained hyperstimulation of catecholamine receptors promotes their down-
regulation, following which there is hypotension during periods of low catechol-
amine secretion [66, 67].
3.5.3 Generalized Hyperhidrosis
Clinical Features
Excessive sweating (hyperhidrosis) is a classic finding in pheochromocytoma.
There is no reported prevalence in patients with pheochromocytomas, although the
triad of hypertension, palpitations, and hyperhidrosis has a specificity of more than
90% in clinching the diagnosis [68].
Pathophysiology
Cholinergic input to the pilosebaceous units is responsible for their secretory output
(this is independent of circulating catecholamines). Catecholamine surges during
acute exacerbations of PPGLs lead to cutaneous vasoconstriction, which reduces
the rate of evaporation of accumulated sweat on the skin. Indeed there is evidence
that topical cholinergic blockers can prevent sweat accumulation, even in the setting
of a sympathoadrenal etiology of hyperhidrosis [69].
Hyperhidrosis, irrespective of the underlying cause, is mediated by the effects of
cholinergic innervation on the sweat glands. It is essential to bear in mind that the
sympathoadrenal system is not directly involved in sweat gland secretions [69].
3.5.4 Cardiogenic Shock
Clinical Features
Pheochromocytomas can cause secondary Takotsubo cardiomyopathy [70]. This
classically presents with heart failure signs or even profound cardiogenic shock [71].
Pathophysiology
• Chronic stimulation of myocardial β1 adrenergic receptors results in significant
downregulation of these receptors. This, in effect, desensitizes the myocardial
cells to catecholamines [67].
• Excessive levels of catecholamines increase the permeability of the myocardial sar-
colemma to calcium influx. This leads to increased levels of calcium in the cytosol of
the cardiac muscle and ultimately initiates a cascade of intracellular processes, which
are followed by irreversible myocardial necrosis and fibrosis [67].
• Catecholamine surges in the setting of pheochromocytomas cause intense stimu-
lation of the α and β adrenergic receptors, leading to vasoconstriction and coro-
nary vasospasm [67].
Clinical Pearl
PPGL is an umbrella term for both pheochromocytomas and paragangliomas.
The term pheochromocytoma refers exclusively to tumors within the adrenal
medulla, while the term paraganglioma refers to tumors involving sympa-
thetic and parasympathetic ganglia [59].
3.6 Nonclassic Congenital Adrenal Hyperplasia (NCCAH) 67

Which genetic conditions are associated with pheochromocytomas [72]?
Sporadic causes of pheochromocytomas account for most cases seen in
practice. Up to a quarter of the cases have a genetic basis, which may include
any of the following:
1 . Multiple endocrine neoplasia (MEN) type 2A and 2B [72]

2. Von Hippel-Lindau disease (VHL) [72]
3. Neurofibromatosis type 1 (NF1) [72]
What clinical features should prompt a clinician to screen a patient for

pheochromocytoma and paraganglioma syndromes (PPGLs)?
1 . Adrenal incidentaloma, even in normotensive subjects [56]

2. Previous history of PPGL [56]
3. Signs and symptoms suggestive of PPGL, especially if paroxysmal [56]
4. Clinical features suggestive of the possibility of a hereditary etiology of
PPGL (e.g., MEN type 2, NF1 and VHL) [56]
5. Hypertensive crises after exposure to drugs associated with PPGL-related
crises (e.g., metoclopramide, beta-blockers, opioids, corticosteroids, glu-
cagon, and neuromuscular blocking agents) [56]
3.6 Nonclassic Congenital Adrenal Hyperplasia (NCCAH)
3.6.1 Clinical Hyperandrogenism (Acne and Hirsutism)
Clinical Features
NCCAH accounts for up to 2% of cases of hyperandrogenemia involving women in
their reproductive years [73]. Hirsutism, which is the growth of terminal male pat-
tern hair, is evaluated with the modified Ferriman-Gallwey score, which happens to
be a somewhat objective clinical assessment tool. There is wide variability in the
prevalence of hirsutism, ranging from 1 to 33% [74].
The degree of hirsutism, however, does not correlate positively with circulating
androgen levels due to differences in skin sensitivity to circulating androgens [75].
Pathophysiology
1. Most patients with NCCAH due to 21 hydroxylase deficiency typically have
normal ACTH levels, in contrast to the high ACTH seen in the classic form.
There is, however, excessive production of androgens in response to normal
ACTH stimulation of the zona reticularis. This has been attributed to a missense
mutation in the CYP21A2 gene, which results in a significant buildup of
androgen precursor steroids, due to reduced activity of the 21-hydroxylase

enzyme [76]. There is an increased production of metabolites, such as DHEA-S,
androstenedione, and testosterone [77]. High circulating androgens account for
the acne and hirsutism seen in NCCAH [76]. (See Sect. 1.1.4 for androgen-medi-
ated hirsutism; see Sect. 6.2.3 for androgen-mediated acne formation.)
2. The elevated levels of adrenal steroids impair negative feedback control of pro-
gesterone on the hypothalamic-pituitary-ovarian axis. This causes hypersecre-
tion of LH due to rapid GnRH pulse frequency, akin to what has been proposed
for the polycystic ovarian syndrome (PCOS) [78]. LH stimulates the theca cells
of the ovaries to increase ovarian androgen production [76, 79].
Clinical Pearl
Other Features of Hyperandrogenemia Seen in NCCAH
Androgenic alopecia, anovulation, and irregular menstruation [74]
3.6.2 Testicular Adrenal Rest Tumors
Clinical Features
Testicular adrenal rest tumors (TARTs) typically occur in males with classical con-
genital adrenal hyperplasia, although it has been reported in NCCAH as well [80].
TARTs in boys with congenital adrenal hyperplasia (CAH) are known to regress in
size with optimal supplementation of hormonal insufficiencies. They are diagnosed
based on clinical and radiographic findings, with biopsies being unnecessary in
most cases [81].
Pathophysiology
Adrenal and gonadal cells are located adjacent to each other in the developing
embryo. Inadvertent translocation of embryonic adrenal cells to the gonads occurs
during gonadal descent. The lack of atrophy of these ectopic adrenal tissues in the
setting of NCCAH or CAH is the cause of TARTs [81]. ACTH binds to ACTH
receptors present on adrenal tissue in the testes, and this trophic stimulation of the
ectopic adrenal tissue by ACTH results in their growth [82].
3.6.3 S
igns of Insulin Resistance (Skin Tags
and Acanthosis Nigricans)
Clinical Features
Insulin resistance has a significant association with NCCAH [83, 84], although
some authors believe this association could be secondary to glucocorticoid use in
this patient population [76, 85]. Hyperinsulinemia-mediated skin manifestations
have been described elsewhere. (See Sect. 4.1.3 for acrochordons and Sect. 4.1.1 for
acanthosis nigricans.)
3.6 Nonclassic Congenital Adrenal Hyperplasia (NCCAH) 69
Pathophysiology
The mechanisms underlying hyperinsulinemia in NCCAH are incompletely under-
stood [84, 86].
Normalization of serum androgen does not ameliorate insulin resistance, making
hyperandrogenemia an unlikely cause of insulin resistance in patients with
NCCAH [87].
Clinical Pearl
Choice of Steroid Replacement Therapy in Pregnant Patients with NCCAH
Exposure of the fetal brain to exogenous steroids can cause intellectual
impairment. Dexamethasone crosses the placenta since it is not metabolized
by placental 11 beta-hydroxysteroid dehydrogenase type 2 (11BSD2).
Prednisone and hydrocortisone, on the other hand, are metabolized by
11BHSD2 and, as such, preferred in pregnancy [76].

What are the genetic differences between NCCAH and the classic congenital
adrenal hyperplasia (Table 3.5)?
What are the various clinicopathologic phenotypes of congenital adrenal
hyperplasia (CAH)?
The primary defect in CAH is an adrenal steroidogenic enzyme defect,
which results in low levels of serum cortisol. The loss of negative feedback
control activates the hypothalamic-pituitary-adrenal axis, which results in
increased adrenocorticotropic hormone (ACTH) production. ACTH stimu-
lates the buildup and subsequent shunting of precursor steroids into either
androgen or mineralocorticoid production [75].
A brief review of the adrenal steroidogenesis pathway is critical in appre-
ciating the various clinicopathologic phenotypes of CAH (Fig. 3.6).
Table 3.5 Comparison of CAH and NCCAH

CAH NCCAH
Large gene deletion involving the Usually, a point mutation (70% of patients) in the
CYP21A2 gene CYP21A2 gene [85]
Loss of 21-hydroxylase enzyme activity Loss of 21-hydroxylase enzyme activity by 20–50%
by 95–100% [85]
Adapted from Trapp et al. [85]
Cholesterol 17-hydroxylase
StAR/SCC
Pregnenolone 17-OH-pregnenolone DHEA

3 βHSD
Progesterone 17-OH-progesterone Androstenedione

21-hydroxylase
Deoxycorticosterone 11-deoxycortisol TESTOSTERONE

11β-hydroxylase
Adrenal cortex
Corticosterone CORTISOL
18-hydroxylase
18-hydroxycorticosterone
Aldosterone
synthase
ALDOSTERONE
Zona glomerulosa Zona fasciculata Zona reticularis
Fig. 3.6 Steroidogenic pathway depicting the various enzyme defects in congenital adrenal
hyperplasia. The steroidogenic acute regulatory protein (StAR), at the level of the adrenal gland,
mobilizes cholesterol from the outer to the inner mitochondrial membrane. The cytochrome P450
side-cleavage enzyme (P450scc) in the inner mitochondrial membrane converts cholesterol to
pregnenolone; this is the rate-limiting step of adrenal steroidogenesis. The downstream effects of
StAR are under trophic stimulation by both ACTH and luteinizing hormone (LH) [88].
Pregnenolone is then converted to the progesterone by 3beta-hydroxysteroid dehydrogenase type
2 (HSD3B2), in the zona glomerulosa. Progesterone is then converted through a series of enzy-
matic steps involving 21 hydroxylase (CYP21A2) and aldosterone synthase into aldosterone. In
the zona fasciculata, pregnenolone is hydroxylated into 17-hydroxypregnenolone by CYP17A1
(17-alpha-hydroxylase enzyme/17,20 lyase). HSD3B2, CYP21A2, and CYP11B1 (11 beta-
hydroxylase) are then involved in downstream reactions leading to the production of cortisol. In
the zona reticularis, CYP17A1 and HSD3B2 are involved in the eventual formation of androgen
precursors such as dehydroepiandrosterone (DHEA) and androstenedione [89]. (Redrawn and
modified from Al Alawi et al. [89])
Phenotypes of Congenital Adrenal Hyperplasia

1. Congenital lipoid hyperplasia (CLH). CLH is due to an autosomal recessive
mutation in the gene encoding StAR. Clinical features include severe adrenal
insufficiency (both mineralocorticoid and glucocorticoid deficiency) and exter-
nal female genitalia in male infants. It is a fatal form of CAH [90].
2. 3Beta-hydroxysteroid dehydrogenase type 2 deficiency. The clinical spectrum of
3BHSD varies from a presentation akin to CLH (both mineralocorticoid and
glucocorticoid deficiency) to an even less severe subtype characterized by the
absence of salt-wasting [91].
3. 17 hydroxylase deficiency. A genetic mutation in CYP17A1 impairs steroidogen-
esis in both the adrenal glands and gonads [92]. Genetic females have normal-
appearing female external genitalia at birth but subsequently present with
delayed puberty. Male infants, on the other hand, are unable to synthesize
References 71
testosterone, critical in developing male external genitalia. This results in the

formation of female appearing external genitalia [93, 94]. Also, males do not
have internal Mullerian structures (uterus and fallopian tubes) since their ana-
tomic testes continue to produce anti-Mullerian hormone (see Sect. 6.6.1).
Despite patients being mildly glucocorticoid deficient, they seldom develop
overt adrenal crises. This is because of the accumulation of precursors such as
corticosterone and 11-deoxycorticosterone (DOC) not only activates the miner-
alocorticoid receptor to maintain blood pressure but also contributes to hyperten-
sion in affected patients [95].
4. 11 beta-hydroxylase deficiency. A genetic mutation in CYP11B1 results in a
defective 11beta hydroxylase, a critical enzyme in cortisol synthesis [96, 97].
There is, therefore, an accumulation of proximal precursors such as DOC and
11-deoxycortisol. DOC has intrinsic mineralocorticoid activity and accounts
for hypertension and hypokalemia observed in these patients [98]. There is
an additional shunting of more proximal steroids into androgen production
(DHEA, DHEA-S, and androstenedione). Genetic males have enlarged penile
shafts at birth due to hyperandrogenemia. Genetic females have ambiguous
genitalia due to exposure to elevated serum androgens during intrauterine
life [98, 99].
5 . 21 hydroxylase deficiency. A genetic mutation in CYP21A2 results in a defective
21 hydroxylase enzyme. 21-Hydroxylation of progesterone (mineralocorticoid
synthesis pathway) and 17-hydroxyprogesterone (glucocorticoid synthesis path-
way) is therefore impaired. There is a subsequent diversion of proximal steroido-
genic precursors into androgen production. Newborns with more deleterious
mutations in the CYP21A2 gene are hemodynamically unstable due to impaired
glucocorticoid and mineralocorticoid synthesis. Genetic females present with
ambiguous genitalia [100].
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Pancreatic Gland Signs
4
Learning Objectives
1. Discover the pathophysiologic basis for some dermatologic manifestations

of hyperinsulinemia
2. Discuss the pathophysiologic basis for diabetic retinopathy and nephropathy
3. Discuss the mechanisms underlying insulin resistance in T2DM patients
4. Categorize various insulin-resistant states and determine their clinical
relevance
5. Discuss the mechanisms underlying the clinical manifestations of neuro-
endocrine tumors, including VIPomas, gastrinomas, insulinomas, PPomas,
and glucagonomas.
4.1 Diabetes Mellitus
Clinical Features
Acanthosis nigricans (AN) is a hyperpigmented lesion with a predilection for flex-
ural areas such as the neck, axilla, and intertriginous regions of the body. Patients
with type 2 diabetes mellitus, an obese phenotype, or the metabolic syndrome are
predisposed to developing this classic skin lesion [1].
Pathophysiology
1. Insulin activates IGF-1 receptors present on fibroblasts and keratinocytes. This
is reported to be an essential mechanistic pathway involved in the development
of AN. Histologically, there is evidence of hypermelanosis and hyperkeratosis.

https://doi.org/10.1007/978-3-030-49872-6_4
78 4 Pancreatic Gland Signs
The histological findings affirm the role of some inciting mediators involved in
the proliferation of keratinocytes and fibroblasts [1].
2. Additionally, hyperinsulinemia causes a decrease in IGF-binding proteins, which
results in a higher level of unbound (active) IGF-1 [1].
3. Interestingly, androgens and growth factor receptors are present on keratinocytes
and fibroblasts as well. It appears these mediators may explain the presence of
AN in other endocrinopathies such as polycystic ovary syndrome (PCOS), con-
genital adrenal hyperplasia (CAH), and acromegaly [1].
Other Endocrinopathies Associated with Acanthosis Nigricans

Cushing’s syndrome; Addison’s disease (see Sect. 3.1.2); PCOS; CAH;
hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN)
syndrome; and acromegaly (see Sect. 1.2.1) [1]
4.1.2 Diabetic Dermopathy
Clinical Features
Diabetic dermopathy (DD) is reported as a cardinal skin manifestation of both type
1 and type 2 diabetes mellitus. It presents as hyperpigmented and circumscribed
macules noted over the pretibial skin. These characteristic lesions have a predilec-
tion for areas prone to trauma and are present in up to 55% of patients with diabetes
mellitus (DM) [2].
Pathophysiology
Neuropathy and microangiopathy induced by uncontrolled diabetes mellitus [2]
4.1.3 Acrochordons (Skin Tags)
Clinical Features
Skin tags have a reported prevalence of 25% in patients with type 2 diabetes melli-
tus. The lesions are pedunculated cutaneous fibromas distributed over flexural areas
in the neck and axilla, in a pattern akin to the distribution of AN [3].
Pathophysiology
Endogenous hyperinsulinemia promotes the activation of fibroblast-bound IGF-1
receptors present in the epidermis. This is followed by the proliferation of skin
fibroblasts and subsequent development of skin tags [2].
4.1.4 Necrobiosis Lipoidica Diabeticorum
Clinical Features
Necrobiosis lipoidica diabeticorum (NLD) is a rare clinical finding in patients with
either type 1 or type 2 diabetes mellitus. The lesions typically start as a red-brown
4.1 Diabetes Mellitus 79
papule that progressively increases in diameter and eventually changes into the clas-
sic waxy, yellowish lesion. There is an occasional central ulceration, which mani-
fests as an atrophic center [4].
Pathophysiology
There is initial tissue hypoperfusion in the skin due to microangiopathy involving
skin capillaries. Microangiopathy occurs as a result of the accumulation of advanced
glycation end products in the vasculature, which consequently promotes local oxi-
dative stress. Inflammatory mediators which have accumulated in response to tissue
hypoperfusion lead to a progressive breakdown in collagen [4].
4.1.5 Lipodystrophy Due to Insulin Injections
Clinical Features
Localized lipodystrophy due to insulin injections is an umbrella term which consists
of the lipoatrophy (LA) and lipohypertrophy (LH) subtypes [5].
LA tends to appear as an area of subcutaneous tissue loss, which creates a dimple
in the skin. LH, however, has a firm, rubbery consistency that is palpable in the
subcutaneous tissue plane. Occasionally, LH lesions may be soft, making them dif-
ficult to discern on routine physical examination [5]. Ultrasound is more sensitive
than the clinical exam for the detection of lipodystrophy. Lipodystrophic areas can
lead to malabsorption of insulin (either delayed or more rapid) from the subcutane-
ous tissue. This reportedly causes wide variability in glycemic control and can dras-
tically impact patient care if it remains undiagnosed [6].
In a meta-analysis of over 12,000 patients with diabetes mellitus, the pooled
prevalence estimate of lipodystrophy was astonishingly high at 38% (95% confi-
dence interval 29–46%). LH is best appreciated clinically by palpating the affected
area with the pulp of the fingertips [7].
Pathophysiology
1. Lipoatrophy occurs as a result of an immune-mediated reaction to insulin; it is
less prevalent now, due to the use of modern human insulin or humanlike insulin
analogs [5].
2. Lipohypertrophy is due to the growth-promoting effects of insulin on fibroblasts
in the subcutaneous tissue. Insulin binds to IGF-1 receptors on fibroblasts. Such
binding leads to the activation and subsequent proliferation of fibroblasts [5].
There are a host of other cutaneous manifestations of DM, well beyond the scope
of this text. Some selected skin manifestations and their pathophysiologic basis are
reviewed in Table 4.1.
Pathophysiology Pearl (Table 4.2)
Table 4.1 Other skin manifestations of diabetes mellitus

Lesion Clinical findings Pathophysiology
Eruptive Yellowish papules located Reduced lipoprotein lipase activity due to insulin
xanthoma over the trunk and extensor resistance or insulinopenia causes impaired
surfaces such as the elbows storage of triglycerides in adipose tissue (see
and knees Sect. 1.4.1). Following which excess circulating
triglycerides accumulate in the skin [3]
Bullosis Usually located on the lower Unknown [3]
diabeticorum extremities. Bullae tend to
contain a clear fluid which
can be aspirated when it
causes discomfort
Scleroderma Thick, indurated plaques tend Reduced breakdown of collagen fibers due to
diabeticorum to be distributed over the nonenzymatic glycosylation of dermal collagen
neck and upper back [3]
Granuloma Firm, erythematous papules Microangiopathy, lymphocytic infiltration, and
annulare with a ringlike configuration eventual connective tissue degeneration [8]
Adapted from Duff [3] and Thornsberry [8]
Table 4.2 Pathophysiologic basis of some forms of diabetes mellitus

Type of diabetes Pathophysiology
Type 1 diabetes mellitus Immune-mediated destruction of pancreatic beta-cells [9]
(T1DM)
Type 2 diabetes mellitus Reduction in incretin effect, suppression of insulin secretion,
(T2DM) increased lipolysis, increased renal conservation of glucose, increased
gluconeogenesis, reduced peripheral utilization of glucose (muscle
and adipose tissue), increased glucagon secretion and central
neurotransmitter dysfunction (hyperphagia) [10]a
Gestational diabetes The physiology of pregnancy (increased food intake, placental
mellitus (GDM) counterregulatory hormones, and a gain of adipose tissue) contributes
to pancreatic beta-cell dysfunction and peripheral insulin resistance
[11]
Cystic fibrosis-related Cystic fibrosis transmembrane conductance regulator (CFTR)
diabetes (CFRD) modulates both pancreatic beta- and alpha-cell function, by altering
multiple electrolyte channels involved in hormone secretion [12]
Posttransplant diabetes Immunosuppressive therapy (glucocorticoid-induced hyperglycemia,
mellitus (PTDM) calcineurin modulators, mTOR modulators) [13]
Pancreatogenic diabetes Anatomic loss of pancreatic beta-cell function (pancreatectomy,
(type 3c DM) chronic pancreatitis, infiltrative tumors) [15]
(pancreoprivic diabetes)
[14]
Maturity-onset diabetes Single gene mutation which impairs insulin secretion [16]. There are
of the young (MODY) at least 13 identified genes, thus far [17]
Latent autoimmune Immune-mediated destruction of pancreatic beta-cells, akin to
diabetes in adulthood T1DM, albeit at a much slower pace [18]
(LADA)
This is classically referred to as the “the ominous octet,” a term coined by Dr. Ralph DeFronzo,
a
mTOR mammalian target of rapamycin

Adapted from Refs. [9–18]
Clinical Pearl
Mucormycosis in the Setting of Diabetic Ketoacidosis (DKA)
Mucormycosis is caused by at least six different families of fungi, includ-
ing Rhizopus species. Patients in DKA are at risk of developing this life-
threatening infection [19]. It classically appears as a dark eschar involving the
oral palate and may, in some circumstances, progress into the nose and brain
(rhinocerebral mucormycosis). Extraoral sites of infection include the skin,
lung, and gastrointestinal tract [20].
Pathophysiology
• Hyperglycemia and ketoacidosis impair the activity of neutrophils critical
in fighting this fungal infection.
• Rhizopus species are “iron-loving” or ferrophilic fungi. An acidotic state,
as occurs in DKA, increases the amount of free iron available for the fun-
gus to grow by reducing the binding of iron to transferrin (an iron-binding
protein) [19].
4.1.6 Diabetic Retinopathy on Direct Ophthalmoscopy
Clinical Features
The direct ophthalmoscope, an essential component of the physical exam, is increas-
ingly not being utilized by present-day physicians. Recent evidence points to an
increasing trend of low competency in the use of direct the ophthalmoscope [21].
Nonetheless, direct ophthalmoscopy conducted by an ophthalmologist has high speci-
ficity but a low sensitivity of 34–50% in detecting early diabetic retinopathy [22].
There are two forms of diabetic retinopathy. Nonproliferative diabetic retinopa-
thy (NPDR) consists of microaneurysms, dot “hemorrhages,” cotton wool spots,
and hard exudates. Dot hemorrhages are microaneurysms seen in cross section.
Proliferative diabetic retinopathy (PDR) has neovascularization, scar tissue for-
mation with or without vitreous hemorrhage, and retinal detachment as manifesta-
tions [23].
Pathophysiology
Multiple mechanisms are involved in the pathogenesis of diabetic retinopathy; a few
of them will be reviewed here.
Polyol Pathway The deleterious effect of sorbitol in retinal cells is due to the imper-
meability of the retinal cellular membranes to sorbitol. High concentrations of sorbi-
tol accumulate and cause significant osmotic damage to the retina [24] (Fig. 4.1).
CH2OH
Glucose
Aldose reductase
Cellular Osmotic Progressive Sorbitol

death damage accumulation
Sorbital
dehydrogenase
CH2OH o
Advanced glycation end products Fructose

(AGEs)
= Impermeable cellular membrane
Fig. 4.1 Schematic representation of the polyol pathway and effects of glucotoxicity. The polyol
pathway is involved in the metabolic handling of excess glucose. Glucose is reduced to sorbitol by
aldose reductase, which is then converted into fructose by the sorbitol dehydrogenase enzyme [24].
Glucotoxicity results in an increased production of the intermediate product, sorbitol, which
causes osmotic damage in involved tissues resulting not only in retinopathy but neuropathy and
nephropathy as well. Breakdown products of fructose cause further damage to the retina by being
converted to advanced glycation end products [25]. (Redrawn and modified from Tarr et al. [24])
Advanced Glycation End Products (AGEs) AGEs are not synonymous with diabe-
tes only; they indeed occur in normal human physiology. The difference in diabetes
mellitus happens to be the accelerated rate of accumulation of these deleterious
factors [26].
AGEs bind to their cognate receptor, i.e., receptor for AGE (RAGE). RAGE
receptors are present in multiple tissues, including but not limited to the vasculature,
renal, hepatic, central nervous system, and smooth muscle [26].
RAGE is abundant in retinal tissue; thus, AGE-to-RAGE binding initiates an
inflammatory cascade, which results in neurovascular damage and eventual devel-
opment of diabetic retinopathy [27] (Table 4.3).
Clinical Pearl
Accumulation of sorbitol in the lens of the eye results in significant osmotic
changes that predispose the diabetic eye to both refractive errors and cataract
formation [30].
Table 4.3 Reasons for the fundoscopic findings of diabetic retinopathy

Fundoscopic finding
(category of retinopathy) Remarks
Microaneurysms of retinal Chronic hyperglycemia-induced apoptosis of capillary
capillaries (NPDR) pericytes (required to ensure the structural integrity of
capillaries) [28]
Hard exudates (NPDR) Increased capillary permeability and extrusion of proteinaceous
exudate (hard exudates) [23]
Dot-and-blot hemorrhages Extrusion of red blood cells out of capillaries results in areas
(NPDR) of hemorrhage with either distinct (dot) or indistinct (blot)
margins [28]
Neovascularization (PDR) Progressive injury to retinal vessels causes ischemia and
secondary formation of new vessels (hypoxia causes the release
of proangiogenic growth factors) [29]
Retinal detachment (PDR) Friable new vessels lead to vitreous hemorrhage and formation
of fibrous tissue. The contraction of fibrotic bands causes retinal
detachment [29]
Macular edema (PDR) Hemorrhagic fluid leaking into the macula [23]
NPDR nonproliferative diabetic retinopathy, PDR proliferative diabetic retinopathy
Adapted from Corcóstegui [23], Wang [28], and Duh [29]
4.1.7 The Diabetic Foot
Clinical Features
The dreaded diabetic foot, a complication of uncontrolled diabetes, predisposes
patients to foot ulcers, with an estimated lifetime risk of 25% [31]. There are two
reported variants of the diabetic foot in the literature; these include the neuropathic
and neuroischemic subtypes. As the name implies, the neuropathic foot has neu-
ropathy as the underlying microvascular complication. The neuroischemic foot has
neuropathy and vasculopathy coexisting in the same foot [32].
Pathophysiology
1. The polyol pathway, which was previously reviewed in the pathogenesis of diabetic
retinopathy, mediates diabetic neuropathy (see Sect. 4.1.6). Accumulation of sorbi-
tol and fructose impairs conductive neuronal function by reducing the synthesis of
myoinositol [31]. There is evidence that exogenous myoinositol supplementation in
patients with diabetic peripheral neuropathy significantly improves symptom
scores, sensory and motor nerve conduction velocity, and neuronal action potential
amplitude [33]. This is because myoinositol plays a permissive role in nerve con-
duction by upregulating neuronal sodium-potassium ATPase activity [34].
2. Depletion of folic acid, B6, and B12 also contributes to diabetic neuropathy, pos-
sibly through an increase in homocysteine. Metformin accelerates clearance of
both folic acid and B12 and paradoxically increases the prevalence of neuropa-
thy despite improved glycemic control [35–37]. There is evidence from both
preclinical and clinical studies in subjects with diabetic peripheral neuropathy
(DPN) which point not only to significantly improved neuropathy symptom
scores but also considerably improved nerve fiber density after a trial of a propri-
etary combination of L-methylfolate, B6, and B12 [38, 39].
3. Motor neuropathy leads to anatomic defects of the foot (Charcot’s foot) [31].
4. Autonomic neuropathy impairs the function of sweat glands, leading to xerosis,
which predisposes the involved foot to skin breaks [31].
5. Sensory neuropathy causes an insensate foot and predisposes the involved foot
to unrecognized injury [31].
Vasculopathy occurs due to the harmful effects of reactive oxygen species
(ROS) on the vasculature. Nicotinamide adenine dinucleotide phosphate (NADPH)
is depleted in the polyol pathway; this leads to the accumulation of reactive oxygen
species (ROS) since NADPH is unable to play its “scavenger role” [31].
6. NADPH is involved in the formation of nitric oxide, a potent vasodilator. NADPH
depletion via the polyol pathway results in reduced levels of nitric oxide [31].
Pathophysiologic Basis of Metformin-Induced Vitamin B12 Deficiency
1. Altered bowel transit time leading to small intestinal bacterial overgrowth
and impaired absorption of vitamin B12 [40].
2. Metformin directly inhibits calcium-dependent vitamin B12-intrinsic fac-
tor transfer at the terminal ileum [40].
Clinical Pearl
The Best Screening Test for Diabetic Peripheral Neuropathy (DPN)
Loss of vibratory sensation (detected with a 128 Hz tuning fork) is the first
objective clinical sign in DPN. It can provide a more sensitive quantitative
assessment of DPN even in patients with apparently normal standard 10 g
monofilament test results [41].
Briefly describe the mechanisms involved in the development of insulin resis-

tance in T2DM patients?
1. There is a reversible defect in tyrosine kinase activity of insulin receptors

present in the liver, adipose tissue, and muscle. This post-receptor signal-
ing defect leads to reduced metabolic effects of insulin, including a
decrease in glycogen synthase activity, an increase in hepatic gluconeo-
genesis, and a reduction in lipolysis [42].
2. Reduced glucose transporter 4 (GLUT-4) expression in skeletal muscle

and adipose tissue accounts for hyperglycemia in insulin resistance
[43–45].
3. Continuous exposure to insulin in the setting of endogenous hyperinsu-
linemia, in contrast to physiologic pulsatile insulin exposure, has been
shown to cause progressive downregulation of peripheral insulin recep-
tors [46].
What are the causes of insulin resistance?

There are three types of insulin resistance.
• Type A insulin resistance occurs as a result of impaired function of the insulin

receptor due to mutations in the insulin receptor gene [47].
• Type B insulin resistance is due to antibodies directed against the insulin recep-
tor [48].
• Type C insulin resistance is due to post-insulin receptor dysfunction (impaired
downstream action of insulin) [49].
Intrinsic defects occur as a result of a defect in the insulin receptor gene, which
impairs its normal physiologic function. Extrinsic defects are due to circulating fac-
tors, e.g., hormones and inflammatory cytokines, which interfere with insulin to
insulin receptor binding [50] (Table 4.4).
Table 4.4 Causes of insulin resistance by the underlying mechanism

Intrinsic defects Extrinsic defects
Leprechaunism (Donohue Pregnancy (physiologic cause) [52]
syndrome) [47, 51]a
Rabson-Mendenhall syndrome Infection and starvation (stress-related conditions) [54]
[47, 53]a
Congenital generalized Glucagonoma [57, 58], thyroid dysfunction [59],
lipodystrophy [55, 56] pheochromocytoma [57, 60],
acromegaly(endocrinopathies) [61]
Familial partial lipodystrophy Type B insulin resistance due to insulin receptor inhibitory
(Dunnigan variant) [62] antibodies [48, 63]
Type A insulin resistance (hyperandrogenism, insulin resistance, and acanthosis nigricans)
a
Adapted from Refs. [47, 48, 51–58, 60–62]

4.2 Rabson-Mendenhall Syndrome

(Type A Insulin Resistance)
Clinical Features
Acanthosis nigricans is a dermatologic manifestation of type A insulin resistance
syndromes [64–66]. The clinical features of acanthosis nigricans have been previ-
ously described (see Sect. 4.1.1).
Pathophysiology
The pathophysiologic basis for acanthosis nigricans due to endogenous hyperinsu-
linemia has been previously described (see Sect. 4.1.1).
Rabson-Mendenhall syndrome is a Type A insulin resistance syndrome that
occurs as a result of mutation of the insulin receptor gene. Intracellular signaling
pathways, including tyrosine phosphorylation and other downstream processes,
become defective, leading to significant impairment in insulin action in target
organs [65, 66].
Persistent hyperinsulinemia accounts for some of the physical manifestations of
RMS, including hypertrichosis and xerosis [67] (Table 4.5).
Mechanism of Insulin Secretion (Fig. 4.2)
Table 4.5 Other physical manifestations of RMS and their underlying pathophysiologic

mechanisms
Physical finding(s) Pathophysiology
Organomegaly (phallic IGF-1, which is a growth factor, shares structural homology
enlargement, clitoromegaly, and with insulin. Hyperinsulinemia accounts for organomegaly
nephromegaly) [68] due to the effects of insulin on the IGF-1 receptor [69]
Hypertrichosis and xerosis [68] Insulin binding to IGF-1 receptors in the integument [68]
Adapted from Sinnarajah [68] and Chong [69]
4.2 Rabson-Mendenhall Syndrome (Type A Insulin Resistance) 87
K+
K+ Channel Ca2+
CH2OH
4
1 L-type voltage-gated
GL Ca2+ channel
UT
Glucose -2 3
K+
Glucose Ca2+
ATP/ADP 6
Glucokinase 2
Insulin
Glucose-6-phosphate
5
Pancreatic beta cell
Fig. 4.2 Mechanism of insulin secretion in the postprandial state. In the fasting (basal) state, the
pancreatic cell membrane remains hyperpolarized, thus limiting insulin secretion. After a meal,
glucose is actively transported into the cytoplasm of the pancreatic beta-cell by glucose transporter
2 (GLUT-2) (step 1) [70, 71]. Glucose goes through an initial phosphorylation step, which is facili-
tated by glucokinase (glycolysis) (step 2). Glycolysis generates a high concentration of intracyto-
plasmic ATP, which then inhibits ATP-sensitive potassium channels on the plasma membrane (step
3) [72, 73]. Impaired potassium conductance leads to depolarization of the plasma membrane and
subsequent activation of voltage-gated calcium channels [74]. These activated calcium channels
funnel calcium into the cytoplasm of the pancreatic beta-cell (step 4), where they mediate the
release of preformed insulin from the secretory granules through a process of exocytosis (steps 5
and 6) [75]. (Redrawn and modified from Fu et al. [70])
What are the objective methods for assessing insulin resistance?

Assessment of insulin resistance is limited by the lack of a single measure,
which is both accurate and applicable in routine clinical practice.
• The hyperinsulinemic-euglycemic glucose clamp

• Fasting insulin levels
• Glucose to insulin ratio
• The homeostatic model assessment of insulin resistance (HOMA-IR)
• QUICKI (an equation dependent on fasting blood glucose and insulin levels)
• Frequently sampled intravenous glucose tolerance tests
There are other measures of insulin resistance, which are beyond the scope
of this book. The gold standard of measuring insulin resistance is the
hyperinsulinemic-euglycemic clamp. It is, however, labor-intensive and not
applicable in practice [76].
Briefly discuss the phases of insulin secretion in normal physiology
Basal Insulin Physiology
In the fasting (basal) state, insulin is released through an interplay of rapid
5 to 15 minute pulses of insulin release and much longer and slower ultradian
oscillations, which last approximately 80–180 minutes [77].
Postprandial Insulin Physiology
The first phase of insulin secretion involves the release of preformed insu-
lin from storage vesicles. This initial step is vital in reducing hepatic glucose
output after a meal.
The second phase involves a more gradual process that requires the synthe-
sis of new insulin. This phase mediates glucose uptake in skeletal muscle and
adipose tissue [78].
4.3 Glucagonoma
4.3.1 Necrolytic Migratory Erythema
Clinical Features
Necrolytic migratory erythema (NME) is a pathognomonic dermatosis of the gluca-
gonoma syndrome. NME is the presenting feature of the glucagonoma syndrome in
up to 70% of patients [79, 80]. Skin lesions are annular, crusted, erythematous
plaques distributed over mainly intertriginous areas, but may be seen on the extrem-
ities and trunk as well [79]. The lesions may be easily misdiagnosed as other causes
of dermatoses, leading to delayed diagnosis in most patients [80, 81].
Pathophysiology
The mechanisms underlying the clinical manifestation of NME are yet to be clari-
fied. These are, however, some proposed mechanisms.
1. Glucagon, being a counterregulatory hormone in glucose metabolism, promotes

gluconeogenesis, which results in the depletion of protein in the epidermal layer
of the skin. This promotes necrolysis in the epidermis [79].
2. Vitamin B, zinc [82], and fatty acid deficiencies are possible reasons for the simi-
larity between NME and other cutaneous dermatoses associated with these defi-
ciency states. Reduction in levels of glucagon either with tumor resection or
somatostatin analog therapy results in prompt resolution of NME [79].
4.4 Carcinoid Syndrome 89
Table 4.6 Clinical features and underlying mechanisms of some manifestations of the gluca-
gonoma syndrome
Clinical feature Mechanism(s)
Weight loss Glucagon acts on glucagon-like peptide-1 (GLP-1) receptors in central
satiety centers (anorexigenic pathway) to facilitate weight loss [83]
Stimulates energy expenditure by activating thermogenesis in brown
adipose tissue [83]
Cardiomyopathy Glucagon binding to its G-protein-coupled receptor increases intracellular
and heart failure cyclic AMP, which activates protein kinase A (PKA). PKA mediates the
phosphorylation of L-type calcium channels of the cardiomyocyte
sarcolemma. This results in an influx of calcium, which promotes
increased myocardial contraction. Prolonged activation of the sarcoplasmic
reticulum leads to calcium leak, accentuated myocardial contractility, and
eventual cardiac remodeling [84, 85]
Adapted from Albrechtsen [83], Zhang [84], and Demir [85]

What are some other clinical features of the glucagonoma syndrome?
(Table 4.6)
What is pseudoglucagonoma syndrome, and how can it be differentiated from

the classic glucagonoma syndrome?
Pseudoglucagonoma syndrome can present with clinical features of a glucagonoma
in the absence of an alpha-cell tumor of the pancreas. Patients may have either ele-
vated or normal glucagon levels and, in some cases, present with the characteristic
NME rash. Malignancies, chronic liver disease, pancreatitis, and non-tropical sprue
are known causes of pseudoglucagonoma syndrome [86].
4.4 Carcinoid Syndrome
4.4.1 Cutaneous Flushing
Clinical Features
Cutaneous flushing has a mean prevalence of 78%, based on cumulative evidence
from case series [87]. It classically involves the face, neck, and upper chest [88] and
is usually triggered by amine-rich foods, pharmacologic agents, or emotional
stress [89].
Repeated episodes of flushing which tend to be transient (lasting 10–30 minutes)
are characteristic of midgut carcinoids. A longer-lasting duration of flushing (up to
several hours) is more characteristic of foregut carcinoids [88].
Pathophysiology
Cutaneous flushing is caused by various vasoactive mediators, including, but not
limited to, histamine, substance P, and prostaglandins. Interestingly, serotonin
blockers do not improve the pathognomonic flushing associated with carcinoid syn-
drome. This rules out serotonin as the bioactive hormone involved in the cutaneous
flushing of carcinoid syndrome (CS) [87].
The duration of flushing is dependent on the venous drainage of the involved
organ. Foregut NETs bypass initial hepatic metabolism; as such, the vasoactive
amines persist longer in circulation, resulting in a more prolonged period of flush-
ing. Midgut carcinoids, on the other hand, tend to cause flushing in the setting of
hepatic metastases [88].
Associated Endocrinopathies/Conditions That Can Present with Flushing

Pheochromocytomas, Cushing’s syndrome, medullary thyroid cancer, rosa-
cea, and mastocytosis [89]
Clinical Pearl
Nature of Flushing and Underlying Etiology
If flushing is dry (i.e., no concomitant hyperhidrosis), then it is of neuroen-
docrine etiology. If it is wet (i.e., associated hyperhidrosis), then it is most
likely of another etiology other than a neuroendocrine origin (e.g., menopause
or anxiety disorder) [88].
4.4.2 Diarrhea
Clinical Features
There is a variable reported prevalence of diarrhea, ranging from 58% to 100% with a
mean of 78% in multiple case series [87]. Diarrhea tends to be secretory and, as such,
persists even when the patient is fasting. This should be contrasted from non-secretory
diarrhea, which improves during a fast and is usually of other etiology [88].
Pathophysiology
Serotonin is believed to be the active peptide mediating diarrhea in patients with the
carcinoid syndrome. Serotonin promotes an increased secretion of intestinal fluid
and ions in the small intestine, which exceeds the bowels’ net absorptive capacity,
resulting in secretory diarrhea. Telotristat ethyl inhibits the rate-limiting step of
serotonin synthesis by impairing the function of TH-1 (see Fig. 4.3) [87, 92].
Amelioration of the symptoms of diarrhea with this TH-1 inhibitor confirms the role
of serotonin in the diarrhea of carcinoid syndrome [87].
Neuroendocrine Tumor Cellular Model
Tryptophan Tryptophan
Neuroendocrine cell
Tryptophan hydroxylase (TH1 subtype)
5-Hydroxytryptophan
Aromatic L-amino acid decarboxylase
Serotonin (5-HT)
Chromogranin A
secreted along
with 5HT
Aldehyde dehydrogenase
Serotonin (5-HT) 5-HIAA
Monoamine oxidase
Fig. 4.3 Schematic diagram of the biosynthesis of serotonin. Tryptophan hydroxylase 1

(TH-1) is the rate-limiting enzyme in serotonin synthesis by neuroendocrine tumors and is
expressed in various tissues, including the gastrointestinal tract, spleen, thymus, and pineal
glands [90]. Tryptophan is initially transported into the neuroendocrine cell (dashed arrow).
Tryptophan is then converted into 5-hydroxytryptophan by tryptophan hydroxylase-1 enzyme
[87, 91]. The conversion of 5-hydroxytryptophan into serotonin (5-hydroxytryptamine, 5-HT)
occurs in an intermediate decarboxylation step, which requires aromatic L-acid decarboxyl-
ase. 5-HT is packaged along with chromogranin A (a neuroendocrine tumor marker) and is
then released into circulation (dotted arrow). 5-HT undergoes metabolism via various enzy-
matic conversion steps, which result in the formation of 5-Hydroxyindoleacetic acid (5-HIAA)
(an inactive metabolite) (wavy arrow) [87, 91]. (Redrawn and modified from Frazer and
Hensler [91])
4.4.3 Bronchospasm
Clinical Features
Patients present with audible wheezing and confirmatory rhonchi on auscultation.
The prevalence of asthma-like features is, however, less frequent when compared to
diarrhea and cutaneous flushing. The reported prevalence rate based on large case
series is about 3–18% [87]. Carcinoid syndrome can be misdiagnosed as asthma,
and treatment with standard anti-bronchospastic therapies can result in the worsen-
ing of symptoms [93].
Pathophysiology
• Bioactive amines such as serotonin mediate bronchospasm.
• Bronchospasm could also be due to central airway obstruction due to the endo-
bronchial location of pulmonary carcinoids [94].
4.4.4 Cardiac Valvular Lesions
Clinical Features
Carcinoid heart disease (CHD) has a prevalence rate ranging from 11% to 70% [87].
Patients can present with right-sided murmurs (tricuspid and pulmonary valves),
peripheral edema, ascites, and other signs of right-sided heart failure [95].
Pathophysiology
The most cited pathophysiologic mechanism happens to be a serotoninergic-mediated
process. Binding of serotonin to ubiquitous 5-Hydroxytryptamine receptor 2B
(5-HT2B) receptors in the heart explains the clinical manifestations of CHD [87].
Serotonin and other vasoactive amines stimulate 5-HT2B receptors present on
the surface of myofibroblasts. This leads to fibrosis and deposition of myxomatous
substances in the endocardium. Again, telotristat, a novel tryptophan hydroxylase
enzyme inhibitor, retarded CHD in two patients enrolled in the landmark TELESTAR
(Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled
Carcinoid Syndrome) phase III trial, further affirming the role of serotonin in this
condition [87].
Clinical Pearl
Carcinoid Heart Disease
Carcinoid heart disease tends to involve the right side of the heart more
often than the left, due to the inactivation of serotonin in the lung. This leads
to the sparing of the left side of the heart from this vasoactive amine [95].
Indeed, left-sided cardiac involvement occurs in patients’ with coexisting
intracardiac shunts since serotonin can bypass “pulmonary inactivation” to
some degree [87].
Left-sided carcinoid heart disease is also common in the context of a high
burden of disease (overwhelms inactivation systems) or carcinoids located in
the bronchopulmonary tree [95].
4.4.5 Other Cutaneous Manifestations (Pellagra)
Clinical Features
Pellagra is described in many medical texts as a syndrome composed of dermatitis,
diarrhea, dementia, and death. The mnemonic “4Ds,” is well-known by many medi-
cal professionals. It is a photosensitive rash that tends to involve sun-exposed areas
such as the face, neck, and forearms. The rash is characteristically hyperpigmented
and scaly [96].
Pathophysiology
Niacin deficiency occurs as a result of significant shunting of tryptophan from nia-
cin synthesis to serotonin synthesis. This is even more profound in patients with a
sizeable metastatic carcinoid tumor burden [97].
Other cutaneous manifestations of carcinoid syndrome include scleroderma [98],
vitiligo, psoriasis, pityriasis versicolor, and Campbell de Morgan spots (cherry red
angiomas). The exact mechanism is unknown but may be due to the cutaneous
effects of a host of vasoactive substances, including prostaglandins, serotonin, his-
tamine, and bradykinin [99].
Achlorhydria-Induced Gastric Carcinoids
How does achlorhydria result in the formation of gastric carcinoids? (Fig. 4.4)
Loss of negative feedback inhibition of G cells due to 1

achlorhydria, leads to hypergastrinemia and
ECL cell hyperplasia. Ingested Food
Activation of G cells
Carcinoid tumor formation

ECL cell
n
stri
2 Ga
Histamine 3
G cell
Somatostatin Parietal
inhibits G cell 5 cell
+)
acid (H
D cell Gastric
4 dy
An
trum Bo
Fig. 4.4 Schematic diagram of achlorhydria-induced gastric carcinoid formation. Ingestion of

food leads to the activation of the G cells of the stomach (step 1). The G cells present in the gastric
antrum release gastrin after the ingestion of food (step 2). Gastrin, in turn, binds to CCK receptors
present on gastric enterochromaffin-like (ECL) cells (dashed arrow), inducing the release of hista-
mine (step 3). Histamine, in turn, binds to H2 receptors on the cell membranes of gastric parietal
cells inducing the release of hydrochloric acid (step 4). The acidic milieu of the gut is critical in
stimulating the release of somatostatin by the delta-cells of the pancreas (step 5). Somatostatin is
critical in providing negative feedback inhibition of gastrin release from the G cells. In the setting
of achlorhydria as might occur in pernicious anemia (antiparietal cell receptor antibody-mediated
anemia), this negative feedback loop involving somatostatin is impaired. This results in the uncon-
trolled release of gastrin from the G cells [100]. Gastrin, apart from stimulating increased hista-
mine production from gastric ECL cells, also leads to their unchecked proliferation (hyperplasia)
(dashed boxes). This uncontrolled proliferation can lead to gain-of-function mutations and even-
tual tumorigenesis (carcinoid formation) [101]. (Based on Nikou et al. [100])

Which neuroendocrine tumors (NETs) can present with carcinoid syndrome
(CS) in the absence of hepatic metastases?
CS has traditionally been assumed only to occur when bioactive neuropep-
tides bypass hepatic inactivation resulting in exposure of these hormones to
the systemic circulation in patients with gastrointestinal NETs. It is worthy to
note that NETs originating from the ovary, testis, and pancreas can present
with CS in the absence of hepatic metastasis [87].
Define carcinoids and the carcinoid syndrome
Carcinoids/Carcinoid Tumors
These are tumors of cells derived from enterochromaffin cells [102]. The
clinical features of carcinoid tumors or carcinoids were described in 1907 by
Oberndorfer. He reported the following features as being pathognomonic of
carcinoids, i.e., small, undifferentiated, well-defined borders, and slow grow-
ing [103].
Carcinoid tumors are now appreciated as tumors with a malignant predis-
position and were redefined in the year 2000 by the World Health Organization
as neuroendocrine tumors (NETs) [104]. Older references to NETs include
carcinoids, APUDoma, argentaffinoma, and argyrophilic cell carci-
noma [104].
Carcinoid Syndrome
Carcinoid syndrome occurs when carcinoid tumors release various peptides
and vasoactive amines directly into the systemic circulation, especially in the
setting of pulmonary or hepatic metastases [102].
4.5 VIPoma
4.5.1 Dehydration Due to Extrarenal Losses
Clinical Features
Secretory diarrhea is a component of WDHA (watery diarrhea, hypokalemia, hypo-
chlorhydria or achlorhydria) syndrome, a common tetrad observed in patients with
VIPomas. Due to the significant amount of gastrointestinal fluid and electrolyte
losses, patients can develop dehydration with resultant hypotension and acute kid-
ney injury [105].
Pathophysiology
Vasoactive intestinal peptide (VIP) potentiates the effect of cyclic adenosine mono-
phosphate (cAMP) at the level of the intestinal epithelium [106] and through vari-
ous intracellular processes results in increased gut motility, increased gastrointestinal
fluid output, and electrolyte losses [105, 107].
4.5 VIPoma 95
Clinical Pearl
NET differentials of chronic diarrhea:
• VIPoma should always be considered as a pancreatic neuroendocrine man-

ifestation of MEN-1 [108].
• Chronic diarrhea also occurs in Zollinger-Ellison syndrome (gastrinoma)
due to suboptimal intestinal absorption of excessive gastric acid output. In
a study involving over 2000 subjects at the National Institutes of Health
(NIH), fasting serum gastrin levels had a positive correlation with diarrhea
as a presenting feature of Zollinger-Ellison syndrome [109].

What are the biochemical abnormalities in patients with VIPomas? (Table 4.7)
What is vasoactive intestinal peptide (VIP)?
• It is a polypeptide with intrinsic adenylate cyclase-activating proper-

ties [110].
• It is expressed in various tissues, including the central nervous system and
gastrointestinal, respiratory, and genital tracts [110].
Effects of VIP
• Gastrointestinal smooth muscle contraction

• Vasodilation
• Increased gastrointestinal and pancreatic secretions [111]
Briefly discuss the other neuroendocrine tumors (NETs) of the pancreas

apart from VIPomas and glucagonomas
The islets of Langerhans in the pancreas are composed of various cell
types (see Table 4.8). There are several reported pathogenesis models for
NETs [125] well beyond the scope of this book; nonetheless, pancreatic NETs
in simple terms are derived from pancreatic ductal stem cells capable of dif-
ferentiating into the various pancreatic cell subtypes [126, 127].
Table 4.7 Pathophysiologic basis for biochemical abnormalities in VIPoma syndromes

Biochemical abnormality Mechanisms
Hypokalemia 1. Gastrointestinal losses due to diarrhea [105]
2. Secondary hyperaldosteronism due to volume contraction [105]
3. Loss of potassium from enterocytes [105]
Hypercalcemia Hyperparathyroidism due to MEN1 [105]
Non-anion gap metabolic Diarrhea [105]
acidosis
Adapted from Abu-Zaid et al. [105]
Table 4.8 Pancreatic islet cells and their corresponding hormones

Islet cell Hormone
(frequency) produced Effects(s)
Beta-cells Insulin and Insulin increases peripheral glucose uptake and reduces hepatic
(50–70%) amylin gluconeogenesis and glycogenolysis [112, 113]
Amylin slows gastric emptying and stimulates satiety [114]
Alpha-cells Glucagon Stimulates hepatic gluconeogenesis and glycogenolysis.
(20–30%) Stimulates hepatic ketogenesis during a prolonged fast [115,
116]
Delta-cells Somatostatin Inhibits the secretion of insulin, glucagon, and PP [112]
(10%)
PP cells Pancreatic Inhibition of glucagon secretion and acts as a satiety hormone
(2%) polypeptide [112]
Epsilon cells Ghrelin Inhibits insulin release after a glucose load. Stimulates GH
(1%) secretion and is also called the “hunger hormone” [117]
G cells Gastrin Pancreatic gastrin producing cells are present during embryonic
(absent) development but undergo involution in adults. Re-expression of
gastrin can, however, occur in the setting of pancreatic
neuroendocrine tumorigenesis (Zollinger-Ellison Syndrome)
[118]. See hypergastrinemia effects in Table 4.9
EC cells Serotonin Classic features of carcinoid syndrome [123, 124]
(rare)
GH growth hormone, EC enterochromaffin cells, PP pancreatic polypeptide
Adapted from Refs. [112–118, 123, 124]
Table 4.9 Other neuroendocrine tumors of the pancreas

NET Clinical feature(s) (pathophysiology)
Insulinoma Whipple’s triad (hyperinsulinemia-induced reduction in glycogenolysis
and gluconeogenesis. Also, insulin promotes increased glucose uptake in
peripheral tissues) [119]
Weight gain (anabolic effects of insulin) [119]
Gastrinoma Multiple peptic ulcers (hypergastrinemia-mediated increased gastric acid
output) [120]
Secretory diarrhea (increased gastric acid output reduces bowel transit
time) [120]
PPoma (pancreatic Weight loss and abdominal discomfort (stimulation of gastrointestinal
polypeptide enzyme secretions) [121]
tumor)
Somatostatinoma Complicated gallstones (somatostatin reduces gallbladder contractility and
secretions leading to sludging and stone formation) [122]
Steatorrhea (impaired release of bilious fluid from the gallbladder) [122]
Hyperglycemia complications (inhibition of insulin secretion) [122]
The other NETs of pancreatic origin include gastrinoma, insulinoma, somatostati-

noma, and PPoma. See Table 4.9 for the pathophysiologic basis of the clinical fea-
tures of these NETs.
References 97
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Parathyroid Gland and Musculoskeletal
Signs 5
Learning Objectives
1. Recognize the effects of hypercalcemia and hypocalcemia on vari-

ous organs
2. Understand the role of parathyroid hormone (PTH) in osteoclastogenesis
3. Understand the mechanisms underlying the classic Albright hereditary
osteodystrophy phenotype of pseudohypoparathyroidism
4. Understand the pathophysiologic basis for the clinical features of Paget’s
disease of the bone
5. Understand the pathophysiology of vitamin D-resistant rickets and hypo-
phosphatemic rickets
5.1 Hyperparathyroidism
5.1.1 Acute Abdomen
Clinical Features
Hyperparathyroidism can cause a myriad of nonspecific abdominal complaints and
may sometimes present as an acute abdomen. Acute pancreatitis and complications
of hypergastrinemia, e.g., peptic ulcer disease, may result in an acute surgical abdo-
men [1]. Acute pancreatitis has been associated with hyperparathyroidism since it
was first described in the 1950s [1]. A study in 2006 reported a 28-fold increase in
the risk of pancreatitis among patients with hyperparathyroidism when compared to
controls in the general population [2].

https://doi.org/10.1007/978-3-030-49872-6_5
104 5 Parathyroid Gland and Musculoskeletal Signs
Pathophysiology
The gastrointestinal manifestations of hyperparathyroidism are mediated by ele-
vated serum calcium:
1. The association between hyperparathyroidism and hypergastrinemia could be

due to multiple endocrine neoplasia syndrome type 1 or a direct causal relation-
ship between serum calcium and gastrin levels [1].
2. Hypercalcemia due to underlying hyperparathyroidism may cause precipitation
of calcium, which impairs drainage of the pancreatic ducts, leading to obstruction
and inflammation of the pancreas. Also, hypercalcemia facilitates the conversion
of inactive trypsinogen to active trypsin. Trypsin activation in the pancreas sets
off an inflammatory cascade that culminates in acute pancreatitis [1].
Clinical Features
Fragility fractures due to hyperparathyroidism in young subjects have been reported
[3]. The loss of cortical bone mineral density is disproportionately higher than that
of lamellar (cancellous) bone, making the distal third radius an ideal site to evaluate
with bone densitometry in patients with this condition [4].
Pathophysiology
In normal physiology, PTH binds to osteoblasts and activates them through complex
downstream processes. An activated osteoblast’s surface-bound receptor activator
of nuclear factor κ-B ligand (RANK-L) binds to receptor activator of nuclear factor
κ-B (RANK) present on the surface of the osteoclast. This promotes osteoclast acti-
vation and subsequently leads to increased bone resorption. PTH also suppresses
the synthesis of osteoprotegerin (OPG) – a soluble decoy receptor for RANK-L,
which results in a higher number of RANK-Ls being available to bind osteoclast
surface-bound RANK (see Fig. 5.1) [5–7].
Pathophysiology Pearl (Table 5.1)
5.1.3 Band Keratopathy/Cataracts
Clinical Features
Band keratopathy is a clinical finding in various conditions, including hyperpara-
thyroidism. It is a whitish-gray opacification involving the cornea with a predilec-
tion for the nasal or temporal regions of the cornea [12].
Pathophysiology
The underlying mechanism is yet to be elucidated. Hyperparathyroidism-induced
hypercalcemia causes an increase in the solubility product of calcium and
5.1 Hyperparathyroidism 105
Activated osteoblast with it’s

Osteoclast precursor Osteoclast with it’s surface bound RANK-Ligand
surface bound RANK
OPG, a decoy Matured Osteoclast

receptor for
RANK-L
Osteoblast precursors Bone resorption pit
Binding of parathyroid hormone (PTH) to the PTH-1R receptor

on osteoblasts initiates osteoclastogenesis
Fig. 5.1 Schematic representation of PTH-mediated osteoblast-osteoclast interaction. PTH binds

to the PTH-1R (parathyroid hormone 1 receptor) on osteoblasts; this is the first step in the eventual
activation of osteoclasts. Osteoblast surface-bound RANK-L binds to RANK on osteoclasts lead-
ing to differentiation of an osteoclast precursor into a mature osteoclast. Mature osteoclasts present
in bone resorption pits are responsible for the liberation of calcium sequestered in hydroxyapatite
crystals. Osteoprotegerin is a soluble decoy receptor for RANK-L, which provides negative feed-
back inhibition of osteoclast activation [11]. (Redrawn and modified from Ikeda and Takeshita [11])
Table 5.1 Other clinical manifestations of hyperparathyroidism

Clinical finding Mechanism
Pigeon chest (an exaggerated Multiple vertebral fractures [8]
protrusion of the anterior chest)
Shortened distal phalanges PTH-mediated bone resorption [9]
Calciphylaxis (tender, necrotic, and Soft tissue calcification due to a high calcium-phosphate
dark eschar involving the skin) solubility product promotes ischemia and necrosis [10]
Adapted from Sharma [8] Lachungpa [9] and Erdel [10]
phosphate, which leads to precipitation of calcium salts. This reported mechanism

is supported by the presence of calcium salt depositions in Bowman’s membrane of
the cornea [12, 13].
5.1.4 Hypertension
Clinical Features
Hypertension is widely accepted as being associated with primary hyperparathy-
roidism. There is a reported prevalence of 20–80%, most likely due to study signifi-
cant heterogeneity [14]. A large retrospective study involving more than 4000
subjects reported higher all-cause mortality and cardiovascular specific deaths when
patients with primary hyperparathyroidism were compared to matched controls [15].
Pathophysiology
1. Elevated levels of PTH activate the renin-angiotensin-aldosterone system

(RAAS). PTH causes an increase in renin secretion through a complex homeo-
static system involving serum calcium, 25 hydroxyvitamin D, and renal 1ɑ
hydroxylase enzyme [16].
2. Binding of PTH to the PTH-1R receptors on the zona glomerulosa cells stimu-
lates the release of aldosterone. Aldosterone mediates fluid and sodium reten-
tion, which leads to an increase in blood pressure [17].
3. PTH binding to cardiac myocyte surface-bound PTH-1R promotes hypertrophy
of the cardiac myocytes due to an upregulation in gene expression and protein
synthesis [18].
4. Hyperparathyroidism causes vasodilatation of vascular smooth muscle. At high
concentrations of circulating PTH, there is a paradoxical impairment of PTH’s
vasodilatory effects. This is believed to be due to the release of endothelin-1 and
IL-6, which promotes increased collagen formation, endothelial dysfunction,
and eventual impairment of vasodilatation [16].
The Role of the Calcium-Sensing Receptor Activation in Mediating Serum Calcium
Calcium Sensing receptor (CaSR) in the parathyroid gland: CaSR present
on the cellular membrane of the chief cells of the parathyroid gland senses the
level of extracellular calcium and regulates calcium concentration by influ-
encing PTH synthesis [19].
Increasing amounts of extracellular ionized calcium activate the CaSR,
which sets off a cascade of intracellular reactions (phospholipase C- and ade-
nylate cyclase-mediated processes), which increases cytosolic calcium con-
centration. Calcium response elements (CRE) present on the PreProPTH gene
detect the high intracellular calcium and downregulates the transcription and
translation of PTH. The net effect of CaSR activation in the parathyroid gland
is, therefore, a reduction in PTH synthesis [20].
Calcium Sensing receptor (CaSR) in the kidney: The CaSR present on the
basolateral surface of the thick ascending limb of Henle’s loop (TALH) is
activated in the setting of hypercalcemia. Through various intracellular pro-
cesses, there is a downregulation of potassium channels and the sodium-
potassium adenosine triphosphatase (Na-K-ATPase). The necessary luminal
positive electrical gradient required for the absorption of divalent cations such
as magnesium and calcium is therefore impaired. This results in hypercalci-
uria and a reduction in serum calcium. The net effect of CaSR activation in the
TALH is, therefore, a reduction in serum calcium [21].
Familial hypocalciuric hypercalcemia is an autosomal dominant disorder
characterized by a loss of function mutation of the CaSR gene. The CaSR is,
therefore, unable to sense the levels of ionized calcium in the extracellular
5.1 Hyperparathyroidism 107
fluid. At the level of the parathyroid gland, this results in PTH synthesis even
in the setting of hypercalcemia. In the TALH, there is increased calcium con-
servation, which leads to mild hypercalcemia. Most patients with this condi-
tion are asymptomatic but may occasionally develop acute pancreatitis or
cholelithiasis. An important endocrinology dictum requires all patients under-
going evaluation for primary hyperparathyroidism to have an assessment of
24-hour urinary calcium excretion. This will prevent inadvertent parathyroid
gland exploration in patients with hypocalciuria in the setting of PTH-
mediated hypercalcemia [22].
Autosomal dominant hypocalcemia with hypercalciuria (ADHH) is char-
acterized by a gain of function mutation of the CaSR. As was previously men-
tioned, CaSR activation in the chief cells of the parathyroid gland reduces
PTH synthesis and, in the TALH, promotes hypercalciuria. The biochemical
phenotype is, therefore, similar to that of idiopathic hypoparathyroidism, i.e.,
hypocalcemia and hyperphosphatemia, however, with a low but detectable
PTH [23]. Patients with ADHH develop significant suppression of PTH after
calcium supplementation and are generally at an increased risk for nephrocal-
cinosis (see Sect. 5.2.1) [24, 25] (Table 5.2).

What is the classic bone manifestation of primary hyperparathyroidism?
Osteitis fibrosa cystica (OFC) is a rare bone manifestation of severe pri-
mary hyperparathyroidism [26, 27] with a reported prevalence between 2%
and 5% in developed countries [28]. This classic lesion of primary hyperpara-
thyroidism can sometimes present with a pathologic fracture and may be mis-
diagnosed as a malignancy [27, 29]. OFC can be challenging to distinguish
from malignancy, based on radiologic features alone [29].
Histologically it has been described as a focus of extensive bone remodel-
ing, characterized by significant osteopenia, fibrosis, and hemorrhage.
Hemosiderin deposition due to the breakdown of red blood cells gives it the
Table 5.2 The effect of calcium-sensing receptor mutations on PTH secretion and renal calcium
conservation
Pathophysiology PTH Serum calcium
FHH Loss-of-function Increased PTH synthesis Hypercalcemia due to increased
mutation of the CaSR and secretion renal calcium reabsorption [22]
ADHH Gain-of-function Decreased PTH Hypocalcemia due to reduced
mutation of the CaSR synthesis and secretion renal calcium reabsorption [23]
ADHH Autosomal dominant hypocalcemia with hypercalciuria, FHH Familial hypocalciuric
hypercalcemia, CaSR Calcium sensing receptor, PTH Parathyroid hormone
Adapted from Papadopoulou [22] and Roszko [23]
classic brown discoloration, widely referred to as “brown tumors” [27].

Lesions of OFC tend to involve the jaw bone, long bones, ribs, and pelvis [30].
What are the skeletal effects of parathyroid hormone (PTH)?
PTH preferentially reduces cortical (compact) bone mineral density at a
rate higher than that of cancellous (trabecular) bone. The distal radius has the
highest content of cortical bone, making it an ideal site for estimating the
effects of PTH on bone via bone densitometry [31] (Table 5.3).
What are the mechanisms underlying the various causes of hypercalcemia?
Idiopathic Causes of Hypercalcemia

Idiopathic hypercalcemia is characterized by elevated levels of 1,25 dihydroxy vitamin D
(calcitriol), hypercalciuria with or without hypophosphatemia. Mutations in the CYP24A
and SLC34A1 are associated with idiopathic hypercalcemia [40, 41] (Table 5.4).
Table 5.3 Mechanisms of the causes of hypercalcemia

Mechanism Cause of hypercalcemia
Increased osteoclast-mediated bone Hyperparathyroidism [32]
resorption Hyperthyroidism [32]
PTHrp-mediated hypercalcemia [33]
Lithium (increased PTH set point)
Prolonged period of immobilization [32]
Hypervitaminosis A [34]
Increased gastrointestinal calcium Lymphomas [33]
absorption (calcitriol mediated) Tuberculomas [35]
Sarcoidosis [36]
Histoplasmosis [35]
Berylliosis [35]
Silicone-implant (foreign body granuloma) [37, 38]
Williams syndrome (increased sensitivity to vitamin D
metabolites) [39]
Increased renal conservation of Inactivating mutation of the CaSR (familial hypocalciuric
calcium hypercalcemia) [32]
Thiazides [32]
Hypervitaminosis D [32]
CaSR Calcium sensing receptor, PTH Parathyroid hormone, PTHrp Parathyroid hormone-
related peptide
Table 5.4 Inactivating gene mutations recently identified in patients with idiopathic hypercalcemia
Gene Physiological role Clinical features
SLC34A1 This gene encodes the renal Hypophosphatemia results in reduced Fibroblast
(autosomal sodium phosphate growth factor 23 (FGF-23) production (a potent
recessive) transporter, pivotal in renal 1alpha hydroxylase inhibitor). Increased
phosphate conservation calcitriol promotes gut absorption of both
calcium and phosphate [41]
CYP24A This gene encodes the Calcitriol-mediated increased intestinal calcium
(autosomal 24-hydroxylase enzyme and phosphate absorption [40]
recessive) which inactivates calcitriol
Adapted from Schlingmann [40] and Schlingmann [41]
5.2 Hypoparathyroidism 109
5.2 Hypoparathyroidism
5.2.1 T
rousseau’s Sign and Chvostek Sign in the Setting
of Hypocalcemia
Clinical Features
Trousseau’s sign usually manifests as limb spasms, best elicited by placing the
cuff of a sphygmomanometer over the upper arm and inflating it to at least
20 mmHg above the systolic blood pressure [42–44]. It is both sensitive and
specific for clinically significant hypocalcemia [42]. A study reported the preva-
lence of Trousseau’s sign as being up to 94% in patients with biochemically
confirmed hypocalcemia, compared with 1% in patients with normal serum cal-
cium [45].
Dr. Franz Chvostek first reported a case of latent tetany in 1870 [46].
Chvostek’s sign is a unilateral twitching of the facial musculature due to the
tapping of the superficial part of the facial nerve. Percussion of the facial nerve
can either be done anterior to the external acoustic meatus or directly on the
cheek [46].
In contrast to Trousseau’s sign, Chvostek’s sign has poor specificity and sensitiv-
ity for hypocalcemia [42]. A systematic review reported the sensitivity of Chvostek’s
sign as ranging from 0% to 100% with a specificity of 78.8–100% among patients
with hypocalcemia [46].
Pathophysiology
1. Extracellular calcium is critical in maintaining the permeability of sodium chan-
nels on neuronal cells. Hypocalcemia increases the influx of sodium and pro-
motes neuronal excitability due to the lowering of the action potential threshold.
This state of neuromuscular excitability is further aggravated by mechanical per-
cussion of the peripheral part of the facial nerve (Chvostek’s sign) [45].
2. Mild hypoxemia due to ischemia within the soft tissues distal to the inflated
sphygmomanometer cuff causes Trousseau’s sign [45].
5.2.2 Seizures
Clinical Features
Hypocalcemia-induced seizures can be a presentation of hypoparathyroidism,
although any perturbation in calcium homeostasis irrespective of the underlying
cause can result in seizures [47].
Pathophysiology
Hypocalcemia increases neuronal excitability through various effects on multiple
neuronal ion channels, including voltage-gated sodium channels, calcium-activated
potassium channels, and GABA receptors. This ultimately increases excitatory
postsynaptic currents, accounting for the seizures observed in patients with clini-
cally significant hypocalcemia [47].
5.2.3 Hypotension
Clinical Features
A case of hypocalcemia-induced hypotension was reported in a letter published
in the Journal of the American Medical Association (JAMA) in 1972. The patient
had refractory hypotension in the setting of uremic pericardial effusion and
symptomatic hypocalcemia. Interestingly, the correction of hypocalcemia led to
prompt resolution of hypotension before the performance of pericardiocentesis
[48]. There have been other reports of hypocalcemia-induced hypotension since
then [49, 50].
Pathophysiology
1. Calcium plays a critical role in the electrical-contraction-coupling cycle of car-
diac myocytes. Reduced contractility of cardiac myocytes is a possible explana-
tion for a low cardiac output in patients with hypocalcemia [49, 51].
2. QT prolongation due to hypocalcemia also increases the risk of arrhythmia-
induced hypotension [49].
5.2.4 Papilledema
Clinical Features
Papilledema, a rare fundoscopic finding in patients with severe hypocalcemia, is
characterized by a blurring of the optic disk margin [52].
Pathophysiology
Hypocalcemia increases adenylate cyclase activity in the choroid plexus and pro-
motes the secretion of cerebrospinal fluid (CSF). An increase in CSF pressure
around the optic nerve head leads to impaired perfusion to the neuron and eventual
neuronal cell death [53].

What is the pathophysiologic basis of ectopic basal ganglia calcifications
(Fahr’s syndrome) in chronic hypoparathyroidism?
Impaired activity of renal sodium-phosphate transporters results in the
accumulation of inorganic phosphate in the extracellular fluid compartment. It
is worthy to note that phosphate accumulation increases the calcium-phosphate
product, a significant risk factor for ectopic calcification [54]. Ectopic calcifi-
cations may also present as cataracts and nephrolithiasis [55, 56].
5.3 Pseudohypoparathyroidism 111
How does hypocalcemia cause pustular psoriasis?
1. Calcium-sensing receptors present on keratinocytes play an essential role

in the differentiation and proliferation of keratinocytes and other skin
appendages [57].
2. Cell adhesion molecules called cadherins require calcium for their optimal
function; hypocalcemia impairs the function of cadherins and predisposes
patients to pustular psoriasis [58].
There are case reports of pustular psoriasis in patients with primary hypo-
parathyroidism, with the lesions resolving in response to correction of hypo-
calcemia [59, 60]. To further substantiate the role of calcium in the pathogenesis
of pustular psoriasis, calcium channel blockers are a known precipitating
cause of psoriasis. In such scenarios, prompt discontinuation of these agents
resulted in the resolution of skin lesions [61].
5.3 Pseudohypoparathyroidism
5.3.1 Short Stature
Clinical Features
Short stature is a cardinal clinical finding in Albright hereditary osteodystrophy
(AHO). The classic AHO phenotype is characterized by round facies, obesity,
brachydactyly, and short stature [62].
Pathophysiology
Short stature in patients with pseudohypoparathyroidism (PHP) occurs due to rapid
chondrocyte differentiation leading to premature closure of the growth plate and
eventual stunting of growth [63].
Impaired activity of Gsɑ affects PTH-mediated signaling in chondrocytes. This
is even more profound during puberty and accounts for the short stature observed in
patients with pseudohypoparathyroidism [64].
PTH binds to the PTH-1R receptor, which leads to dissociation of Gsɑ
from the heterotrimeric G protein. Gsɑ subsequently activates adenylyl
cyclase (AC). This is followed by AC-mediated conversion of ATP to cyclic
AMP. The second messenger, cyclic AMP activates protein kinase A
(PKA), which subsequently phosphorylates various target proteins involved

in transcription and translation of several downstream cyclic AMP-
responsive genes. A loss-of-function mutation involving the gene encoding
the alpha subunit of the Gs protein, i.e., GNAS gene, results in pseudohy-
poparathyroidism [64].
Resistance to PTH action in the proximal renal tubule leads to hypocalce-
mia and hyperphosphatemia, a biochemical profile akin to what is observed
in patients with isolated hypoparathyroidism. Patients, however, have a para-
doxical elevation in serum PTH, hence the name, pseudohypoparathyroid-
ism [64].
5.3.2 Obesity
Clinical Features
Most adults with PHP1A have a body mass index (BMI) >25 kg/m2 [64]. The
reported prevalence of obesity is more than 66%, higher than the 32% prevalence
rate reported for the general population [65].
Pathophysiology
1. Melanocortin signaling pathways that regulate satiety are dependent on Gsɑ
activity. Gsɑ activity is defective in PHP, which leads to impaired satiety, ulti-
mately leading to obesity [64].
2. There are β adrenergic receptors in adipose tissue, which presumably play a
role in lipolysis. Downstream signaling of these receptors is dependent on
Gsɑ activity; as such, decreased fat mobilization occurs in patients with
PHP [66].
3. Growth hormone (GH) deficiency is a contributory factor as well since growth
hormone-releasing hormone (GHRH) signaling is dependent on the stimulatory
G-protein, Gsɑ [65].
5.3.3 Brachydactyly
Clinical Features
The characteristic skeletal feature of PHP happens to be shortening of the metacar-
pals and metatarsals. This skeletal change tends to involve the fourth and fifth meta-
carpals and metatarsals [64, 67].
Pathophysiology
Impaired activity of Gsɑ affects parathyroid hormone-related peptide (PTHrp)-
mediated signaling critical in chondrocyte proliferation in the growth
plate [64].
5.3 Pseudohypoparathyroidism 113
5.3.4 Dental Manifestations
Clinical Features
Multiple dental abnormalities including delayed or even failed eruption of the teeth,
blunting of the roots, hypodontia, and ankylosis [64, 68]. Patients should be referred
to dentists for optimal care of the teeth [68].
Pathophysiology
Downstream signaling for PTH-1R in the tooth is affected due to impaired Gsɑ
activity. This highlights the vital role of PTH in mediating tooth maturation and
mineralization [64].
Pseudopseudohypoparathyroidism (PPHP)
This is a unique clinical and biochemical subtype of inactivating PTH/
PTHrp signaling disorders (iPPSDs). The new iPPSD nomenclature acknowl-
edges the spectrum of clinicopathologic phenotypes in patients with pseudo-
hypoparathyroidism [69].
The Guanine nucleotide binding protein, alpha stimulating (GNAS) gene
is critical in the transcription of the stimulatory G protein (Gsα). Gsα in most
tissues is expressed in a biallelic fashion, i.e., there are distinct paternal and
maternal alleles. The clinical and biochemical features are, therefore, depen-
dent on the parent of origin of the mutant allele [70].
The paternal Gsα gene in normal physiology is not expressed in the proxi-
mal renal tubule, pituitary gland, and gonadal tissue. It, therefore, plays no
role in renal electrolyte (calcium and phosphorus) handling or activation of
Gsα-coupled receptors such as luteinizing hormone (LH), parathyroid hor-
mone (PTH), and thyroid-stimulating hormone (TSH). An affected child who
inherits a mutated Gsα gene from a father will, therefore, present with PPHP
(i.e., short stature with no apparent biochemical or hormonal perturba-
tions) [70].
Maternal Gsα gene expression, on the other hand, ultimately determines
the downstream effects of Gsα-coupled receptors, including LH, PTH, TSH,
and GHRH. Also, unlike the paternal allele, the maternal allele is expressed in
pituitary, renal, and gonadal tissues. A mutation in the maternal Gsα gene,
therefore, results in the classic pseudohypoparathyroidism type 1A (PHP1A)
phenotype (see Table 5.5) [71, 72].
Pseudohypoparathyroidism type 1B (PHP1B) occurs when there is an
imprinting (methylation) defect in the maternal GNAS gene. It is worthy to
note that, in contrast to PPHP and PHP1A, there is no mutation in the Gsα
gene [73].
Table 5.5 Clinical and biochemical features of some forms of iPPSD

iPPSD AHO Other hormone resistance states PTH resistance
PPHP Present Absent Absent [74, 75]
PHP1A Present Present Present [71, 72]
PHP1B Absent Infrequent Present [73]
PHP1C Present Present Present [62]
iPPSD inactivating PTH/PTHrp signaling disorders, AHO Albright’s hereditary osteodystrophy
Other hormone resistance states LH and TSH resistance
PTH resistance low calcium, high phosphorus and a paradoxically high PTH
PHP1C Pseudohypoparathyroidism type 1C
Adapted from Refs. [62, 71–75]

What is the classic phenotype of AHO?
Dr. Fuller Albright first described Albright hereditary osteodystrophy
(AHO) in 1942. The classic phenotype has the following features, brachydac-
tyly, short stature, and round facies. The classification system for this group
of inactivating PTH/PTHrp signaling disorders is based on the presence or
absence of the classic AHO phenotype and Gsɑ activity in response to exog-
enous PTH administration [69].
What are the other endocrinopathies which might be associated with some
forms of pseudohypoparathyroidism?
• Resistance to the effects of TSH at the level of the thyroid gland results in
hypothyroidism.
• Gonadotropin resistance leading to delayed puberty, oligomenorrhea, and
cryptorchidism.
• Growth hormone-releasing hormone (GHRH) resistance causes GH
deficiency.
• Prolactin deficiency.
Interestingly, ACTH, CRH, and vasopressin action are not affected in iPPSDs,
because both the maternal and paternal copies of the GNAS gene are expressed
in these tissues, as such a mutation in one parental allele does not result in hor-
monal defects since the normal parental allele is present. This highlights the tis-
sue-specific expression of both maternal and paternal copies of the gene [76].
5.4 Paget’s Disease of Bone
5.4.1 Fractures and Bone Deformity
Clinical Features
Patients with Paget’s disease of bone (PDB) have a significant clinical fracture prev-
alence ranging between 10% and 30%. They may either be incomplete fissure frac-
tures involving part of the cortical bone or complete transverse fractures. Fractures
5.4 Paget’s Disease of Bone 115
typically affect weight-bearing bones, which have a pre-existing deformity [77].

Bowing deformities tend to involve weight-bearing long bones in the lower extrem-
ity [78]. Patients may also present with skull and facial deformities such as frontal
bossing [79].
Pathophysiology
PDB starts as a focal area of increased osteoclastogenesis (bone resorption), which
is then followed by rapid bone formation, a process that leads to improperly formed
bone (woven bone). The affected bones are, therefore, unable to withstand mechani-
cal stress and, as such, are prone to deformities and fractures [79]. The etiology of
the insult, which sets off the inevitable skeletal changes, is incompletely understood
[80, 81].
5.4.2 Congestive Heart Failure
Clinical Features
Heart failure can occur in patients with extensive pagetoid changes in the bone; it is,
however, an uncommon presentation of PDB [80, 82].
Pathophysiology
PDB causes high output cardiac failure because increased vascularization of bones
affected by pagetic changes results in a reflex increase in stroke volume. This leads
to cardiac remodeling and eventual decompensation (Frank-Starling law of the
heart) [83].
5.4.3 Sensorineural Hearing Loss
Clinical Features
Sensorineural hearing loss (SNHL) is a known neurologic complication of PDB
involving the skull [84]. The classic Weber and Rinne tests, which involve the use
of a tuning fork, can be used at the bedside to differentiate conductive from
SNHL. The tests require the use of a 512 Hz (Hertz) tuning fork in assessing both
bone and air conduction [85].
A recent systematic review evaluated the accuracy of the Weber and Rinne
tests. It showed wide variability in the sensitivity and specificity of these tests
since adherence to testing protocols were operator dependent [86]. We will refer
readers to other clinical examination texts for the standard protocol of these tun-
ing fork tests.
Interestingly it is reported that Ludwig van Beethoven suffered from PDB and
that his SNHL may have influenced some of his musical compositions [87].
Pathophysiology
A double-blind prospective study in 2004 involving 64 subjects with Paget’s
disease of the skull evaluated the auditory thresholds and auditory brainstem
responses. The extent of pagetoid involvement of the temporal bone, measured
by computed tomography, was compared to objectively measured levels of

hearing loss. There was a statistically significant positive correlation between
the extent of pagetoid involvement of the cochlear capsule and the degree
of SNHL.
Pagetoid involvement of the cochlear capsule is the cause of SNHL and not the
previously reported mechanism of auditory nerve compression [84].

What are the other cardiac manifestations of Paget’s disease, apart from high
output cardiac failure?
Aortic stenosis, atherosclerosis, and endocardial calcifications [77]
How are patients with PGD more likely to present?
Up to 70% of patients are asymptomatic due to a prolonged period of
latency in PGD. In symptomatic patients, a dull and deep aching pain involv-
ing pagetic bones is a more likely complaint at presentation [88].
5.5 ereditary Vitamin D-Resistant Rickets Type 2

H
(HVDRR-II)
5.5.1 Rickets
Clinical Features
Dr. Fuller Albright reported a case of vitamin D-resistant rickets in 1937. He postu-
lated the underlying cause of rickets in his case report as being due to “an intrinsic
resistance to the anti-rachitic action of vitamin D” [89]. The clinical features of
rickets occur at a young age [90, 91] and classically manifests before fusion of the
growth plates [92]. Rickets tends to affect the distal forearms, knees, and costochon-
dral regions [93]. The typical features include swelling of the costochondral joints
(rachitic rosary), widening of the wrist joint, and an exaggerated genu varum in
children [94].
Pathophysiology
HVDRR-II is an autosomal recessive condition due to a mutation in the vitamin D
receptor gene, which results in impaired activity of vitamin D due to end-organ
resistance to the action of 1,25-dihydroxyvitamin D. Patients develop hypocalcemia
with or without hypophosphatemia [95].
There is another form of vitamin D-dependent rickets, which is due to a mutation
in the gene encoding the renal 1-alpha-hydroxylase enzyme [96].
Transformation of cartilage into bone involves a cycle of laying down of
cartilage matrix, its resorption, and replacement by series of woven bone and
then the eventual formation of mature lamellar bone. Mineralization of newly
5.6 X-Linked Hypophosphatemic Rickets 117
Table 5.6 Pathophysiologic basis of other clinical features of rickets

Clinical feature Underlying cause
Decreased linear growth Impaired mineralization in the growth plate [94]
Tetany Hypocalcemia [94]
Hypotonia Hypocalcemia [94]
Recurrent respiratory Hypotonia involving respiratory musculature results in an inability to
infections clear airway secretions [94]
Adapted from Sahay and Sahay [94]
formed osteoid is defective due to lack of calcium and phosphorus [92], which
results in the formation of defective bones unable to withstand mechanical
stress. This leads to the typically exaggerated genu varum seen in rickets [93]
(Table 5.6).

How can HVDRR-II be differentiated from vitamin D resistance due to 1ɑ
hydroxylase deficiency, biochemically?
Low serum calcium and phosphate with high parathyroid hormone levels
occur in both conditions. 1,25 hydroxyvitamin D3 is, however, low in 1ɑ
hydroxylase deficiency but high in HVDRR [91].
What are the roles of the parathyroid gland, kidneys, and bone in calcium
and phosphate homeostasis?
1. PTH promotes a net increase in serum calcium and decrease in serum

phosphorus [97].
2. 1,25-Dihydroxy vitamin D3 promotes a net increase in both serum calcium
and phosphorus [98].
3. FGF-23 promotes a net decrease in serum phosphate [99]. Refer to Fig. 5.2.
5.6 X-Linked Hypophosphatemic Rickets
5.6.1 Short Stature
Clinical Features
Patients with X-linked hypophosphatemic rickets (XLHR) have short stature, with
the length of the lower limbs more significantly affected than that of the trunk. This
results in an abnormal upper segment to lower segment ratio (lower segment = from
the top of the symphysis pubis to the heel; upper segment = height minus lower seg-
ment) [101]. Early treatment with oral phosphate supplementation and calcitriol
improves growth rates and other skeletal outcomes [102].
Parathyroid
gland
Calcium
Phosphorus + – Calcitriol
FGF23
PTH
Calcium
Calcitriol
PTH
Ca2+ P Ca2+ + Phosphorus
FGF23 Bone
Ca2+ P P
– ??
1,25(OH)2vitD (Calcitriol)
Low phosphorus
+ – FGF23 + Stimulatory serum factor
PTH
Kidney – Inhibitory serum factor
Fig. 5.2 The role of various hormones in calcium and phosphorus homeostasis. PTH facili-
tates the leaching of calcium from bone by mediating the activation of osteoclasts. In the
kidney, PTH stimulates renal 1ɑ hydroxylase activity (increased calcitriol production), which
ultimately promotes reabsorption of calcium in the distal nephron and inhibits phosphate
conservation in the proximal renal tubules [97]. 1,25-Dihydroxy vitamin D3 (active vitamin
D) has various effects, including stimulation of osteoclast differentiation (bone), calcium
conservation (distal renal tubule), phosphate conservation (proximal nephron), and calcium
and phosphate reabsorption in the small intestine [98]. FGF-23 inhibits both phosphate con-
servation by the proximal renal tubule and 1ɑ hydroxylase activity in the proximal renal
tubule [99]. Hypophosphatemia and intravenous iron infusions have been reported as factors
that inhibit the gene encoding FGF-23 [100]. Solid arrow from an organ (parathyroid gland,
bone, and kidney) represents the active secretion of a hormone. Dotted arrow represents the
effects of the designated hormone on serum calcium and phosphate levels. (Based on
Goltzman et al. [97])
Pathophysiology
1. Growth plate activity is highest around the knees and determines the final skel-
etal height. Impaired endochondral bone formation due to significant hypophos-
phatemia accounts for a disproportionate shortening of the lower limbs compared
to the upper limbs [103].
2. Mechanical loading of the lower extremities leads to the characteristic bowing of
the legs and subsequent shortening of the patient’s final height [103].
5.6 X-Linked Hypophosphatemic Rickets 119
5.6.2 Dental Abscess
Clinical Features
Unprovoked dental abscesses occur in the absence of trauma or dental caries. Active
dental surveillance to optimize oral hygiene is recommended, and there are no
active therapies to prevent this complication [104].
Pathophysiology
Phosphate forms an essential component of hydroxyapatite crystals (mineralized
bone). Evidence suggests that patients with XLHR have poor mineralization of the
dentine layer of the tooth situated below the enamel. Eventual expansion of the pulp
cavity leads to a breach in this protective dentine layer and predisposes patients to
dental infections [105].

What is the role of fibroblast growth factor 23 (FGF-23) in calcium and phos-
phate homeostasis?
1. FGF-23 is a phosphaturic hormone secreted by osteocytes [105], which

increases phosphate excretion at the level of the proximal tubule by inhib-
iting the expression of sodium-phosphate transporters needed in phosphate
conservation [101].
Also, it decreases 1ɑ hydroxylation activity and potentiates 24ɑ hydrox-
ylation of vitamin D, leading to low levels of serum calcitriol [106, 107].
In theory, the physiologic effect of FGF-23 is a reduction in both renal and
gastrointestinal phosphate absorption [108].
What is the underlying cause of X-linked hypophosphatemia (XLH)?

A mutation in the PHEX (phosphate-regulating gene with homologies to
endopeptidase on the X chromosome) gene results in impaired expression of
a peptidase involved in the inactivation of FGF-23. This promotes increased
circulating levels of FGF-23, which causes hypophosphatemia and reduced
bone mineralization [106].
There is a new FDA-approved monoclonal antibody for the treatment of XLH
called burosumab. Burosumab binds circulating intact FGF23 and, thereby,
blocks its biologic effects in target tissues. It improves renal tubular phosphate
conservation and serum phosphorus levels and promotes linear growth [108].
An important differential diagnosis of XLH is Tumor-induced osteomalacia
(TIO). TIO is caused by increased production of FGF-23 by mesenchymal
tumors. FGF-23 causes reduced insertion of sodium phosphate channels in the
renal tubules, which results in increased urinary loss of phosphorus. Besides,
there is decreased production of calcitriol due to FGF-23-mediated inactiva-
tion of 1ɑ hydroxylase activity (see Fig. 5.3). Additionally, affected patients
develop poor bone mineralization due to significant hypophosphatemia [109].
+ Stimulatory action of FGF23

Vitamin D3
– Inhibitory action of FGF23 25-hydroxylase
25-OH-D3
24α-hydroxylase 1α-hydroxylase
24,25-OH-D3 1,25-OH-D3 25-OH-D3
Inactive + Active –
FGF-23
–
Renal phosphate conservation Sodium-phosphate
transporter
Fig. 5.3 The role of FGF-23 in positive and negative feedback pathways involved in vitamin D
homeostasis. Vitamin D3 undergoes an initial hydroxylation step in the liver and is then transferred
to the kidneys for 1 alpha hydroxylation (dashed arrow) [97]. The conversion of 25 hydroxyvita-
min D3 to its active form, i.e., 1,25-dihydroxy vitamin D3, is inhibited by FGF-23. Also, FGF-23
facilitates the inactivation of active vitamin D into its inactive form, i.e., 24,25 dihydroxy vitamin
D3, by potentiating the action of the 24-hydroxylase enzyme. The net effect is a reduction in the
production of active vitamin D in the presence of FGF-23 [106, 107]. Furthermore, FGF-23 pro-
motes renal phosphate loss [101]. (Based on Goltzman et al. [97])
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Reproductive Organ Signs
6
Learning Objectives
1. Discover the pathophysiologic mechanisms underlying the classic Turner’s

syndrome phenotype
2. Recognize the signs of hyperandrogenism seen in polycystic ovarian syn-
drome (PCOS)
3. Understand the hypothalamic-pituitary-gonadal axis
4. Identify the clinical features of the female menopausal state
5. Identify hormone resistance states involving estrogens and androgens and
their unique clinical manifestations
6.1 Turner’s Syndrome
6.1.1 Short Stature
Clinical Features
Short stature is a measured height of less than −2.5 standard deviations below the
mean for the general population. It is a common clinical finding in patients with
Turner’s syndrome (TS). In a recent study involving 176 girls with Turner’s syn-
drome, the midparental height was sensitive and served as a valuable tool in assess-
ing short stature in children [1]. Growth failure during childhood results in a
predictable short stature in adult life. The average height of women with untreated
TS is about 4 feet, 8 inches [2].

https://doi.org/10.1007/978-3-030-49872-6_6
128 6 Reproductive Organ Signs
Pathophysiology
Mutations in the SHOX gene (short-stature homeobox-containing gene), which is
present on the short arm of the X chromosome, is responsible for the short stature
observed in patients with TS. There are two inherited copies of the SHOX gene in
normal women; one is on the active and the other on the inactive copy of the X
chromosome. This allows the gene to escape the effects of lyonization. Furthermore,
genetic males also possess the SHOX gene on their Y chromosomes. The ultimate
determinant of height is, therefore, dose-dependent with regard to the SHOX gene
[3]. SHOX gene is expressed in mesenchymal tissue and is responsible for chondro-
blast development in long bones of the upper and lower extremities. A single
remaining copy of the SHOX gene (haploinsufficiency), as occurs in TS, is unable
to facilitate the growth of long bones. This accounts for the eventual short stature of
patients with Turner’s syndrome [4, 5].
1. Mosaics 45,XO with (46,XX) may present with normal puberty and spon-
taneous menarche due to less severe ovarian defects, but almost univer-
sally have a short stature due to SHOX gene insufficiency [6].
2. TS patients with SHOX gene “overdosage,” may present with tall stature.
The reasons for this include the following:
• There is sustained growth of long bones due to an excess of this important

osteogenic factor, i.e., SHOX gene.
• Gonadal dysgenesis leads to hypoestrogenemia and delayed fusion of the
epiphyseal plate, leading to continuous growth. It is worthy to note that
estrogen is critical in promoting fusion of the growth plate, a step required
for cessation of vertical growth.
Interestingly the effect of the SHOX gene in determining final height is

much more significant than hypoestrogenemia. Therefore, TS patients with
overdosage of the SHOX gene will continue to grow even after initiating
estrogen replacement therapy [3].
Clinical Pearl
What are the musculoskeletal monitoring recommendations for patients
with TS?
1. Examine annually for scoliosis or even six-monthly, if a patient is on

growth hormone supplementation therapy [7].
2. Monitor bone mineral density every 5 years when patients are on estrogen
replacement therapy [7].
6.1 Turner’s Syndrome 129
6.1.2 Webbed Neck and Lymphedema
Clinical Features
Patients with TS have a characteristic webbed neck (pterygium colli). Swelling of the
hands and feet is also noted in infancy and facilitates early diagnosis of this condition [8].
Pathophysiology
Hypoplasia or aplasia of the lymphatic system causes impaired lymphatic drainage.
Cervical lymphedema manifests clinically as a webbed neck [8].
Clinical Pearl
What are the screening recommendations regarding hypothyroidism and
celiac disease in patients with TS?
1 . Annual screening for hypothyroidism [7].

2. Celiac screening is recommended every 2 years [7].
6.1.3 Hypertension
Clinical Features
Arterial hypertension has a reported prevalence of 13–58% in adult patients with
TS. This confers a higher than fourfold increase in the risk of hypertension-related
mortality in this patient population [9].
Pathophysiology
1. TS patients have significant metabolic comorbidities, including obesity, endothelial
dysfunction, and hyperlipidemia, factors that increase the risk of hypertension [9, 10].
2. Activation of the renin-angiotensin-aldosterone axis has been proposed as a pos-
sible cause of hypertension in patients with TS [9].
3. Coarctation of the aorta and abnormal aortic arch morphology are contributing
factors [9, 10].
4. Congenital renal abnormalities, e.g., horseshoe kidneys, predispose TS patients
to recurrent infections, renal fibrosis, and secondary hypertension [9].
Clinical Pearl
What are the cardiovascular screening recommendations for patients with TS?
1. Annual assessment of blood pressure, glycated hemoglobin, and fasting

lipid profile [7].
2. In patients older than 16 years of age, annual transthoracic echocardiography,
or cardiac MRI, is recommended due to the risk of aortic root dilatation [7].
6.1.4 Melanocytic Nevi
Clinical Features
Melanocytic nevi have a reported prevalence of 25–100%. These pigmented nevi
tend to increase in size and number over time, with an increased risk of malignant
transformation when they reach a size greater than 5–10 mm [11].
Pathophysiology
The pathophysiologic basis of melanocytic nevi (MN) is multifactorial. Genetics,
sunlight exposure, and sex hormones are possible reasons for MN formation. The
mechanisms involved in the development of MN, however, remain unclear at this
time [11, 12].
6.1.5 Sexual Infantilism
Clinical Features
Girls with TS at the time of puberty are usually amenorrheic with no secondary
sexual characteristics; however, those with mosaicism may develop primordial fol-
licles in their ovaries, leading to estrogen-mediated breast development and hypo-
menorrhea [6].
Pathophysiology
The degree of gonadal dysgenesis is due to chromosomal pairing failure involving
a region of the long arm of the X chromosome (Xq13-q26) during meiotic prophase.
The greater the pairing anomaly, the more severe the extent of eventual gonadal
dysgenesis and hypoestrogenemia [13].

Why are patients with Turner’s syndrome at risk for diabetes mellitus?
Haploinsufficiency of the X chromosome affects genes encoding critical
proteins involved in glucose sensing (glucokinase) or target tissue effects of
insulin (hepatic nuclear factors). This results in impaired insulin secretion in
response to hyperglycemia.
These defects contribute to progressive weight gain (due to hyperinsu-
linemia), which promotes peripheral insulin resistance. Patients progress
through a stage of glucose intolerance before developing overt type 2 diabetes
mellitus [14].
Which endocrinopathies are common in patients with Turner’s syndrome?
Ovarian failure, autoimmune thyroid disease, type 1 or 2 diabetes, dyslip-
idemia, and osteopenia [15]
6.2 Polycystic Ovarian Syndrome 131
6.2 Polycystic Ovarian Syndrome
6.2.1 Hirsutism
Clinical Features
Hirsutism is defined as the presence of terminal, pigmented hair in a male pattern
distribution. It is a common dermatologic manifestation of polycystic ovary syn-
drome (PCOS) with a reported prevalence of 50–70% [16].
The original assessment of hirsutism using the Ferriman-Gallwey score assigned
a grade ranging from 0 to 4, depending on the presence and extent of terminal hair
distribution involving 11 anatomic sites [17].
The forearm and lower leg have been excluded in the modified score since
terminal hair growth in these areas is inconsistently associated with hyperan-
drogenemia. The modified Ferriman-Gallwey score objectively assesses nine
anatomic regions for evidence of terminal hair growth [18]. A modified
Ferriman-Gallwey score of ≥8 is consistent with clinically significant hirsut-
ism [19, 20].
Pathophysiology
Circulating androgens are responsible for hirsutism, although the degree of hirsut-
ism is not necessarily determined by the severity of hyperandrogenemia. This has
been attributed to interindividual differences in the response of hair follicles to
androgens [16] (see Sect. 1.1.5).
Hirsutism, like acne, and male pattern alopecia are dependent on the local abun-
dance of 5α-reductase (which reduces testosterone to active dihydrotestosterone) in
the pilosebaceous unit [21].
The local concentration of 5α-reductase in the skin varies by ethnicity. For exam-
ple, hirsutism tends to be more common in women of Mediterranean background
and less frequent and milder in women of East Asian or Native American back-
ground [22–24].
Endocrine Conditions Associated with Virilization
• Adrenal tumors.
• Cushing’s syndrome.
• Classic and nonclassic congenital adrenal hyperplasia.
• Hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN
syndrome).
• Ovarian hyperthecosis.
• Ovarian tumors.
• The features of virilization include acne, male pattern baldness, deep male
voice, and clitoral enlargement [25].
Clinical Features
Acanthosis nigricans (AN) is a classic dermatologic manifestation of PCOS and
other endocrinopathies associated with insulin resistance. It is a velvety, dark, and
plaque-like skin lesion which has a predilection for flexural areas such as the neck
and axillary regions. 50% of patients with the classic obese PCOS phenotype have
AN [26].
Pathophysiology
Hyperinsulinemia stimulates keratinocytes and fibroblasts directly, leading to their
proliferation [26]. Additional mechanisms accounting for hyperinsulinemia-induced
hirsutism have been described earlier (see also Sect. 4.1.1).
6.2.3 Acne
Clinical Features
Acne is a common skin manifestation of PCOS, with a highly variable prevalence,
based on ethnicity. Asian Indians have the highest prevalence, with the lowest being
among Pacific Islanders [27].
Pathophysiology
1. Hyperinsulinemia in the setting of PCOS potentiates the excretion of sebum
through the effects of insulin acting on IGF-1 receptors present on sweat
glands [16]. Accumulation of sebum establishes a milieu conducive for the
proliferation of Propionibacterium acnes and eventual formation of come-
dones [28].
2. Dihydrotestosterone (an androgen) binds to its receptors on sweat glands and
influences their output of sebum, as well [29]. Interestingly, the severity of
acne is not dependent on the degree of hyperandrogenemia and may be due to
the variable sensitivity of pilosebaceous units to circulating androgens [30].
6.2.4 Obesity
Clinical Features
The prevalence of obesity in patients with PCOS is between 40 and 80%. In contrast
to women outside the USA, PCOS patients in the USA have relatively higher body
mass indexes (BMIs) [31].
Pathophysiology
Circulating levels of androgen influence the distribution of body fat. Men have
higher levels of testosterone and, as such, have a higher concentration of fat in the
central abdomen compared to the hips or lower body.
6.2 Polycystic Ovarian Syndrome 133
Women with PCOS have high levels of testosterone, which changes the typical
gynoid fat distribution into an android one. This is the reason for increased central
or visceral adiposity [31].
More recent evidence refutes this hypothesis in women with PCOS. Although
obese and nonobese women with PCOS had high levels of androgens compared to
matched controls without PCOS, there was no difference in visceral adiposity
between these two groups of PCOS subjects in this study [32]. The mechanisms
remain incompletely understood at this time.
Pathogenesis of PCOS (Fig. 6.1)
1
Increased activity of the
GnRH pulse generator
4 Elevated testosterone blocks estrogen-mediated

negative feedback inhibition of GnRH activity
LH
FSH
5 Increased adrenal androgen production
Hyperinsulinemia
LH
FSH
2 TESTOSTERONE ESTROGENS
3 Low SHBG production

Theca cell Granulosa cell
Fig. 6.1 Schematic representation of the pathophysiologic basis of PCOS. Step 1: Increased activity
of the GnRH pulse generator stimulates central gonadotrophs and results in an increase in luteinizing
hormone (LH) with a concomitant decrease in follicle-stimulating hormone (FSH) [33, 34]. Step 2:
LH stimulates theca cells of the ovaries to produce testosterone. Low FSH, on the other hand, results
in less stimulation of the granulosa cell-mediated conversion of theca cell-derived testosterone into
estrogens [35]. Step 3: Reduced levels of circulating sex hormone-binding globulin (SHBG) [36]
worsen the degree of hyperandrogenemia, as well. Both hyperandrogenemia and hyperinsulinemia
impair hepatic SHBG synthesis [37], and since SHBG binds more avidly to estrogens than it does
androgens, low levels of circulating SHBG increase the free androgen to free estrogen ratio. Step 4:
Hyperandrogenemia impairs negative feedback effects of estrogen on the pituitary gonadotrophs,
which results in unimpaired LH release and maintenance of a vicious cycle of hyperandrogenemia
[38]. Step 5: Adrenal-derived androgens play a contributory role, although the mechanisms are
incompletely understood [39]. (Redrawn and modified from Chaudhari et al. [34])

What are the reasons for insulin resistance in patients with PCOS?
1. Post-insulin to insulin receptor binding defects contributes to insulin resis-

tance in patients with PCOS [40].
2. Reduction in glucose transporter 4 (GLUT-4) receptors in adipose tissue
leads to reduced glucose uptake [40].
3. Persistent hyperglycemia promotes rebound and persistent hyperinsu-

linemia. A prolonged period of hyperinsulinemia leads to progressive beta-
cell dysfunction and death [40].
4. Androgens may play a modest role in insulin resistance, although elevated
serum androgens alone cannot explain insulin resistance in PCOS [40].
5. Comorbid dyslipidemia contributes to lipotoxicity-induced insulin resis-
tance [41].
6. There is also an increase, partially obesity-related, in inflammatory adipo-
kines such as tumor necrosis factor alpha (TNF-α), which induces insulin
resistance. Furthermore, there is a concomitant decrease in the insulin-
sensitizing adipokine, adiponectin [42, 43].
What conditions should be ruled out as part of the evaluation of PCOS?

Hypothyroidism, prolactinoma, nonclassic congenital adrenal hyperpla-
sia, Cushing’s syndrome, androgen-secreting tumor, and acromegaly. Also, it
is prudent to rule out pregnancy, primary ovarian insufficiency, or functional
hypothalamic amenorrhea in select patients based on the clinical presentation
[44]. It should go without saying that pregnancy must always be excluded in
any woman of reproductive age with amenorrhea.
6.3 Male Hypogonadism
6.3.1 Decreased Testicular Volume
Clinical Features
Testicular volume (TV) is a valuable surrogate marker of testosterone production
and spermiogenesis function [45]. Decreased testicular volume is associated with
male hypogonadism and is more likely in primary hypogonadism compared to sec-
ondary hypogonadism [46].
The Prader orchidometer is an objective means of assessing testicular volume
clinically. A cross-sectional study of over 400 subjects showed a strong, statistically
significant positive correlation between clinical assessment of testicular volume
using an orchidometer and ultrasound estimates [47].
6.3 Male Hypogonadism 135
Considerable tact and excellent reassurance skills are essential when using an
orchidometer in order to prevent the patient from feeling inadequate.
A recent study evaluated the association between serum testosterone levels and
adult testicular volumes in patients with either primary or secondary hypogonad-
ism. A testicular volume of >30 cc, estimated by an orchidometer combined with
BMI measurements, had a high predictive value in assessing if testosterone levels
were optimal. TV combined with BMI had a sensitivity and specificity of 85.3%
and 86.5%, respectively [45].
Pathophysiology
More than 90% of the testicular volume is accounted for by the quantity of
sperm-producing seminiferous tubules. Testicular size is, therefore, predictive
of spermiogenesis potential. Leydig cells do not contribute substantially to the
final testicular volume; therefore, perturbations in seminiferous tubule func-
tion can result in a significant reduction in testicular size independent of Leydig
cell function [48].
FSH and intratesticular testosterone promote the development of Sertoli cells
(SCs), which are present on the epithelial cells of the seminiferous tubules. LH, on
the other hand, stimulates the Leydig cells of the testes, which are responsible for
the synthesis of testosterone [49].
In the setting of male hypogonadism, low levels of testosterone result in less tro-
phic stimulation of the Sertoli cells present in the testis, leading to their eventual
atrophy. This explains the low TV observed in patients with male hypogonadism [50].
Pathophysiology Pearl Figure 6.2
Clinical Pearl
What is the normal adult testicular size?
4 to 5.5 cm in length × 2.5 cm in width × 3 cm in the anteroposterior
dimension.
The volume is reported as being greater than 20 ml in whites and African
Americans [55] (Fig. 6.3).
6.3.2 Gynecomastia
Clinical Features
Gynecomastia is the presence of palpable glandular breast tissue in men [56] and
should be differentiated from pseudogynecomastia, which is an enlargement of the
breasts due to an accumulation of fat [57]. Gynecomastia is a reported finding in
male hypogonadism [46].
BRAIN
H
nR
G
d
an
LH H T
of D
n d
i tio an
b E2
hi
in T, LH FSH –
c k by –
ba on + +
e ed ucti
f d
ive pro
g at
Ne Inhibin B
FSH-R Inhibits pituitary FSH
LH-R
production
Leydig cell Sertoli cell
Testosterone
TESTIS
Spermiogenesis
Aromatase 5α−reductase Facilitated by Leydig cell derived
testosterone
E2 DHT
Fig. 6.2 Schematic diagram of the hypothalamic-pituitary-testicular axis. Gonadotropin-releasing

hormone (GnRH) produced from the hypothalamus directly stimulates pituitary gonadotropes to
release FSH and LH. LH binds to the G-protein-coupled LH receptor (LH-R) on the Leydig cell
and stimulates the formation of testosterone [51]. Testosterone (T) is then converted to estradiol
and dihydrotestosterone (DHT) by peripheral aromatase and the 5ɑ-reductase enzymes, respec-
tively (solid lines) [52]. Negative feedback inhibition of both gonadotropes and hypothalamic
GnRH neurons is mediated by testosterone and estradiol (E2) (broken lines) [53]. FSH binds to the
G-protein-coupled FSH receptor (FSH-R) on the Sertoli cell of the testis, a process that promotes
the formation of sperms (spermatogenesis), androgen-binding proteins (ABPs), and inhibin B
(solid lines). Spermatogenesis in the Sertoli cell is indeed under trophic stimulation by Leydig
cell-derived testosterone [50]. Inhibin B suppresses FSH release from pituitary gonadotropes
through a negative feedback loop (broken lines) [54]. (Based on Shalet [51])
Fig. 6.3 The Prader

orchidometer. The
objective assessment of
testicular volume requires
the use of an
orchidometer – sequential
beads labeled with an
estimated testicular
volume. Palpation and
inspection of the testes
facilitate an approximation
of testicular volume, by
comparing it to the beads
on the orchidometer [45].
(Based on Ruiz-Olvera
et al. [45])
6.3 Male Hypogonadism 137
Pathophysiology
There are multiple receptors in the male breast for sex hormones and prolactin. In
theory, estrogens stimulate the formation of the glandular breast tissue, while andro-
gens lead to their regression. A tilt in the balance, in favor of estrogen, causes gyne-
comastia [56].
6.3.3 Loss of Height or Fragility Fractures
Clinical Features
Male hypogonadism contributes to a low bone mineral density, which can present as
a fragility fracture [46]. The prevalence of secondary osteoporosis or osteopenia in
patients with male hypogonadism remains unclear at this time [58].
Pathophysiology
1. Estrogen plays a vital role in maintaining bone mass in both adult males and
females by inhibiting osteoclast activity (bone resorption). In males, testosterone
is converted to estrogen by the aromatase enzyme present in adipose tissue.
Testosterone, therefore, exerts indirect beneficial effects on bone mineral den-
sity [59].
2. Reduced muscle bulk and strength predispose hypogonadal men to falls, which
increases their fracture risk [60].
Aromatase Deficiency and Estrogen Resistance
There is a single case report to date of a male with estrogen resistance and
a clinical phenotype similar to that of men with congenital aromatase
deficiency.
Clinical Features
• Tall stature with eunuchoid proportions due to persistent growth into
adulthood
• Delayed bone age
• Low bone mineral density
Pathophysiology
Estrogen promotes skeletal maturation, epiphyseal fusion, the arrest of linear
growth (in the peripubertal period), and maintenance of bone mineral density
in adulthood. Typically, subjects with estrogen resistance or aromatase defi-
ciency do not gain these beneficial effects of estrogen on skeletal metabo-
lism [61].
6.3.4 Change in Body Composition
Clinical Features
Patients with male hypogonadism are predisposed to low muscle mass and strength
in mainly the lower extremities [62].
For the most part, hypogonadism is associated with an increase in abdominal fat,
which explains the increased waist-to-hip ratio seen in subjects with hypogonad-
ism [63].
Pathophysiology
Low testosterone causes a reduction in muscle protein synthesis, which contributes
to reduced muscle mass [63].
Testosterone inhibits lipoprotein lipase activity in adipose tissue. In male hypo-
gonadism, the low levels of testosterone are unable to inhibit lipoprotein lipase
activity; this results in increased lipid storage [63]. (see Sect. 1.4.1).

What are the clinical features of Klinefelter’s syndrome (KS)?
Klinefelter’s syndrome is characterized by features of hypogonadism (low
libido, infertility, sparse androgenic hair growth), gynecomastia, tall stature,
and small testes [64] (Table 6.1).
What is the genetic basis of Klinefelter’s syndrome, and how is it different
from 46,XX testicular disorder of sex development?
KS, a cause of hypergonadotropic hypogonadism, occurs in the setting of
an XXY karyotype (extra X chromosome). Lyonization or inactivation of the
X chromosome [67] may be somewhat incomplete, resulting in the expression
of some residual active genes from the incompletely inactivated extra X chro-
mosome [68].
80–90% of patients with KS have the 47,XXY genotype. Other karyotypes
which occur in KS include 48,XXXY, 48,XXYY, or mosaics (coexistence of
47,XXY and normal 46,XY). These less common karyotypes account for up to
20% of patients [65].
In contrast to KS patients, who tend to be tall, males with 46,XX testicular
disorder of sex development present with short stature due to paternal inheri-
tance of an abnormal X chromosome [69].
During meiosis in the male parent, part of the Y chromosome material
becomes affixed to the X chromosome. The sex-determining region of the Y
chromosome (SRY) gene, which affects sex differentiation, is transferred to the
defective X chromosome. The male infant has a normal male external genitalia,
due to the presence of the SRY region; however, the azoospermia factor (AZF)
region, which is critical in mediating spermiogenesis, becomes defective during
meiosis in the affected parent. The affected male offspring develops oligosper-
mia as a consequence of inheriting a defective azoospermic factor [70].
6.4 Menopause 139
Table 6.1 The mechanisms underlying other clinical features of KS

Clinical feature(s) Mechanism(s)
Loss of facial, chest, and pubic hair Androgen deficiency [65]
Eunuchoid body habitus (arm span > Testosterone deficiency and delayed epiphyseal
height; waist-to-floor > waist-to-crown) closure due to hypoestrogenemia [65]
Absent frontal hair recession Androgen deficiency [65, 66]
Adapted from Bonomi [65] and Urysiak-Czubatka [66]
6.4 Menopause
6.4.1 Vaginal Dryness
Clinical Features
Vaginal dryness is a known manifestation of menopause and has a reported preva-
lence ranging from 8% to 43% [71, 72]. Patients have other vulvovaginal signs,
including shortening of the vagina and uterovaginal prolapse [73].
Pathophysiology
1. Hypoestrogenemia results in thinning of the vaginal mucosa due to low levels of
local estrogen in the superficial cells of the vagina [74, 75]. The normal thick and
moist vaginal mucosa is converted into a thin epithelium as a consequence of
hypoestrogenemia [76].
2. Reduction in mucosal blood flow impairs vulvovaginal secretions [76].
Clinical Features
The most important risk factor for low bone mineral density (BMD) in older women
is menopause. The estimates of low postmenopausal BMD are as high as 40%
depending on age and ethnicity. Fragility fractures are lower in postmenopausal
African American women, compared to their age-matched Caucasian controls.
African American postmenopausal women tend to have higher cortical and trabecu-
lar BMD than Caucasians, and this may be the reason for their low fracture rates [77].
Pathophysiology
1. Estrogen deficiency accelerates the rate of osteoclastogenesis (contributes to a
significant decline in bone mineral density) [78].
2. Estrogen plays a critical role in preventing osteoblast apoptosis [78].
3. FSH spikes contribute to accelerated bone loss by stimulating osteoclastogene-
sis, especially in late premenopause and early menopause. Interestingly, women
with central (low FSH) rather than primary hypogonadism (high FSH) lose less
bone mineral density [79, 80].
6.4.3 Change in Body Composition
Clinical Features
Menopause is associated with increased central (visceral) adipose tissue deposition
[81–83]. Postmenopausal women have a higher waist-to-hip ratio when compared
to premenopausal controls. Indeed, in a study involving 358 women, central adipos-
ity was more likely to be present in postmenopausal women, even after controlling
for confounders such as the body mass index [84].
Pathophysiology
1. There is a predictable reduction in resting energy expenditure (REE), which mir-
rors estrogen levels in postmenopausal women [82]. A decline in REE results in
reduced oxidation of fat [82] and leads to the accumulation of visceral and sub-
cutaneous adipose tissue [81].
2. Estrogen causes accumulation of fat in the femoro-gluteal region, while andro-
gens influence abdominal fat distribution. In postmenopausal women, a low
estrogen state causes a reduction in hepatic production of sex hormone-binding
globulin (SHBG). Low SHBG increases the levels of unbound active androgens.
A shift in the balance toward androgens accounts for the central accumulation of
fat observed in the postmenopausal period [85].

What are hot flashes in the menopausal age group?
Hot flashes happen to be the most prevalent symptom experienced by
women during the climacteric [86]. Hot flashes present as intermittent periods
of localized heat sensation, flushing (erythema), and excessive sweating
involving the face and chest. The majority of patients experience amelioration
of symptoms within 2 years [87].
Approximately 10% of patients might experience persistent bothersome
hot flashes 10 years after their last menstrual period [88]. Discontinuation of
hormone replacement therapy (HRT) may result in the resumption of symp-
tomatic hot flashes at any time after menopause. Hot flashes are consistently
associated with GnRH and FSH spikes and are generally not an issue in
women with central hypogonadism (normal or low FSH) [89].
What are the cardioprotective effects of estrogen?
1. 17β-Estradiol increases the rate of ApoA-I synthesis (high-density lipo-

protein) while decreasing the rate of ApoB-100 synthesis (triglyceride-
laden lipoproteins) [90](see Fig. 7.2).
2. Estrogen increases the expression of LDL receptors on the surface of cells,
which improves LDL clearance from peripheral tissues [91].
3. Estrogen directly increases the activity of lipoprotein lipase (lipid storage)
and reduces the activity of hormone-sensitive lipase (lipid release) in adi-
pose tissue (see Sect. 1.4.1) [90].
6.5 Estrogen Resistance 141
6.5 Estrogen Resistance
6.5.1 Tall Stature
Clinical Features
Tall stature was described in an index case of estrogen resistance in a male patient
[92]. A recent case series including two females and one male, however, reported
tall stature as an inconsistent finding in estrogen resistance [93]. Estrogen resistance
is a rare condition with very few published case reports, making the exact estima-
tion of prevalence uncertain [94].
Pathophysiology
Estrogen promotes both early pubertal growth spurt and subsequent closure of the
epiphysis in late puberty [92]. The rate of attainment of final skeletal height is
dependent on growth plate senescence (fusion), which is mediated by estrogen act-
ing on its cognate receptors on chondrocytes [95, 96]. Estrogen plays this critical
role in both males and females [61].
Mutation of the estrogen receptor leads to insensitivity to estrogen, resulting in
impaired growth plate senescence [93]. Delayed growth plate fusion contributes to
tall stature in these patients [97].
Clinical Features
Acanthosis nigricans (AN) was reported in an index case estrogen resistance in a
male patient. The lesions were distributed in the bilateral axillae [92].
Pathophysiology
The reason for AN in the setting of insulin resistance and glucose intolerance was
unexpected, although the authors proposed a possible reason for this clinical find-
ing [92].
An increase in circulating estrogens improves glycemic control by facilitating
insulin secretion and improving its target tissue effects. Due to acquired defects in
estrogen receptors, estrogen is unable to play this physiological role, leading to
insulin resistance [92].

What are the clinical features of females with estrogen resistance? [98]
• Low bone mineral density

• Impaired breast development
• Delayed puberty
• Lack of epiphyseal closure leading to tall stature
We have discussed the clinical features of classic estrogen resistance in

the context of the estrogen receptor-ɑ gene (ESR1); there has been a
recently reported mutation of the estrogen receptor-β (ESR2). What are the
clinical features of this recently described ESR2 mutation in a female
patient?
• Streak ovaries
• Absent puberty
• Absent breast development
• Infantile uterus
• Osteoporosis with closed epiphysis
In contrast to patients with classic ESR1 mutations, patients with estrogen

resistance due to ESR2 mutations have streak ovaries because the ESR2
receptor signaling pathway is critical for the differentiation and growth of the
ovaries [98, 99].
6.6 Complete Androgen Insensitivity
6.6.1 Abnormalities of the External and Internal Genitalia
Clinical Features
Patients with complete androgen insensitivity have a short vagina with an absent
cervix on pelvic examination [100]. Due to the normal-appearing female external
genitalia, the diagnosis is often delayed [101].
Pathophysiology (Fig. 6.4)
6.6.2 Normal Breast Tissue Development
Clinical Features
Patients with CAIS usually have normal female breast tissue development [104].
Aberrant breast tissue anywhere along the mammary line has been reported as well
[105]. There is spontaneous breast development around puberty; as such, patients
can grow up with a female gender identity [106].
The standard practice is to bring up CAIS subjects as females, although there is
a recent case of gender dysphoria in a 17-year-old patient with CAIS. The patient
underwent female-to-male gender reassignment surgery and subsequently received
gender-affirming hormone therapy [107].
6.6 Complete Androgen Insensitivity 143
Clinical features of CAIS

Bipotential gonad
Müllerian duct XY SRY present SRY absent XX

regression Testis Ovary
Müllerian duct
Sertoli No AMH
AMH development
cell
Wolffian duct
Testosterone Leydig No Testosterone
regression
(Androgen) cell
5αR Wolffian duct development
Normal male external No DHT Normal female external

DHT
genitalia development genitalia development
Fig. 6.4 Schematic diagram of normal differentiation of the bipotential gonad and the implica-
tions of complete androgen insensitivity. Complete androgen insensitivity syndrome (CAIS)
occurs as a result of a mutation of the gene responsible for the translation of the androgen receptor
(AR) [102, 103]. In utero, the bipotential gonad differentiates into either male or female gonad
with ultimate phenotypic features being under the influence of the transcription factor, SRY (sex-
determining region of the Y chromosome), androgens, and anti-Mullerian hormone (AMH) [104].
In a genetic male (XY), the SRY transcription factor present on the short arm of the Y chromosome
plays a pivotal role in the differentiation of the bipotential gonad into a testis. AMH secreted by the
Sertoli cells of the testis causes regression of the Mullerian ducts, which are responsible for the
formation of the upper female genital structures (upper one-third of the vagina, uterus, and fallo-
pian tubes) [104]. Androgens from the testes bind to androgen receptors and mediate the develop-
ment of the Wolffian duct into male internal genital structures (seminal vesicles, epididymis, and
vas deferens). Due to the mutation of the AR, the Wolffian ducts regress as well, leading to the
formation of the lower female genitalia (lower two-third of the vagina, labia, and clitoris) [104].
(SRY sex-determining region of the Y chromosome, 5ɑR 5 alpha-reductase). (Redrawn and modi-
fied from Hughes et al. [104])
Pathophysiology
Aromatization of androgens into estrogen promotes breast tissue development in
patients with CAIS [103].
Clinical Pearl
What are the other clinical features of CAIS? [106]
Primary amenorrhea, inguinal hernias, and sparse or absent pubic and axil-
lary hair

Why should patients with CAIS and undescended testes undergo orchiectomy?
The risk of malignancy of an abdominally located testes increases with
age, with an anticipated risk of malignancy of 3.6% at 25 years and an even
higher risk of 33% by 50 years of age [108].
Why do patients with CAIS have incomplete or minimal axillary and
pubic hair?
Vellus (nonpigmented or nonsexual) hair may be found in the pubic and
axillary areas because it is not androgen-dependent. Darker terminal hair,
which happens to be androgen-dependent, is, however, sparse or absent in
CAIS. The inability of androgens to act at the hair root due to mutation of the
androgen receptor accounts for these findings [109].
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Signs in Disorders of Lipid Metabolism
and Obesity 7
Learning Objectives
1. Understand the pathophysiologic basis for the cutaneous manifestations of

lipid disorders
2. Understand lipid metabolism and how various enzyme defects account for
the clinical and biochemical phenotypes seen in various causes of
dyslipidemia
3. Recognize the pathophysiologic basis for the clinical manifestations of
monogenic causes of obesity (congenital leptin and POMC deficiencies)
7.1 Signs in Disorders of Lipid Metabolism
7.1.1 Corneal Arcus
Clinical Features
Corneal arcus (CA) is a circumferential deposition of lipids in the cornea and
appears as whitish-gray deposits around the cornea with a predilection for the supe-
rior and inferior limbus of the cornea. It eventually progresses to involve the entire
peripheral rim of the cornea [1].
CA is widely accepted as a typical sign of the aging process, although it might
signify the presence of dyslipidemia [2, 3]. A population-based prospective study
involving more than 3600 subjects in Asia assessed the association of CA with car-
diovascular disease (CVD) events.
The authors prospectively evaluated CVD events after an initial confirmation of
the presence of CA. After adjusting for baseline traditional risk factors, CA was
associated with a clinically significant increased odds ratio (OR) of 1.52 [1.07 to
2.16] for incident CVD [4].

https://doi.org/10.1007/978-3-030-49872-6_7
152 7 Signs in Disorders of Lipid Metabolism and Obesity
Pathophysiology
• Unlike atherosclerosis, CA is not due to endothelial dysfunction. There is no
evidence of foam cells (lipid-filled macrophages), which implies there is an
alternative mechanism explaining the characteristic histopathologic findings
in CA [5].
• There is a mismatch between the influx and efflux of lipids in the cornea, with
the balance tilted toward excessive lipid influx [5]. Indeed, the 12 o’clock posi-
tion of the peripheral cornea tends to have a higher density of deposited lipids
since the superior corneal limbus is more vascularized compared to the rest of the
peripheral cornea [6].
• Other less validated reasons for CA include an immune-mediated reaction to
either age-related ocular degeneration or inflammation [7].
7.1.2 Xanthomas and Xanthelasma
Clinical Features
Xanthomas represent localized regions of accumulated lipids in the skin, subcutane-
ous tissues, and tendons [8, 9]. They may be plaque-like, papular, or nodular lesions,
depending on the morphologic subtype [8, 10].
Tuberous xanthomas are characteristically distributed over pressure points (sites
of trauma) such as the elbows and knees [9]. They are firm, yellowish-red papulo-
nodular skin lesions [11], which vary in size from a few millimeters [12] to massive
xanthomas [13]. Tuberous xanthomas occur in patients with familial hypercholes-
terolemia (type 2A hyperlipoproteinemia) [14, 15] and familial dysbetalipoprotein-
emia (type 3 hyperlipoproteinemia) [16].
Eruptive xanthomas (EX), on the other hand, tend to present in patients with type
1, 4, or 5 hyperlipoproteinemia [16]. EX has a reported prevalence of 1.7 for every
10,000 patients [17]. Secondary causes of EX include diabetes mellitus, hypothy-
roidism, alcohol use, cholestasis, and estrogens [18].
• They may vary from yellowish-orange to reddish-brown papules with a circum-

ferential erythematous hue. EX are usually located over extensor surfaces of the
extremities but may occur in flexural areas and the trunk.
• EX lesions exhibit the Koebner phenomenon, i.e., new lesions develop along the
sites of cutaneous trauma or irritation [19].
Palmar xanthomas (PX) appear as yellowish-orange macules with a predilection

for the palmar creases [20]. They are pathognomonic for type 3 hyperlipoprotein-
emia (familial dysbetalipoproteinemia) [16] and may, on rare occasions, occur in
patients with familial hypercholesterolemia [21]. PX should be distinguished from
planar xanthomas, which are whitish plaques and tend to extend beyond the con-
fines of the palmar creases [20]. Palmar xanthomas are classically referred to as
xanthoma striatum palmare [22].
7.1 Signs in Disorders of Lipid Metabolism 153
Xanthelasmas are the most common cutaneous xanthoma [23] and are distrib-
uted over the inner canthus of the upper eyelids [24, 25]. The lesions are soft, yel-
lowish plaques and may be observed in other sites apart from the periorbital region,
such as the axilla, neck, and trunk [26]. In a large prospective cohort study involving
more than 12,000 subjects [3], investigators were able to demonstrate that xanthe-
lasmas were independently associated with ischemic heart disease after controlling
for some CVD risk factors such as elevated plasma cholesterol and triglycerides [3].
Pathophysiology
Unlike the underlying pathophysiology of corneal arcus [5], the formation of xanthomas
is similar to that of atherosclerotic plaques. Leakage of lipids from cutaneous vessels
results in excessive lipid deposition in the skin [27]. Dermal lipids are then phagocy-
tosed by macrophages, which evolve into foam cells (lipid-laden macrophages), a criti-
cal step in the formation of xanthomas. Xanthomas, in effect, represent oxidized LDL
cholesterol particles present in the skin and connective tissue [5, 8, 10, 28].
7.1.3 Skin Crease (Frank’s Sign)
Clinical Features
Frank’s sign is a diagonal wrinkle involving the skin of the ear lobe [29]. This pre-
sumed dermatologic manifestation of atherosclerotic disease was first reported by
Dr. Sanders Frank in 1973, in a letter titled “Aural Sign of Coronary-Artery Disease,”
published in the New Journal of Medicine (NEJM) [30].
It is thought to increase with age and is associated with some cardiovascular risk
factors [5]. There is conflicting evidence in the literature regarding the association
of Frank’s sign with atherosclerotic disease [31, 32]. The association of Frank’s sign
with atherosclerotic disease might, however, not necessarily imply a direct causal
relationship.
Pathophysiology
Dyslipidemia-induced microangiopathy leading to ischemia and eventual breakdown
of elastic fibers accounts for the skin changes seen with Frank’s sign [31]. The reason
for the predilection of this cutaneous lesion for the ear lobe is, however, unclear.
7.1.4 Lipemia Retinalis
Clinical Features
It is a rare fundoscopic examination finding in patients with markedly elevated
serum triglycerides [33]. The vessels in the posterior pole and peripheral aspect of
the retina develop a creamy white appearance that can be visualized on the fundo-
scopic exam [34–36]. Some patients may have deterioration of visual acuity, which
improves upon initiation of anti-lipidemic therapy [33].
Pathophysiology
The creamy appearance of the retinal vessels has been attributed to the high content
of triglyceride-rich chylomicrons reflecting direct light from the ophthalmo-
scope [37].
What are lipoproteins?
Lipoproteins: They are a complex composition of cholesterol esters and
triacylglycerols in a dense lipid core, with a circumferential rim of free cho-
lesterol, apolipoproteins, and phospholipids. This intricate configuration
allows water-insoluble cholesterol and triacylglycerols to be ferried through
the circulatory system to their target tissues [38, 39]. The classification of
lipoproteins depends on their size, lipid composition, and specific apolipopro-
teins subtype. There are various lipoproteins, including low-density lipopro-
tein (LDL), high-density lipoproteins (HDL), very low-density lipoproteins
(VLDL), intermediate-density lipoproteins (IDL), and chylomicrons [40].
Apoproteins/apolipoproteins: These complex proteins present on the sur-
face of lipoproteins play critical roles in lipoprotein physiology by providing
structural integrity to lipoproteins, modulating lipoprotein-related enzymatic
action, and serving as ligands for various lipoproteins at specific target tis-
sues [41].
Lipoprotein Metabolism
Lipoprotein metabolism aims to transfer dietary sources of triglycerides to
both muscle and adipose tissue for energy metabolism and storage, respec-
tively. It also facilitates the cycling of cholesterol between the liver and
peripheral tissues, a process critical for the formation of steroid hormones,
cell membranes, and bile acids [42].
Step 1: Bile salts emulsify fat globules into smaller fatty droplets that con-
tain triglycerides (TAGs) and cholesterol esters (CEs). Dietary triglycerides
are then hydrolyzed into free fatty acids (FFAs) and monoacylglycerol (MAG)
in the intestinal lumen by pancreatic lipases. This initial step enables the even-
tual transfer of TAGs from the intestinal lumen into the circulatory system.
The products of hydrolysis of TAGs, i.e., FFAs and MAG, are then repack-
aged into micelles, which then diffuse into the cytosol of the enterocyte [42,
43]. Once in the enterocyte, FFAs and MAG are then resynthesized into TAGs
in preparation for delivery to the circulatory system. TAGs, cholesterol esters,
cholesterol, and apolipoprotein B-48 (Apo B-48) are then packaged into
chylomicrons in the enterocyte [44]. This concludes the formation of the first
lipoprotein in the exogenous lipoprotein pathway [45].
Step 2: Chylomicrons enter systemic circulation via the thoracic duct, thus
bypassing the portal circulation [43, 46].
Once in the systemic circulation, HDL transfers apolipoprotein CII (Apo-
CII) and apolipoprotein E (Apo-E) to chylomicrons. Apo-E allows the bind-
ing of lipoproteins to specific LDL receptors or LDL-like receptors present in
various tissues (liver and adrenal cortex). Apo-CII, on the other hand, is criti-
cal in activating the lipoprotein lipase, present on the capillary endothe-
lium [47].
Step 3: Chylomicrons reach adipose tissue and muscle, where lipoprotein
lipase (produced by adipocytes and muscle cells) present on the endothelial
lining of capillaries hydrolyzes TAGs into FFAs and monoacylglycerol. FFAs
are then taken up by adipocytes and muscle cells for energy metabolism [42].
Chylomicron remnants, which are formed after this step, then release the pre-
viously acquired apo-CII, which was needed for lipoprotein lipase activity,
back to HDL [48]. This concludes the exogenous lipoprotein pathway, which
facilitates the transfer of dietary sources of fatty acids from the intestine to
muscle and adipose tissue, for both storage and metabolism [49].
Step 4: Chylomicron remnants, which contain mostly cholesterol and cho-
lesterol esters, bind to the hepatic LDL receptor and are transported into the
liver [50].
Step 5: Once in the liver, TAGs, cholesterol esters, and Apo-B100 are
repackaged into VLDL. VLDL in circulation, just like chylomicrons, receives
Apo-E and Apo-CII from HDL. VLDL is transported to adipose tissue and the
muscle, where, again, lipoprotein lipase facilitates the hydrolysis of TAGs
into FFAs and monoacylglycerol. FFAs can then be stored in fatty tissue or
used for energy metabolism by muscle. The loss of TAGs from VLDL results
in the formation of intermediate-density lipoproteins (IDL) or VLDL rem-
nants. Again, Apo-CII will be released back to HDL after the formation of
IDL [47, 51].
Step 6: IDL in circulation, with its surface-bound Apo-E, has an affinity
for tissues with LDL or LDL-like receptors. IDL binds to the hepatic LDL
receptor, where it is taken up by the liver for further processing. Apo-B100
and cholesterol esters are then repackaged into a new lipoprotein called
LDL [47].
Step 7: LDL binds LDL-like receptors in the gonads for gonadal steroido-
genesis [52] and the adrenal cortex for adrenal steroidogenesis [53, 54]. LDL
can also bind LDL receptors present in muscle and adipose tissue, where it
can be taken up for further processing. Ultimately, LDL tracks back to the
liver to conclude the endogenous lipoprotein pathway, whose primary pur-
pose is to transfer cholesterol and TAGs from the liver to peripheral tissues
[55]. Figure 7.1 depicts critical steps in the lipoprotein synthesis pathway.
ApoB48
Fat globule ApoCII
CEs
TAG Repackaging of various
ApoE
lipoprotein particles ApoB100
(VLDL and LDL)
Emulsification
1
4
TAG 6
PL
2
CEs CEs
FFAs + MAG CEs CEs CEs
TAG TAG TAG TAG TAG
CM VLDL IDL LDL
CMR
5 7
3
LPL Steroidogenesis
TAG FFAs + MAG
Artherogenesis
Target tissues : Skeletal muscle and adipose tissue
Fig. 7.1 Exogenous and endogenous lipoprotein pathway. Emulsification of fat globules into tiny
fat droplets by bile (step 1) [42–44] facilitates the hydrolysis of triacylglycerides (TAGs) into free
fatty acids (FFAs) and monoacylglycerol (MAG) by pancreatic lipase (PL) in the intestinal lumen.
Chylomicron (CM) formed from repackaged TAG, cholesterol esters (CEs), and various apopro-
teins (step 2) [43, 46, 47] are delivered to target tissues where TAG is hydrolyzed by lipoprotein
lipase (LPL) (step 3) [42, 48, 49]. Chylomicron remnants (CMR) are transported to the liver for
further processing (step 4) [50]. VLDL released from the liver is destined for adipose tissue and
skeletal muscle, where stores of TAG are released for hydrolysis by LPL (step 5) [47, 51]. IDL
formed after VLDL processing in target tissues is destined for the liver (step 6) [47]. LDL, a cho-
lesterol ester (CE)-rich lipoprotein, is critical in steroidogenesis in various tissues and plays a
central role in atherogenesis (step 7) [53–55]. (Redrawn and modified from Ramasamy [42])
Reverse Cholesterol Transport Pathway
HDL is responsible for transferring cholesterol and triglycerides from
peripheral tissues back to the liver [56] and finally into the intestine for excre-
tion [57] (Fig. 7.2).

What are the underlying pathophysiologic mechanisms for the various types
of dyslipidemia?
Type 1 Hyperlipoproteinemia
Deficiencies of either lipoprotein lipase (LPL) [63] or apolipoprotein CII
(Apo-CII) have been reported [45]. These defects result in an elevated level of
triglyceride-rich chylomicrons. Clinical features include recurrent pancreatitis,
lipemia retinalis, tubero-eruptive xanthomas, and hepatosplenomegaly [64].
Sources of cholesterol
Dietary cholesterol Cholesterol

Bile acids
Glucose
FFAs TAG
Acetyl CoA
HL
HMG-CoA
ABCA1
LCAT
C C CE CE
TAG
Nascent HDL Mature HDL
Adipose tissue CETP
Muscles
TAG TAG
ApoA1
CE CE
SR-B1 VLDL, CM and LDL
LDL-R
Fig. 7.2 Schematic representation of reverse cholesterol transport pathway. Free cholesterol from
extrahepatic tissues (muscles and adipose tissue) is transferred to ApoA-1 to form the nascent HDL
particle; this process is facilitated by ATP-binding cassette transporter A1 (ABCA1) present on the
cell membrane of extrahepatic tissues (muscles, adipose tissue, and intestine). Cholesterol (C) is
then converted to cholesterol esters by Lecithin-cholesterol acyltransferase (LCAT), which is criti-
cal in the formation of mature HDL [47]. Cholesterol ester transfer protein (CETP) is essential in
the transfer of cholesterol esters and triglycerides between other circulating lipoproteins (chylomi-
crons, VLDL, LDL) and HDL. CETP transfers CEs from HDL to other lipoproteins and carries
TAGs from these lipoproteins back to the mature HDL particle. HDL, therefore, becomes rich in
TAGs at the expense of CEs [58]. HDL binds to the hepatic scavenger SR-B1 receptor, where it
releases its cholesterol esters without being internalized by the liver. It then returns to circulation
as a smaller HDL particle, to repeat the process of cholesterol and triglyceride acquisition [59, 60].
HDL may also be hydrolyzed by hepatic lipase (HL) into FFAs, converting it back to a smaller
HDL particle, which can then be recycled in the process of cholesterol acquisition. HDL can also
bind the hepatic LDL-R receptor [61], a process that facilitates the release of cholesterol to the
liver for bile acid synthesis [62]. (Redrawn and modified from Ramasamy [42])
We will refer readers to step 3 of the lipoprotein synthesis pathway

reviewed in Fig. 7.1. Note the importance of Apo CII and lipoprotein lipase in
the hydrolysis of triglyceride-laden chylomicrons.
Type 2A Hyperlipoproteinemia (Familial Hypercholesterolemia)
Mutations in the LDL receptor (LDL-R) and apolipoprotein B (ApoB)
genes have been reported [65], with mutations of the LDL-R accounting for
85–90% of cases [66]. Activating mutations in proprotein convertase subtili-
sin kexin type 9 (PCSK9), an enzyme complex involved in the recycling of the
LDL-R, limits the life span of the LDL-R and is responsible for a small subset
of cases of type 2A hyperlipoproteinemia [66].
There is an elevated level of total cholesterol and LDL. HDL and TAGs are
usually normal [66].
Clinical features include corneal arcus, xanthelasma, or tuberous xantho-
mas [66].
Type 2B Hyperlipoproteinemia (Familial Combined Hyperlipidemia)
It is the most common genetic cause of dyslipidemia in the general popula-
tion. The primary defect in type 2B hyperlipidemia is yet to be elucidated
[67]; it, however, leads to excessive production of VLDL (triglyceride-laden
lipoprotein) [68] and LDL [69, 70].
This clinical phenotype fits the typical “atherogenic lipid triad,” which
consists of an elevated serum concentration of small dense LDL with high
TAGs, high apolipoprotein B, and reduced HDL [68]. Physical findings sug-
gestive of dyslipidemia are uncommon in familial combined hyperlipidemia
[71]. It is worthy to note that the most frequent cause of dyslipidemia in the
general population seldom has any of the physical manifestations we dis-
cussed earlier in this chapter.
Type 3 Hyperlipoproteinemia (Dysbetalipoproteinemia)
Elevated VLDL remnants (IDL) and chylomicrons account for the high
levels of both total cholesterol and triglycerides in these patients [72]. There
is a defect in the processing of chylomicrons and VLDL by the liver, which
results in an increased circulating half-life of VLDL and chylomicrons. CETP,
therefore, has an opportunity to transfer more cholesterol esters from HDL to
CM and VLDL due to the high levels of the latter two lipoproteins in circula-
tion. Elevated concentrations of these abnormal lipoproteins result in high
blood cholesterol-triglyceride ratio [72].
Type 4 Hyperlipoproteinemia (Simple Hypertriglyceridemia)
An isolated elevation of VLDL characterizes simple hypertriglyceridemia.
Unlike the monogenic inheritance pattern of familial hypercholesterolemia,
type 4 hyperlipoproteinemia is instead mostly polygenic in its etiology [71].
There is an elevated level of mainly VLDL-derived plasma triglycerides [71]
and concomitant lowering of HDL cholesterol [73].
Clinical features include eruptive xanthomas, lipemia retinalis, and hepa-
tosplenomegaly [71]. Type 4 hyperlipoproteinemia seldom causes acute pan-
creatitis except during specific metabolic stresses, when the type 4 phenotype
can change to a type 5 phenotype with both increased VLDL and chylomi-
crons [71].
This form of hyperlipoproteinemia is sometimes called diabetic dyslipid-
emia as it is frequently encountered in people with type 2 diabetes mellitus
(T2DM) and is considered part of the metabolic (insulin resistance) syndrome
[73]. It is also associated with cardiovascular disease [74] and nonalcoholic
fatty liver disease [75].
Type 5 Hyperlipoproteinemia
The etiology is multifactorial, including genetic mutations that result in
altered triglyceride metabolism. Acquired factors such as alcohol,
uncontrolled diabetes, steroids, estrogens, and medications play contributory

roles in type 5 hyperlipoproteinemia. It is characterized by VLDL and chylo-
micron elevation, which results in an elevation of both triglycerides and total
cholesterol [76].
The clinical features are similar to those of type 1 hyperlipoproteinemia
[71]. Unlike familial hyperchylomicronemia, patients with type 5 hyperlipo-
proteinemia are at risk for cardiovascular disease [77–79].
There is evidence that although large chylomicrons are unable to penetrate
the vasculature, VLDL and smaller remnants of chylomicrons can disrupt the
integrity of the vascular endothelium. This sets off an inflammatory cascade
that culminates in significant atherogenesis [80]. A useful mnemonic for
remembering the features of this type of dyslipidemia is 1 + 4 = 5 because it
has the combined features of types 1 and 4 hyperlipoproteinemia.
Tangier Disease
Tangier disease is named after the island in Chesapeake Bay, from which
the first reported cases hailed [81]. It is caused by a genetic mutation in the
ATP-binding cassette transporter A1 (ABCA1) gene, a gene that encodes the
critical regulatory membrane transporter ABCA1. ABCA1 mediates the trans-
fer of free cholesterol from extrahepatic tissues to apoA-1, to form the nascent
HDL particle [82].
It is a severe form of “hypolipoproteinemia,” which affects HDL metabo-
lism. Patients have very low serum HDL and low total cholesterol with nor-
mal or even high triglycerides [82]. The clinical features include
yellowish-orange discoloration of the tonsils, tonsillar enlargement, hepato-
splenomegaly, and peripheral neuropathy [81].
The defect in ABCA1-mediated mobilization of peripheral cholesterol
leads to the accumulation of lipids in various tissues, including the spleen,
nerves, skin, and lymphoid tissue. Indeed, the accumulation of lipids in neu-
rons leads to their devitalization and eventual demyelination.
Familial LCAT Deficiency
Lecithin-cholesterol acyltransferase is a regulatory enzyme required for
the esterification of peripherally acquired free cholesterol into cholesterol
esters in the nascent HDL particle [83]. It is a rare condition with about 100
case reports to date [84].
Familial LCAT deficiency is due to mutations in the LCAT gene, which
results in reduced esterification of free cholesterol into cholesterol esters.
Patients with LCAT deficiency, therefore, have a high free cholesterol to
esterified cholesterol ratio [85, 86].
Subjects with partial LCAT deficiency classically present with extensive
corneal opacification that is often referred to as fish-eye disease (FED).
Complete LCAT deficiency is composed of a triad of corneal opacification
(FED), anemia, and renal dysfunction [87].
A summary of the various clinical phenotypes of hyperlipoproteinemias
is based on Dr. Donald S. Fredrickson’s classification, which was first
Table 7.1 Fredrickson classification of hyperlipoproteinemias

Type Primary hyperlipidemia classification Elevated lipoprotein
1 Familial hyperchylomicronemia syndrome Chylomicrons [64]
2A Familial hypercholesterolemia LDL [66]
2B Familial combined hypercholesterolemia LDL, VLDL [69]
3 Familial dysbetalipoproteinemia IDL [70, 72]
4 Simple hypertriglyceridemia VLDL [71]
5 Familial hypertriglyceridemia Chylomicrons, VLDL [76]
Adapted from references [64, 66, 69–72, 76]
published in the journal Circulation in 1965 [88]. The classification system

is an oversimplification of the defects in lipoprotein metabolism but is a
good starting point in terms of appreciating the various forms of hyperlipo-
proteinemias (Table 7.1).
Why do patients with hypertriglyceridemia develop acute pancreati-
tis? [89]
1. Pancreatic lipases hydrolyze elevated triglycerides present in the capillar-

ies of the pancreas into FFAs and MAGs. Free fatty acids bind to serum
calcium and cause direct damage to capillaries. This sets off a cascade of
inflammatory reactions, which leads to the formation of multiple micro-
thrombi that subsequently clogs up capillaries and contributes to isch-
emia [90].
2. High levels of circulating serum chylomicrons cause extensive sludging of
blood in the pancreatic capillaries, which leads to pancreatic ischemia and
acidemia [90].
3. Also, FFAs activate trypsinogen, a critical step that finally initiates pancre-
atitis [90].
7.2 Congenital Leptin Deficiency
7.2.1 Obesity
Clinical Features
Congenital leptin deficiency is associated with significant early-onset obesity [91].
Patients exhibit a somewhat ravenous food-seeking behavior and, as such, present
with extreme obesity at a very young age [92].
Pathophysiology
1. Accumulation of fat mass due to excess caloric intake accounts for the obesity
observed in patients with congenital leptin deficiency [93]. Leptin, a hormone
secreted by white adipose tissue, is involved in triggering satiety through the
central anorexigenic pathway [91]. Leptin binds to leptin receptors present on
proopiomelanocortin (POMC) processing neurons in the arcuate nucleus of the
hypothalamus to cause satiety [94]. Congenital leptin deficiency, therefore,
causes hyperphagia and promotes excess weight gain [91].
7.3 Proopiomelanocortin (POMC) Deficiency 161
2. Leptin also increases energy expenditure by potentiating sympathetic nerve

activity in brown adipose tissue, a process which results in increased thermogen-
esis. Reduced energy expenditure, which occurs as a consequence of leptin defi-
ciency, contributes to obesity [95].

What is the genetic basis of congenital leptin deficiency?
The majority of patients with congenital leptin deficiency were conceived
in consanguineous relationships [96]. It occurs as a result of a genetic muta-
tion in the leptin receptor (LEPR) gene; thus, a defective protein is transcribed
and translated [92].
What are the other endocrine effects of leptin?
1. Hypothalamic-pituitary-thyroidal axis: Leptin regulates the release of

thyroid-stimulating hormone (TSH) [97]. Central hypothyroidism occurs
due to leptin-mediated signaling defects in the hypothalamic-pituitary-
thyroid axis. Indeed, the amelioration of hypothyroidism occurs after opti-
mal leptin replacement therapy [98].
2. Hypothalamic-pituitary-gonadal axis: Leptin regulates the release of
gonadotropin-releasing hormone (GnRH) [95]. Patients with congenital
leptin deficiency are hypogonadal due to defective GnRH release [97].
7.3 Proopiomelanocortin (POMC) Deficiency
7.3.1 Triad of Obesity, Adrenal Insufficiency, and Reddish Hair
Clinical Features
Early-onset obesity was reported as a clinical finding in the first case of POMC
deficiency. Other clinical findings in this recently discovered monogenic cause of
obesity included reddish pigmentation of body hair and features of central adrenal
insufficiency [99]. Multiple case reports have been published since the index case
[100–103].
Pathophysiology
Patients with POMC deficiency have a mutation in the POMC gene. POMC serves
as a prohormone from which ACTH, ɑ-MSH, and other anterior pituitary peptide
hormones are derived [104].
1. Hyperphagia occurs due to signaling defects in the hypothalamic leptin-

melanocortin anorexigenic pathway due to an absence of POMC [105].
2. The absence of melanocyte-stimulating hormone accounts for the hypopig-
mented skin and reddish hair seen in patients with this disorder [105]. ɑ-MSH
mediates skin pigmentation by binding to the melanocortin type 1 receptor

(MC1-R) present on skin melanocytes [106].
3. The absence of ACTH results in central adrenal insufficiency [105]. Under phys-
iologic conditions, ACTH binds to melanocortin type 2 receptors in the adrenal
cortex to facilitate glucocorticoid synthesis [107].
POMC and the Anorexigenic (Satiety) Pathway
• POMC processing occurs in the arcuate nucleus of the hypothalamus, pitu-

itary, and other parts of the brain. POMC is transcribed into a large poly-
peptide that undergoes proteolysis by the prohormone convertase 1
enzyme, to form ACTH and β-lipoprotein. β-Lipoprotein is subsequently
converted into ɑ-MSH and β-endorphin, respectively, by prohormone con-
vertase 2 [108]. See Fig. 3.2.
• POMC then binds to melanocortin-4 receptors of the hypothalamus to trig-
ger satiety (anorexigenic pathway) [109].

How do craniopharyngiomas cause hypothalamic obesity?
Craniopharyngiomas are benign tumors typically located in the sellar or
parasellar regions. Treatment options for lesions located in the hypothalamus
include surgical resection and radiation therapy [110].
Patients invariably develop hyperphagia and obesity because of tumor
location or surgical treatment. Disruption of hypothalamic tracts, e.g., POMC
signaling anorexigenic pathways, explains in part the onset of hyperphagia in
these patients [111, 112].
What are the other clinical features seen in patients with POMC defi-
ciency? (Table 7.2)
Table 7.2 Clinical features of POMC deficiency and their underlying mechanisms
Clinical features Mechanism
Hypopigmented skin Defects in MSH-mediated melanocyte activation [102]
Hypogonadotropic Defects in POMC-mediated signaling of GnRH release [102]
hypogonadism
Central hypothyroidism Defects in POMC-mediated signaling of TRH release [102]
Hyponatremia Increased ADH secretion in the setting of central hypocortisolemia.
Elevated CRH is a secretagogue for antidiuretic hormone [102]
CRH corticotropin-releasing hormone
Adapted from Çetinkaya et al. [102]
7.4 Lipodystrophy Syndromes 163
7.4 Lipodystrophy Syndromes
7.4.1 Atrophy of Adipose Tissue
Clinical Features
The distribution of adipose tissue atrophy is variable in patients with lipodystrophy
syndromes and is dependent on the underlying cause [113, 114] (Table 7.3).
Pathophysiology
1. Several enzymes involved in triglyceride and phospholipid metabolism are

impaired (Congenital generalized lipodystrophy). These complex enzyme
defects impair both the synthesis of phospholipids in adipose tissue and adipo-
cyte differentiation.
2. Autoimmune-mediated panniculitis (inflammation of subcutaneous tissue).
3. Protease inhibitors impair various factors involved in adipose tissue synthesis.
4. Nucleoside reverse transcriptase inhibitors cause toxicity of mitochondria in adi-
pose tissue, which leads to their atrophy [116].
7.4.2 Hepatomegaly
Clinical Features
The rate of hepatomegaly varies from as low as 29% in acquired partial lipodystro-
phy to as high as 84% in congenital generalized lipodystrophy [117].
Pathophysiology
The etiology of hepatomegaly in lipodystrophy is indeed multifactorial; there are
metabolic, genetic, and viral causes depending on the type of lipodystrophy
syndrome.
1. Autoimmune hepatitis.
2. Viral-induced mitochondrial dysfunction in adipose tissue.
Table 7.3 Distribution of fat loss in lipodystrophy syndromes

Type of lipodystrophy Distribution of adipose atrophy
Familial partial lipodystrophy Loss of subcutaneous tissue fat in the extremities and trunk.
(Dunnigan variety) Increased fat deposition in the supraclavicular region [115]
Acquired generalized A generalized progressive loss of subcutaneous tissue fat
lipodystrophy [116]
Acquired partial lipodystrophy Selective loss of subcutaneous tissue fat involving the trunk,
(APL, Barraquer-Simons upper limbs, and head [117, 118]
syndrome)
Localized lipodystrophy Medication-induced loss of subcutaneous tissue. It tends to
involve sites of injection, e.g., insulin-mediated lipodystrophy
[119]
Table 7.4 Mechanisms underlying other manifestations of lipodystrophy syndromes

Clinical feature Mechanism
Acanthosis nigricans Insulin resistance [118]
Virilization Hyperinsulinemia-induced hyperandrogenemia [119]
Xanthomas Hypertriglyceridemia-induced [120]
Prominent veins and muscles in The loss of subcutaneous tissue fat makes superficial
the extremities vessels more visible [120]
Adapted from Hsu [118] Tsoukas [119] and Handelsman [120]
3. Insulin resistance and hypertriglyceridemia in the setting of lipodystrophy syn-

dromes cause nonalcoholic fatty liver disease [117].
Patients with lipodystrophy syndromes may present with acanthosis nigricans,

virilization, xanthomas, or prominence of superficial venous vasculature on the
extremities (Table 7.4).
Clinical Pearl
Acquired Lipodystrophy Syndrome due to Immune Checkpoint Inhibitors
Immune checkpoint inhibitors are a novel class of cancer therapy used in
the management of some malignancies; they are associated with untoward
immune-related adverse reactions [121].
There is a single case report to date of a patient treated with nivolumab
(anti-programmed cell death protein 1 monoclonal antibody) who developed
an acquired form of partial lipodystrophy syndrome. The patient was severely
insulin resistant and experienced progressive loss of adipose tissue in a cra-
niocaudal direction, pathognomonic for APL [122].
APL occurred within 8 weeks of initiating nivolumab, and she was noted
to have a significant loss of subcutaneous tissue fat involving the face, extrem-
ities, and gluteal regions [122].

What are the mechanisms responsible for the insulin resistance seen in
patients with lipodystrophy syndromes?
1. The loss of adipose tissue reduces the storage site for free fatty acids
(FFAs). Excess FFAs are alternatively stored in the liver and muscle
instead. This state of lipotoxicity impairs insulin action in these peripheral
tissues [119].
References 165
2. Adiponectin, a vital adipocytokine, reduces hepatic glucose production

and increases fatty acid oxidation in the muscle. Atrophy of adipose tissue
reduces the levels of this adipocytokine, which ultimately results in gluco-
toxicity and excess circulating FFAs. Both factors contribute to hyperinsu-
linemia [119].
3. Leptin, another adipocytokine, is low in the setting of adipose tissue atro-
phy. Leptin induces satiety through the central anorexigenic pathway –
loss of leptin results in weight gain, which further exacerbates insulin
resistance [119].
Which clinical features should prompt screening for lipodystrophy

syndrome?
The typical distribution of subcutaneous fat loss with or without any of the
following features:
1. Insulin resistance (more than 200 international units of U-100 insulin per
day) [120]
2. Triglycerides ≥500 mg/dL [120]
References
1. Moosavi M, Sareshtedar A, Zarei-Ghanavati S, Zarei-Ghanavati M, Ramezanfar N. Risk fac-
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Eponymous Terms and Selected
Historical Figures in Endocrinology 8
Learning Objectives
1. Recognize selected eponyms in the field of endocrinology, not covered in

other sections of this text
2. Recall some exciting facts about the clinicians behind some notable endo-
crine eponyms
8.1 Eponyms Related to the Pituitary Gland
8.1.1 Wolfram Syndrome (DIDMOAD)
Clinical Features
These include diabetes insipidus, diabetes mellitus, optic nerve atrophy, and deaf-
ness (sensorineural hearing loss), hence the acronym DIDMOAD [1].
Pathophysiology
A mutation in the WFS1 gene, which encodes an endoplasmic reticulum protein,
accounts for the clinical manifestations of Wolfram syndrome (WS). The endoplas-
mic reticulum (ER) is pivotal in mitigating the effects of cellular stress, and in the
presence of WFS1 gene mutation, this protective effect is impaired, resulting in
defective cellular function of nerves and pancreatic beta-cells [2].

https://doi.org/10.1007/978-3-030-49872-6_8
172 8 Eponymous Terms and Selected Historical Figures in Endocrinology
Table 8.1 Eponyms related to the pituitary gland

Eponym Description
Nelson’s The unregulated expansion of a pituitary tumor after bilateral adrenalectomy in
syndrome patients with refractory Cushing’s disease (loss of negative feedback control by
adrenal-derived cortisol) [7]
Cushing’s Pituitary ACTH-dependent Cushing’s syndrome [8]
disease
Sheehan’s Hypopituitarism in the setting of postpartum hemorrhage [9]
syndrome
Simmonds’ Generalized cachexia due to damage to the anterior pituitary gland [10, 11]
disease
ACTH adrenocorticotrophic hormone
8.1.2 Histiocytosis X
Clinical Features
Histiocytosis X is known by a plethora of other eponyms, including Hand-Schüller-
Christian disease, Langerhans cell histiocytosis (LCH), and Letterer-Siwe disease
[3]. It is a rare condition that may remain undiagnosed due to its variable presenta-
tion. Dermatologic manifestations happen to be common in subjects with LCH. The
skin lesions can be suggestive of other cutaneous conditions such as eczema and
seborrheic dermatitis, leading to delayed diagnosis [4]. Other physical findings
include lymphadenopathy, cerebellar ataxia, tachypnea, and dehydration (central
diabetes insipidus), depending on the organs involved by the disease process [5].
Pathophysiology
It is a disease of immune dysregulation involving an essential antigen-presenting
cell, i.e., the dendritic cell. Despite previous controversies regarding the etiology of
this condition, more recent evidence points to LCH being a neoplastic condition.
Indeed, activating somatic mutations have been identified in more than 75% of
patients with LCH [6]. Interestingly, LCH does not originate from cutaneous
Langerhans cells, but rather derivatives of dendritic cells present in the bone mar-
row [3] (Table 8.1).
8.2 Eponyms Related to the Thyroid Gland
8.2.1 Pendred’s Syndrome
Clinical Features
The clinical features of Pendred’s syndrome include sensorineural hearing loss
(SNHL), goiter, and hypothyroidism [12].
8.2 Eponyms Related to the Thyroid Gland 173
Pathophysiology
A mutation in the SLC26A4 gene, which encodes pendrin, an anion exchanger, leads
to Pendred’s syndrome [13]. Pendrin is a chloride-iodide cotransporter pivotal in trans-
membrane transport of anions in the thyroid gland, inner ear, and kidneys. It is essential
in the shuttling of iodide from the thyroid follicular cell into the central colloid, a criti-
cal step required for the iodination of the thyroglobulin molecule. Pendrin is also
involved in chloride and bicarbonate exchange in both the kidneys and the endolym-
phatic sacs. Impaired function of pendrin causes hypothyroidism, goiter, SNHL [14],
and metabolic alkalosis (especially in the presence of a high bicarbonate load) [12].
Clinical Pearl
There are a few anatomical eponyms related to the thyroid gland. These
include Berry ligament (suspensory ligament of the thyroid gland) [15],
Lalouette’s pyramid (pyramidal lobe of the thyroid gland) [16], Zuckerkandl
tubercle (a normal anatomic protrusion from the posteromedial border of the
thyroid gland) [17], and thyroid artery of Neubauer (thyroidea ima artery)
[18] (Table 8.2).
Table 8.2 Eponyms related to the thyroid gland

Eponym Description
Jod-Basedow Iodine-induced hyperthyroidism [19, 20]. “Jod” is the German word for
syndrome iodine [21]. Patients with endemic goiter, euthyroid Graves’ disease, and
Hashimoto’s thyroiditis are at risk for this condition [21, 22]
Plummer’s Toxic multinodular goiter [23, 24]
disease
De Quervain’s Subacute granulomatous thyroiditis [25]
thyroiditis
Hashimoto’s Chronic inflammatory infiltration of the thyroid gland associated with
thyroiditis progressive fibrosis of the thyroid parenchyma [26]
Riedel’s A rare, benign, inflammatory condition of the thyroid with associated fibrosis
thyroiditis of thyrocervical tissues. It can present with hypocalcemia (fibrotic infiltration
of the parathyroid glands) or hypothyroidism [27]. Patients may also present
with neuronal paralysis due to nerve infiltration [28]
Wolff-Chaikoff A temporary reduction in thyroid hormone synthesis in the setting of an acute
effect iodine load. The Wolff-Chaikoff effect is an adaptive response to transient
changes in iodine concentration [29, 30]. There is a brief inhibition of the
thyroid peroxidase enzyme after an acute iodine load. Also, impaired activity
of the sodium-iodide symporter reduces further iodine uptake, an adaptation
that facilitates the eventual resumption of thyroid hormone synthesis [31]
Refetoff A syndrome of inappropriately normal or high serum TSH in the setting of
syndrome thyroid hormone excess. The syndrome is also known as thyroid hormone
resistance [32]
Hashitoxicosis An initial transient hyperthyroid phase of Hashimoto’s thyroiditis [33]
8.3 Eponyms Related to the Adrenal Glands
8.3.1 Carney Dyad or Carney-Stratakis Syndrome
Clinical Features
Patients develop gastric gastrointestinal stromal tumors (GISTs) and paraganglio-
mas (PGLs) [34].
Pathophysiology
An autosomal dominant mutation of the succinate dehydrogenase (SDH), an
enzyme critical in the electron transport chain. SDH genes are tumor suppressor
genes; as such, a loss-of-function mutation in these genes predisposes patients to
tumors [35].
The Carney triad is composed of the features of the Carney dyad (GISTs and
PGLs) and pulmonary chondromas. Unlike the Carney dyad, the Carney triad
occurs in the absence of a mutation in the SDH gene. A defect in the SDH
gene function, however, occurs as a result of an epigenetic phenomenon char-
acterized by hypermethylation of the SDH gene [35].
The Carney triad and dyad should be distinguished from the classic Carney
complex (see Table 8.3).
Table 8.3 Eponyms related to the adrenal glands

Eponym Description
Addison’s Primary adrenal insufficiency characterized by glucocorticoid, androgen, and
disease mineralocorticoid deficiency [39, 40]
Conn’s Primary hyperaldosteronism with adrenal adenoma(s) [41]
syndrome
Schmidt’s Addison’s disease associated with autoimmune thyroid disease in patients with
syndrome polyglandular autoimmune syndrome type 2 [42]
Carpenter’s Schmidt’s syndrome with associated type 1 diabetes mellitus in patients with
syndrome polyglandular autoimmune syndrome type 2 [42, 43]
Cushing’s Hypercortisolemia due to a cortisol secreting tumor, pituitary, or ectopic source
syndrome of excess adrenocorticotropic hormone (ACTH) production or exposure to
supraphysiologic levels of exogenous glucocorticoids [44, 45]
Addisonian Pernicious anemia in the setting of Addison’s disease [46]
anemia
Carney A mutation in the gene encoding the type 1 alpha subunit of protein kinase A is
complex implicated in the Carney complex. Clinical features include functional pituitary
tumors, cardiac myxomas, café-au-lait macules, and ACTH-independent
hypercortisolemia (PPNAD) [47]
PPNAD primary pigmented nodular adrenocortical disease
8.4 Eponyms Related to the Pancreas 175
8.3.2 Allgrove Syndrome
Clinical Features
Allgrove or triple A syndrome is composed of a triad of achalasia, alacrimia (absence
of tears), and adrenal insufficiency [36]. Adrenal insufficiency contributes signifi-
cantly to the morbidity and mortality observed in patients with Allgrove syn-
drome [37].
Pathophysiology
Triple A syndrome occurs as a result of a mutation in the AAAS gene, which encodes
a protein called ALADIN. ALADIN is critical in maintaining the integrity of cel-
lular membranes [38], control of steroidogenesis, and redox reactions in the adrenal
gland [37].
8.4 Eponyms Related to the Pancreas
8.4.1 Kussmaul’s Breathing (Diabetic Ketoacidosis)
Clinical Features
Patients with severe metabolic acidosis as might occur in diabetic ketoacidosis
develop a terminal, deep, and rapid respiratory pattern called Kussmaul’s respira-
tion. It heralds an impending state of respiratory failure requiring assisted ventila-
tion [48]. A characteristic fruity odor due to acetone, often described as similar to
the smell of nail polish remover, can be appreciated during the physical examina-
tion [49].
Pathophysiology
Metabolic acidosis triggers a compensatory increase in the respiratory rate in order
to reduce dissolved carbon dioxide and thus maintain serum pH. An initial phase of
tachypnea progresses through hyperpnea (increased tidal volume) and culminates
into the preterminal respiratory pattern of Kussmaul’s respiration [48].
Kussmaul’s respiration, a compensatory response to metabolic acidosis, increases
intra-alveolar pressures and may predispose patients to alveolar rupture and pneu-
momediastinum (Hamman’s syndrome) [50].
8.4.2 Somogyi Effect
Clinical Features
The Somogyi effect has classically been described as rebound early-morning hyper-
glycemia in the setting of significant fasting, overnight hypoglycemia. This colorful
eponym in diabetology was first reported by Michael Somogyi in 1959 [51].
Table 8.4 Eponyms related to the pancreas

Eponym Description
Wermer’s Multiple endocrine neoplasia type 1 (pancreatic tumors, parathyroid tumors,
syndrome pituitary tumors, adrenal cortical tumors, and schwannomas) [53]
Whipple’s A triad of hypoglycemic symptoms, biochemically confirmed hypoglycemia,
triad and reversal of hypoglycemic symptomatology after correction of
hypoglycemia [54]
Zollinger- Hypergastrinemia in the setting of a pancreatic gastrin-secreting neuroendocrine
Ellison tumor [55, 56]. Most gastrinomas occur in the gastrinoma triangle, which is an
syndrome imaginary triangle drawn through the pancreatic head, porta hepatis, and the
transition point between the second and third parts of the duodenum [55]
Verner- Syndrome of chronic watery diarrhea, hypokalemia, and achlorhydria (WDHA
Morrison syndrome) occurs in patients with vasoactive intestinal peptide-secreting
syndrome pancreatic neuroendocrine tumors [57]
Pathophysiology
The long-held belief has been that a period of hypoglycemia during an overnight
fast triggers a counterregulatory hormonal response, which results in fasting hyper-
glycemia in the morning [52]. In a prospective study involving 262 subjects, the
investigators used continuous glucose monitoring to assess trends in glycemic con-
trol among patients on a basal-bolus regimen. In subjects who developed nocturnal
hypoglycemia, fasting hyperglycemia in the morning did not occur, discounting the
Somogyi effect as a cause of fasting hyperglycemia [51] (Table 8.4).
8.5 ponyms Related to the Parathyroid Glands

E
and Bone Metabolism
8.5.1 Albers-Schönberg Disease
Clinical Features
Autosomal dominant osteopetrosis type 2 (ADO2) is also known as Albers-
Schönberg disease. The clinical features of this disease include nontraumatic frac-
tures, cranial nerve palsies, and osteoarthritis [58].
Pathophysiology
A series of genetic mutations leading to defective bone resorption have been
implicated in the etiopathogenesis of osteopetrosis [58, 59]. Expansion of cortical
bone results in craniofacial changes (including macrocephaly) and compressive
neuropathies. Bone mineral density is significantly high due to impaired osteo-
clastic activity, although this is paradoxically associated with increased fragility
fractures [60].
8.7 A Brief Account of Selected Historical Figures in Endocrinology 177
Table 8.5 Eponyms related to the parathyroid glands and bone metabolism
Eponym Description
Albright’s hereditary Shortened fourth metacarpals or metatarsals in patients with
osteodystrophy pseudohypoparathyroidism or pseudopseudohypoparathyroidism
[62]
Von Recklinghausen’s Osteitis fibrosa cystica with the formation of peculiar brown tumors
disease of bone [63]
Albright’s anemia Association of primary hyperparathyroidism with anemia [64, 65]
DiGeorge syndrome Hypoparathyroidism, congenital heart disease, and a poorly
developed thymus [66]
Sipple’s syndrome Multiple endocrine neoplasia type 2A (medullary thyroid cancer,
pheochromocytomas, and parathyroid hyperplasia or adenomas) [53]
Adapted from Refs. [53, 62–66]
8.5.2 McCune-Albright Syndrome
Clinical Features
McCune-Albright syndrome is characterized by fibrous dysplasia of bone, sexual
precocity, and characteristic macular lesions called “café-au-lait” skin pigmenta-
tion [61].
Pathophysiology
Mutation in the GNAS gene, which encodes the alpha subunit of the stimulatory
G-protein, is implicated in this syndrome. The mutation results in constitutive acti-
vation (activation in the absence of hormonal stimulation) of this G-protein, which
fuels most of the downstream effects of several hormones. Patients can present
hyperthyroidism, precocious puberty, fibrous dysplasia, growth hormone excess,
and Cushing’s syndrome [61] (Table 8.5).
8.6 Miscellaneous Eponyms
Additional eponyms in endocrinology are briefly outlined in Table 8.6.
8.7 Brief Account of Selected Historical Figures

A
in Endocrinology
8.7.1 Harvey Cushing (1869–1939)
Harvey Cushing, a graduate of Harvard Medical School (1891–1896). A neurosur-

geon by training who became internationally recognized in the early 1900s. He
made significant contributions to the field of neurosurgery and is known as the
father of modern neurosurgery. He, however, holds a special place in clinical endo-
crinology due to his description of “pituitary basophilia” or Cushing’s disease, a
clinical syndrome eponymously named after him [74].
Table 8.6 Additional miscellaneous eponyms

Eponym Description
Stein-Leventhal syndrome Polycystic ovarian syndrome [67]
Von Hippel-Lindau Germline mutation in the VHL tumor suppressor gene
syndrome Pheochromocytomas
Renal cell carcinomas
Central nervous system hemangioblastomas
Pancreatic cysts [68]
Von Recklinghausen’s Neurofibromatosis type 1. Mutation of NF-1 tumor suppressor gene
disease Café-au-lait skin pigmentation
Axillary (Crowe’s sign) and inguinal freckles
Neurofibromas
Pheochromocytomas
Eye manifestations (optic gliomas and pigmented hamartomas
involving the iris) [69]
Mayer-Rokitansky- Agenesis of the Mullerian duct. The genetic basis is still under
Kuster-Hauser (MRKH) investigation. Congenital Mullerian abnormalities ranging from
syndrome minor anomalies to total aplasia of Mullerian derivatives [70]
Burger-Grutz syndrome Lipoprotein lipase (LPL) deficiency due to a genetic mutation in
the LPL gene. Classified as Fredrickson type 1 hyperlipidemia
Xanthomas, lipemia retinalis, hepatosplenomegaly, and pancreatitis
[71]
Montgomery’s syndrome It is also referred to as xanthoma disseminatum (XD). Generalized
xanthomas involving the skin and mucous membranes in the
absence of hyperlipidemia [72] and may be associated with
diabetes insipidus [73]
Medical Trivia
1. Harvey Cushing’s mentor was William Osler, a name known by many a
medical trainee. They formed a professional and personal relationship dur-
ing their time together at Johns Hopkins Hospital in Maryland. He wrote a
two-volume biography of Osler in 1925.
2. The anesthesia record, which details a patient’s vital signs during surgery,
is credited to him.
3. Other non-endocrine eponyms bearing his name include Cushing’s ulcers
and Cushing’s reflex [75].
8.7.2 Hakaru Hashimoto (1881–1934)
Hakaru Hashimoto, a graduate of Fukuoka Medical College (1903–1907). He

reported a case series of a previously unknown form of thyroid disease. Four female
patients aged 40 years and older underwent partial thyroidectomy and were found
to have the characteristic histological findings of chronic lymphocytic thyroiditis.
Hashimoto used the term struma lymphomatosa to describe the unique chronic
inflammation of the thyroid gland [76]. Chronic lymphocytic thyroiditis is epony-
mously named “Hashimoto’s thyroiditis” [77].
Hashimoto compared his findings with those reported in Riedel’s thyroiditis.
Patients with struma lymphomatosa, however, had less fibrosis noted on histology.
Also, the thyroid gland of his subjects on clinical examination did not have the hard
consistency of Riedel’s thyroiditis, which made it a distinct clinical entity [78].
Medical Trivia
1. Hashimoto’s discovery was mostly unrecognized for decades. His findings
were again reported by another clinician who seemingly was unaware of
Hashimoto’s original paper from 1912. He was eventually recognized at an
international thyroid conference in 1938 [78].
2. His paper on struma lymphomatosa was initially published in the German
language [79].
8.7.3 Thomas Addison (1793–1860)
Thomas Addison graduated from the University of Edinburgh Medical School in

1815. Addison’s anemia was first reported in the London Medical Gazette in 1849
as “Anaemia – disease of the suprarenal capsules in which the disease is not dis-
tinctly separated from a new form of anemia.” Trousseau (1801–1867) was the first
to use the eponym “Addison’s disease” [80].
Medical Trivia
1 . Pernicious anemia is eponymously called Addison’s anemia [81].
2. The classical description of vitiligo is credited to Addison [81].
8.7.4 Fuller Albright (1900–1969)
Fuller Albright enrolled at Harvard Medical School in 1920. His research findings
have been influential in our understanding of calcium and bone metabolism. He
shares the eponymous term, McCune-Albright syndrome, with Donovan McCune.
He also made significant contributions to our understanding of osteoporosis,
hyperparathyroidism, and Cushing’s disease [82].
Medical Trivia
1. Albright had an initial desire to become an orthopedic surgeon but had to
shelve those dreams because he did not have the dexterity required in this
surgical subdiscipline. He was fascinated by calcium metabolism and sub-
sequently turned his interests to the field of endocrinology [82].
He investigated the role of estrogen in bone metabolism and postulated
that estrogens stimulate osteoblast function and thus improve bone health
[82]. Albright developed Parkinson’s disease when he was 36 years of age
and unfortunately, suffered an intracranial hemorrhage during a pallidot-
omy, a novel procedure at the time for Parkinson’s disease [82].
8.7.5 Jerome W. Conn (1907–1994)
Jerome W. Conn, a graduate of the University of Michigan Medical School

(1929–1932). He made a lasting contribution to our understanding of the renin-
angiotensin-aldosterone axis [83]. Primary hyperaldosteronism due to a unilateral
aldosterone-secreting tumor is widely reported as Conn’s syndrome [84].
Medical Trivia
1. Conn had an interest in diabetes pathophysiology, and his publications
have provided insights into our understanding of insulin-resistant
states [85].
2. Jerome Conn completed a year of training in general surgery, but redi-
rected his interests to internal medicine and, subsequently, endocrinol-
ogy [85].
8.7.6 Frederick Banting (1891–1941)
Frederick Banting completed his medical education at the University of Toronto in

1916. He is known for the discovery of insulin, an honor he graciously shared with
a junior colleague, Charles H. Best [86].
Medical Trivia
Banting and J.R.R Macleod were awarded the Nobel Prize in Medicine and
Physiology in 1923 [87].
8.7.7 Robert Graves (1797–1853)
Robert Graves completed his medical education at the University of Dublin in 1818.
He described exophthalmic goiter but was arguably not the first to describe this
malady. von Basedow and others documented the clinical features of diffuse toxic
goiter before Robert Graves. Graves’ disease is also referred to as Basedow’s dis-
ease in some medical circles [88].
Medical Trivia
1. He described the “pinpoint” pupillary findings in patients with a pontine
hemorrhage.
2. Graves advocated for discontinuation of the practice of phlebotomy as a
means of treating pyrexia.
3. He proposed the concept of timing of peripheral pulses [88].
8.7.8 Edward Kendall (1888–1972)
Edward Kendall completed his BSc, MSc and Ph.D. degrees at Columbia University,
New York City. He shared the 1950 Nobel Prize for Medicine and Physiology with
Philip Hench (1896–1965), for the discovery of cortisone [89].
Medical Trivia
1. Kendall crystallized thyroxine in 1914, during his time at Mayo Clinic
(Rochester, Minnesota).
2. He isolated at least 28 adrenocortical hormones, including cortisone, a
hormone he initially designated as “compound E” [89].
Clinical Pearl
Occam’s Razor
A principle in medicine that posits that a single unifying diagnosis should
be considered as an explanation for multiple presenting symptoms [90]
Hickam’s Dictum
A principle in medicine which reminds clinicians of the importance of
recognizing that two or more distinct diagnoses can co-exist in the same
patient [91]. Humorously, this is sometimes referred to as the dictum of fleas
and lice, which states, “A diagnosis of fleas does not exclude a diagnosis of
lice in the same patient” [92].
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Appendix
ppendix 1: Selected Genetic Mutations and Their

A
Corresponding Endocrine States
Table A.1 Pituitary gland

Gene(s) Endocrine condition
AIP Familial isolated pituitary adenoma (FIPA) syndrome
KAL1, FGFR1 Kallmann syndrome
PROP1, POUF1F1 Combined pituitary hormone deficiency
Menin Multiple endocrine neoplasia type 1
PRKAR1A Carney complex
GnRH-1, KISS 1 Normosmic idiopathic hypogonadotropic hypogonadism
(IHH)
DAX1 Normosmic IHH and adrenal insufficiency
LEP Normosmic IHH and obesity
Table A.2 Thyroid gland Gene(s) Endocrine condition

SCN4A Hypokalemic periodic paralysis
SLC26A4 Pendred’s syndrome
PAX8, TSHR Congenital hypothyroidism
THRB, THRA Thyroid hormone resistance
Table A.3 Adrenal gland

Gene(s) Endocrine condition
ALADIN Triple A syndrome (primary adrenal insufficiency, alacrima,
and achalasia)
RET Multiple endocrine neoplasia types 2A and 2B
TSC1, TSC2 Tuberous sclerosis complex
VHL Von Hippel-Lindau syndrome
ABCD1 X-linked adrenoleukodystrophy
MC2R Familial glucocorticoid deficiency
SDHx Hereditary pheochromocytoma-paraganglioma syndromes
TP53 Adrenocortical carcinoma
KCNJ5 Familial hyperaldosteronism
SDHx refers to SDHA, SDHB, SDHB, and SDHAF2

https://doi.org/10.1007/978-3-030-49872-6
188 Appendix
Table A.4 Pancreatic gland Gene(s) Endocrine condition

GCK Monogenic diabetes (uncomplicated
course)
HNF1A Monogenic diabetes (sulfonylurea
responsive)
WFS1 Wolfram syndrome (DIDMOAD)
KCNJ11 Neonatal diabetes
ABCC8, KCNJ11 Congenital hyperinsulinism
Table A.5 Parathyroid Gene(s) Endocrine condition

gland, calcium, and bone CASR Familial hypocalciuric hypercalcemia
metabolism ELN Williams-Beuren syndrome
AIRE Autoimmune polyglandular syndrome
type 1
COL1A1, COL1A2 Osteogenesis imperfecta
GCM2, PTH Familial isolated hypoparathyroidism
22q11.2 DiGeorge syndrome
PHEX Hereditary hypophosphatemic rickets
Table A.6 Lipids Gene(s) Endocrine condition

and obesity CETP CETP deficiency
ABCA1 Tangier disease
LEP Congenital leptin deficiency
Apo C-II Hypertriglyceridemia-related disorders
LPL Hypertriglyceridemia-related disorders
LDL-R, PCSK-9 Familial hypercholesterolemia
LCAT Familial LCAT deficiency
MTP Abetalipoproteinemia
Apo E Dysbetalipoproteinemia
ABCG5 Sitosterolemia
ppendix 2: Examination of the Thyroid Gland,

A
an Endocrine Approach
Illustration of the optimal position of the palms and use of the second, third, and
fourth digits in palpating the thyroid gland in the low anterior neck
Our approach involves sequentially inspecting, palpating, percussing (where rel-
evant), and auscultating the thyroid.
Inspection of the Thyroid Gland
• A visible anterior neck mass, which is mobile on deglutition, implies an enlarged

gland. Offer the patient a glass of water to drink. The normal thyroid gland can-
not be visualized on inspection.
• Positive Pemberton’s sign is suggestive of significant retrosternal extension of
a goiter.
Appendix 189
Fig. A.1 Examination of

the thyroid gland
Palpation
• Optimal positioning of the neck will facilitate palpation of the gland. The
patient’s neck should be in a relaxed position, which prevents extensive nuchal
extension or flexion. The sternocleidomastoid muscle should not be under ten-
sion, and there should be adequate room between the chin and the sternum to
allow proper positioning of the hands.
• Sequentially palpate each thyroid lobe and isthmus. Occasionally there might be
an accessory extension of the isthmus – the pyramidal lobe. Check for the con-
sistency of the gland. Avoid deep palpation if the gland is tender, as might occur
in De Quervain’s thyroiditis. The normal thyroid has a mild firm consistency.
The overlying skin is usually freely mobile over it. If the gland is attached to the
overlying skin, it might be suggestive of either a malignancy or Riedel’s
thyroiditis.
• Attempt to feel for any discrete thyroid nodule. These are best appreciated using
the pulp of your examining fingers (second, third,, and fourth digits).
• Ask the patient to swallow during palpation, and check for any retrosternal
extension of the thyroid gland.
• Grade thyromegaly with the WHO classification system (see Sect. 2.3.2).
• Palpate all regional lymph node groups (I to VI).
Percussion
• Percussion of the sternal manubrium may be required in patients with a sus-

pected retrosternal goiter. The percussion note will be dull. This step is seldom
warranted, especially if there is no palpable thyroid tissue extending below the
proximal portion of the manubrium (thoracic aperture).
190 Appendix
Auscultation
• In patients with hyperdynamic circulation, as might occur in overt Graves’ dis-

ease, a bruit may be appreciated over the superior poles of the thyroid in the
vicinity of the superior thyroid arteries.
Appendix 3: Mnemonics in Endocrinology
Pheochromocytomas (the 10 Percent Rule)

• 10% are familial
• 10% are malignant
• 10% are extra-adrenal
More recent evidence points to a genetic cause of pheochromocytomas in up to

30% of patients. This mnemonic provides an understanding of the general behavior
of these tumors.
Pheochromocytomas (8Ps of Presentation)

• Pallor (not flushing)
• Perspiration
• Panic
• Pain (headache)
• Postural dizziness
• Panic attack
• Palpitations
• Paradoxical hypertension in the setting of beta-receptor blockers
Insulinoma (Rule of 10s)

• 10% are malignant
• 10% are multifocal
• 10% are due to multiple endocrine neoplasia type 1
• 10% are ectopic
Insulinomas are usually unifocal and benign.
Causes of Addison’s disease (ADDISON)

• Autoimmune adrenalitis (primary adrenal insufficiency)
• Drugs (inhibitors of steroidogenesis, ketoconazole, mitotane)
• Diffuse amyloid deposition (amyloidosis)
• Infectious agents (tuberculosis, human immunodeficiency virus)
• Secondary causes (hypopituitarism)
• Other causes (adrenal hemorrhage)
• Neoplasia (usually metastases from primary tumors in the lung, breast, stomach,
kidney, rectosigmoid colon or melanoma)
Appendix 191
Causes of Diabetic Ketoacidosis (6 Is)

• Infection (urinary or respiratory tract infections)
• Insulinopenia (absolute in type 1 diabetes, relative in type 2 diabetes)
• Infarction (silent myocardial infarction)
• Injury (significant trauma or stress)
• Index presentation (newly diagnosed type 1 diabetes)
• Issues of adherence to insulin therapy
Cause of Hypercalcemia (SHIFT in calcium)

• Sarcoidosis and other granulomatous diseases
• Hyperparathyroidism, hyperthyroidism, hypervitaminosis A and D
• Immobilization (increased bone resorption)
• Familial (familial hypocalciuric hypercalcemia)
• Tumors, thiazide diuretics, lithium
Clinical features of Cushing’s Syndrome (MOON FACIES)

• Menstrual disorders
• Osteopenia or osteoporosis
• Obesity (central distribution of fat)
• Neurosis (depression or psychosis)
• Face (plethora, hirsutism, acne)
• Altered muscle physiology (proximal muscle weakness)
• Supraclavicular and dorsocervical fat pads
• Infection
• Elevated blood pressure
• Skin (easy bruisability)
Causes of hypoglycemia, FEELING Dizzy

• False hypoglycemia (pseudohypoglycemia not meeting Whipple’s criteria)
• Exogenous (insulin or insulin secretagogue)
• Ethanol
• Liver failure
• Immune dysfunction (stimulating anti-insulin antibodies)
• Neoplastic (insulinoma or sarcomas producing IGF-2)
• Glandular dysfunction (pituitary insufficiency, adrenal insufficiency)
• Drugs (quinolones, pentamidine, beta-blockers, ACE inhibitors)
Multiple Endocrine Neoplasia Type 1 (PPP)

• Pituitary adenoma
• Pancreatic adenoma
• Parathyroid adenoma
Multiple Endocrine Neoplasia Type 2A (MPP)

• Pheochromocytoma
• Medullary thyroid carcinoma
• Parathyroid adenoma
192 Appendix
Multiple Endocrine Neoplasia Type 2B (MPM)

• Pheochromocytoma
• Medullary thyroid carcinoma.
• Mucosal neuromas and a marfanoid body habitus
Management of Osteoporosis (ABCDE)

• Activity (weight-bearing exercise)
• Bisphosphonates
• Calcium supplementation
• D (vitamin D supplementation)
• Estrogens (menopausal hormone therapy)
Causes of Gynecomastia (MAKE BREAST)

• Marijuana
• Alcohol
• Klinefelter’s syndrome
• Estrogen excess
• Baby (circulating maternal estrogens)
• Receptor blockers (ketoconazole, calcium channel blockers, and H2 blockers)
• Elderly
• Antineoplastic agents (alkylating agents)
• Spironolactone
• Tumors (adrenal or testicular)
Index
A 1ɑ hydroxylase deficiency, 117

Acanthosis nigricans (AN), 6, 132 Albers-Schönberg disease, 176
clinical features, 77 Albright hereditary osteodystrophy
diabetes mellitus, 77, 78 (AHO), 111, 114
estrogen resistance, 141 Aldosterone-mediated sodium and water
polycystic ovary syndrome, 132 conservation, 56
RMS Allgrove’s syndrome, 175
clinical features, 86 Apolipoprotein CII (Apo-CII), 155
insulin resistance, 87, 88 Apoproteins/apolipoproteins, 154
insulin secretion, 87, 88 Arginine vasopressin (AVP), 19
pathophysiology, 86 Aromatase deficiency, 137
Achlorhydria-induced gastric carcinoids, 93 Arterial hypertension, 129
Acne, 132 Atrial fibrillation, 57
Acquired lipodystrophy syndrome, 164 Audible wheezing, 91
Acrochordons (skin tags), 9, 78 Autonomic neuropathy, 84
Acromegaly, 9, 10 Autosomal dominant hypocalcemia with
Acanthosis nigricans, 8–9 hypercalciuria (ADHH), 107
acrochordons, 9–10 Azoospermia factor (AZF) region, 138
colonic polyps, 10–11
frontal bossing, 9
hypertension, 11–12 B
prognathism, 9 Band keratopathy/cataracts, 104, 105
Tinel sign, 11 Basal insulin physiology, 88
Acute abdomen, 103, 104 β adrenergic receptors, 112
Acute pancreatitis, 103, 160 17β-estradiol, 140
Addison’s disease, 55 11 beta-hydroxylase deficiency, 71
Adenylyl cyclase (AC), 111 11 beta-hydroxysteroid dehydrogenase, 2
Adipocytokine, 165 3beta-hydroxysteroid dehydrogenase type 2
Adiponectin, 165 deficiency, 70
Adrenal insufficiency, 161–163 Bile salts, 154
Adult growth hormone deficiency, 14–16 Bitemporal hemianopsia, 13–14
abnormal body composition, 14–16 Brachydactyly, 112
hypertriglyceridemia-induced pancreatitis Bradycardia, 28
management, 14 Bronchospasm, 91
QoL scores, 15 Brown adipose tissue, 161
Advanced glycated end products (AGEs), 82 Bullosis diabeticorum, 80

https://doi.org/10.1007/978-3-030-49872-6
194 Index
C striae and skin atrophy, 4

Calcium sensing receptor (CaSR) Cutaneous flushing, 89–91
kidney, 106 Cutaneous xanthoma, 153
parathyroid gland, 106 Cystic fibrosis-related diabetes (CFRD), 80
Carcinoid heart disease (CHD), 92
Carcinoid syndrome (CS), 94
bronchospasm, 91 D
carcinoid heart disease, 92 Dental abscess, 119
cutaneous flushing, 89–91 Dental manifestations, 113
diarrhea, 90 Dermal lipids, 153
pellagra, 92, 93 Diabetes mellitus
Cardiogenic shock, 66 acanthosis nigricans, 77, 78
Carney complex, 12 acrochordons, 78
Carney Dyad/Carney-Stratakis syn- diabetic dermopathy, 78
drome, 174–175 diabetic foot
Carpal tunnel syndrome (CTS), 11 clinical features, 83
Central diabetes insipidus diabetic peripheral neuropathy, 84
NSAIDs, 20 pathophysiology, 83, 84
polyuria and polydipsia, 18, 19 diabetic ketoacidosis, 81
prostaglandin E2, 20 diabetic retinopathy
triphasic response, 20 advanced glycated end products, 82
Cervical lymphedema, 129 clinical features, 81
Charcot's foot, 84 fundoscopic findings, 83
Cholesterol esters (CEs), 154 polyol pathway, 81, 82
Chronic diarrhea, 95 lipodystrophy due to insulin injections, 79
Chrousos syndrome, 62 necrobiosis lipoidica diabeticorum, 78, 79
Chvostek’s sign, 109 pathophysiology, 80
Chylomicrons, 155 skin manifestations, 80
Colonic polyps, 10–11 Turner’s syndrome, 130
Complete androgen insensitivity syn- Diabetic dermopathy (DD), 78
drome (CAIS) Diabetic dyslipidemia, 158
clinical features, 143 Diabetic foot
external and internal genitalia abnormali- clinical features, 83
ties, 142 diabetic peripheral neuropathy, 84
normal breast tissue development, 142, 143 insulin resisance, 84, 85
pubic hair and and axillary areas, 144 pathophysiology, 83, 84
undescended testes, 144 Diabetic ketoacidosis (DKA), 81, 175
Congenital adrenal hyperplasia, 6 Diabetic peripheral neuropathy (DPN), 83, 84
Congenital growth hormone receptor Diabetic retinopathy
deficiency (GHRD), 18 advanced glycated end products, 82
Congenital hyperplasia (CAH), 78 clinical features, 81
Congenital leptin deficiency, 160, 161 fundoscopic findings, 83
Congenital lipoid hyperplasia (CLH), 70 polyol pathway, 81, 82
Congestive heart failure, 115 Diarrhea, 90
Corneal arcus (CA), 151, 152 Dietary triglycerides, 154
Craniopharyngiomas, 162 Dihydrotesterone, 132
Cushings disease 1,25-dihydroxy vitamin D3, 117
facial plethora, 4–5 Direct ophthalmoscopy, 81
fat maldistribution, 3–4 Dot-and-blot hemorrhages (NPDR), 81, 83
fragility fractures, 6, 7 Dry skin (xerosis), 29
hirsutism, 5, 6 Dysbetalipoproteinemia, see Type III
hyperpigmentation, 7–8 hyperlipoproteinemia
hypertension, 6 Dyslipidemia, 151, 156, 158, 159
proximal myopathy, 1–3 Dyslipidemia-induced microangiopathy, 153
Index 195
E Gestational diabetes mellitus (GDM), 80

Ectopic basal ganglia calcifications, 110 Glucagonoma, 88, 89
Edward Kendall (1888-1972), 181–182 Glucocorticoid-induced osteoporosis
Endogenous hypercortisolism, 6 (GIOP), 6
Enterochromaffin cells, 94 Glucose transporter 4 (GLUT-4) recep-
Eruptive xanthomas (EX), 80, 152 tors, 134
Estrogen receptor ɑ gene (ESR1), 142 Gonadal dysgenesis, 128, 130
Estrogen receptor β (ESR2), 142 Granuloma annulare, 80
Estrogen resistance, 137 Graves’ disease, 32
acanthosis nigricans, 141 cutaneous hyperpigmentation, 38
clinical features, 141 gynecomastia, 37
ESR1 and ESR2 mutations, 142 lymphadenopathy, 37
tall stature, 141 onycholysis, 35
Euthyroid goiter with thoracic outlet syndrome pretibial myxedema, 34, 38
Horner’s syndrome, 41, 42 tachycardia, 36, 37
nodular goiter formation, 41 thyroid acropachy, 34, 35
Pemberton’s sign, 39, 40 thyroid bruit and thrill, 36
Riedel’s thyroiditis, 41 thyroid eye disease, 32–34
superior vena cava syndrome, 40 thyroid hormone synthesis, 38, 39
WHO classification, 40 thyrotoxic periodic paralysis, 35
upper eyelid retraction, 33
weight loss, 38
F Growth hormone (GH) deficiency, 112
Facial plethora, 4, 5 Growth hormone-releasing hormone (GHRH)
Fahr’s syndrome, 110 resistance, 16, 114
Familial combined hyperlipidemia, see Type Gsα gene, 113
IIb hyperlipoproteinemia Guanine nucleotide binding protein, alpha
Familial glucocorticoid deficiency stimulating (GNAS) gene, 112, 113
generalized glucocorticoid resistance, 62 Gynecomastia, 12–13, 37, 135, 137
hyperpigmentation, 61
hypoglycemia, 61–63
Familial hypercholesterolemia, see Type IIa H
hyperlipoproteinemia Hakaru Hashimoto (1881-1934), 178–179
Familial hypocalciuric hypercalcemia, 106 Hard exudates (NPDR), 83
Familial LCAT deficiency, 159 Harvey Cushing (1869-1939), 177–178
Fasting insulin levels, 87 Hashimoto’s thyroiditis
Ferriman-Gallwey score, 67, 131 bradycardia, 28
Ferrophilic fungi, 81 dry skin, 29
Fibroblast growth factor 23 (FGF-23), 117, galactorrhea, 30, 31
119, 120 hyporeflexia, 30
Folic acid, 83 macroglossia, 29
Fractionated metanephrines, 65 pericardial and pleural effusions, 28
Fragility fractures, 104, 139 pituitary pseudotumor, 32
Frank’s sign, 153 proximal myopathy, 30
Frank-Starling law of the heart, 36, 115 Queen-Anne’s sign, 27–28
Frederick Banting (1891-1941), 180–181 Hereditary vitamin D resistant rickets type 2
Free fatty acids (FFAs), 154, 155 1ɑ hydroxylase deficiency, 117
Frontal bossing, 9 calcium and phosphorus homeostasis, 118
Fuller Albright (1900-1969), 179–180 1,25-dihydroxy vitamin D3, 117
FGF-23, 117
PTH, 117
G rickets, 116, 117
Galactorrhea, 12–13, 30, 31 Hickam’s dictum, 181
Gastric carcinoids, 93 Hirsutism, 5, 6, 14, 131
196 Index
Histiocytosis X, 172 I
Homeostasis model assessment – insulin Idiopathic hypercalcemia, 108
resistance (HOMA-IR), 87 Inactivating PTH/PTHrp signaling disorders
Horner’s syndrome, 41, 42 (iPPSD), 113
Hot flashes, 140 Insulin-like growth factor 1 (IGF-1), 16
Houssay phenomenon, 55 Insulin resistance, 6, 84, 85
5-HT2B receptors, 92
HVDRR-II, see Hereditary vitamin D resistant
rickets Type 2 J
Hydrolysis of TAGs, 154 Jerome W. Conn (1907-1994), 180
17 hydroxylase deficiency, 70 Journal of the American Medical Association
21 hydroxylase deficiency, 71 (JAMA), 110
Hypercalcemia, 104, 106–108 Juxtaglomerular apparatus, 53
Hypergastrinemia, 103, 104
Hyperglycemia, 80, 81, 83, 85, 96
Hypergonadotropic hypogonadism, 138 K
Hyperhidrosis, 66 Klinefelter’s syndrome (KS), 138, 139
Hyperinsulinemia, 78, 85, 86, 132 Koebner phenomenon, 152
Hyperinsulinemic-euglycemic clamp, 88 Kussmaul’s breathing, 175
Hyperlipoproteinemia, 156–160
Hyperparathyroidism
acute abdomen, 103, 104 L
band keratopathy, 104, 105 Laron type dwarfism
clinical manifestations, 105 obesity, 16, 17
fragility fractures, 104 short stature, 16
hypertension, 105, 106 small genitalia, 17, 18
osteoblast-osteoclast interaction, 105 Latent autoimmune diabetes of adulthood
Hyperphagia, 161 (LADA), 80
Hyperprolactinemia, 12 Lecithin cholesterol acyltransferase, 159
Hypertension, 55–57, 105, 106, 129 Leptin, 161, 165
Hypertrichosis, 86 Leptin receptor (LEPR) gene, 161
Hypertriglyceridemia, 160 Lipemia retinalis, 153, 154
Hypertriglyceridemia-induced pancreatitis Lipid metabolism
management, 14 apoproteins/apolipoproteins, 154
Hypocalcemia, 109–112 congenital leptin deficiency, 160, 161
Hypogonadism, 12 corneal arcus, 151, 152
Hypothalamic-pituitary-gonadal axis, 161 familial LCAT deficiency, 159
Hypokalemia, 58 Frank’s sign, 153
Hypoparathyroidism lipemia retinalis, 153, 154
Chvostek’s sign, 109 lipodystrophy syndrome (see
ectopic basal ganglia calcifications, 110 Lipodystrophy syndromes)
hypotension, 110 lipoproteins (see Lipoproteins)
papilledema, 110 pancreatitis, 160
pustular psoriasis, 111 POMC (see Proopiomelanocortin (POMC)
seizures, 109 deficiency)
Trousseau’s sign, 109 reverse cholesterol transport pathway,
Hypoplasia, 129 156, 157
Hyporeflexia, 30 Tangier disease, 159
Hypotension, 110 type I hyperlipoproteinemia, 156
Hypothalamic-pituitary-testicular axis, 136 type IIa hyperlipoproteinemia, 157
Hypothalamic-pituitary-thyroidal axis, 161 type IIb hyperlipoproteinemia, 158
Index 197
type III hyperlipoproteinemia, 158 Metformin, 83

type IV hyperlipoproteinemia, 158 Microaneurysms of retinal capillaries
type V hyperlipoproteinemia, 158, 159 (NPDR), 83
xanthelasmas, 153 Mineralocorticoid replacement therapy, 53
xanthomas, 152, 153 Modified Ferriman-Gallway score, 131
Lipoatrophy (LA), 79 Monoacylglycerol (MAG), 154
Lipodystrophy syndromes, 79 Monogenic obesity, 161
adipose tissue atrophy, 163 Mosaics 45, 128
fat loss distribution, 163 Motor neuropathy, 84
hepatomegaly, 163 Mucormycosis, 81
insulin resistance, 164, 165 Multiple endocrine neoplasia (MEN)
mechanisms, 164 type 1, 12
screening for, 165 Muscle weakness, 57
Lipohypertrophy (LH), 79 Myo-inositol, 83
Lipoproteins, 154
metabolism, 154, 155
synthesis pathway, 155 N
Low-density lipoprotein (LDL), 154–156 Necrobiosis lipoidica diabeticorum
Lymphadenopathy, 37 (NLD), 78, 79
Necrolytic migratory erythema (NME), 88
Nelson’s syndrome, 7, 8
M Neovascularization (PDR), 83
Macroglossia, 29 Neuroendocrine tumor cellular model, 90
Macular edema (PDR), 83 Neuroendocrine tumors (NETs), 94–96
Male hypogonadism Niacin deficiency, 93
aromatase deficiency, 137 Nicotinamide dehydrogenase phosphate
body composition changes, 138 (NADPH), 84
estrogen resistance, 137 NME, see Necrolytic migratory erythema
fragility fracture, 137 Nonclassic congenital adrenal hyperpla-
gynecomastia, 135, 137 sia (NCCAH)
height loss, 137 clinical hyperandrogenism, 67–68
Klinefelter’s syndrome, 138, 139 congenital adrenal hyperplasia, 69–71
normal adult testicular size, 135 insulin resistance, 68, 69
testicular volume, 134, 135 steroid replacement therapy, 69
46XX testicular disorder, 138 testicular adrenal rest tumors, 68
Maternal Gsα gene expression, 113 Non-proliferative diabetic retinopathy
Maturity onset diabetes of the young (NPDR), 81
(MODY, 80 Normal adult testicular size, 135
McCune-Albright syndrome, 12, 177 Normal breast tissue development, 142, 143
Medullary thyroid cancer Novel tryptophan hydroxylase enzyme
cervical mass, 44 inhibitor, 92
endocrine conditions, 44
facial flushing, 44
prophylactic total thyroidectomy, 44 O
Melanocortin signaling pathways, 112 Obesity
Melanocortin type 1 receptor (MC1-R), 162 congenital leptin deficiency, 160, 161
Melanocytic nevi (MN), 130 polycystic ovary syndrome, 132, 133
Melanocyte-stimulating hormone, 161 proopiomelanocortin, 161
Melanogenesis, 54 pseudohypoparathyroidism, 112
Menopause Occam’s razor, 181
body composition changes, 140 Onycholysis, 35
cardioprotective effects of estrogen, 140 Orchidometer, 134, 135
fragility fractures, 139 Organomegaly, 86
hot flashes, 140 Osteitis fibrosa cystica (OFC), 107
vaginal dryness, 139–141 Osteoblasts, 6
198 Index
Osteoclastogenesis, 115 cardiogenic shock, 66

Osteocytes, 7 catecholamine and fractionated metaneph-
Osteoprotegerin (OPG), 104 rines, 65
catecholamine-induced hyperglycemia, 64
clinical features, 67
P genetic conditions, 67
Paget’s disease of bone (PDB) hyperhidrosis, 66
cardiac manifestations, 116 hypertension, 63–65
congestive heart failure, 115 hypotension, 65
fractures and bone deformity, 114, 115 PHP, see Pseudohypoparathyroidism
sensorineural hearing loss, 115, 116 Pituitary pseudotumor, 32
Palmar xanthomas (PX), 152 Polycystic ovary syndrome (PCOS), 6, 78
Pancreatic glands acanthosis nigricans, 132
carcinoid syndrome (see Carcinoid acne, 132
syndrome) evaluation, 134
diabetes mellitus (see Diabetes mellitus) hirsutism, 131
glucagonoma (see Necrolytic migratory insulin resistance, 134
erythema (NME)) obesity, 132, 133
RMS (see Rabson-Mendenhall syn- pathophysiology, 133
drome (RMS)) Polyol pathway, 81, 82
VIPomas (see VIPomas) POMC, see Proopiomelanocortin
Pancreatic islet cells, 96 Postprandial insulin physiology, 88
Pancreatogenic diabetes (Type 3c DM), 80 Posttransplant diabetes mellitus (PTDM), 80
Parathyroid glands Postural hypotension
HVDRR-II (see Hereditary vitamin D clinical features, 51
resistant rickets Type 2 juxtaglomerular apparatus, 52, 53
(HVDRR-II)) pathophysiology, 51
hyperparathyroidism (see Prader orchidometer, 134, 136
Hyperparathyroidism) Pressure natriuresis, 58
hypoparathyroidism (see Pretibial myxedema (PM), 34
Hypoparathyroidism) Primary adrenal insufficiency
PDB (see Paget's disease of bone (PDB)) hyperpigmentation, 53, 54
PHP (see mineralocorticoid replacement therapy, 53
Pseudohypoparathyroidism (PHP)) postural hypotension
XLHR (see X-linked Hypophosphatemic clinical features, 51
Rickets (XLHR)) juxtaglomerular apparatus, 52, 53
Parathyroid hormone (PTH) pathophysiology, 51
autosomal dominant hypocalcemia with Primary hyperaldosteronism
hypercalciuria, 107 atrial fibrillation, 57
CaSR, 106 dehydration, 57–59
familial hypocalciuric hypercalcemia, 106 hypertension, 55–57
osteitis fibrosa cystica, 107, 108 muscle weakness, 57
skeletal effects, 108 pseudohyperaldosteronism (see
Parathyroid hormone-related peptide (PTHrp) Pseudohyperaldosteronism)
mediated signaling, 112 screening, 58, 59
PCOS, see Polycystic ovary syndrome sodium and water-conserving effects, 58
PDB, see Paget’s disease of bone Prognathism, 9
Pellagra, 92, 93 Prolactinoma
Pendred’s syndrome, 172, 173 bitemporal hemianopsia, 13–14
Persistent hyperinsulinemia, 86 galactorrhea, 12–13
Pheochromocytomas and paraganglioma gynecomastia, 12–13
syndrome hypogonadism, 12
cardiac effects of catecholamines, 63 Proliferative diabetic retinopathy (PDR), 81
Index 199
Proopiomelanocortin (POMC) deficiency Riedel’s thyroiditis, 41, 179

adrenal insufficiency, 162 RMS, see Rabson-Mendenhall syndrome
anorexigenic (satiety) pathway, 162 Robert Graves (1797-1853), 181
clinical features, 162
craniopharyngiomas, 162
reddish hair, 161 S
Propionibacterium acnes, 132 Scleroderma diabeticorum, 80
Proprotein convertase subtilisin kexin type Secretory diarrhea, 94
9 (PCSK9), 157 Seizures, 109
Proximal myopathy, 30 Sensorineural hearing loss (SNHL), 115, 116
Pseudoglucagonoma syndrome, 89 Sensory neuropathy, 84
Pseudohyperaldosteronism Serotonin, 90, 92
cardiac arrest, 60 Sertoli cells (SCs), 135
causes, 59 Sex hormone-binding globulin (SHBG), 140
clinical manifestations, 60 Sexual infantilism, 130
folliculitis and atopic dermatitis, 60–61 Short stature, 16
PHA type 1 mimics, 60 pseudohypoparathyroidism, 111, 112
Pseudohypoparathyroidism (PHP) Turner’s syndrome, 127, 128
Albright hereditary osteodystrophy, 114 X-linked hypophosphatemic rickets,
brachydactyly, 112 117, 118
dental manifestations, 113 Short stature homeobox-containing (SHOX)
obesity, 112 gene, 128
pseudopseudohypoparathyroidism, Simple hypertriglyceridemia, see Type IV
113, 114 hyperlipoproteinemia
short stature, 111, 112 Skin atrophy, 4
Pseudohypoparathyroidism type 1B Skin crease, see Frank’s sign
(PHP1B), 113 Sodium-potassium adenosine triphosphatase
Pseudopseudohypoparathyroidism (Na-K-ATPase), 106
(PPHP), 113 Somogyi effect, 175–176
Pubic hair, 144 Steroid replacement therapy, 69
Pustular psoriasis, 111 Striae, 4
Superior vena cava (SVC) syndrome, 40
Q
Queen-Anne’s sign, 27–28 T
QUICKI, 87 Tachycardia, 36, 37
Tall stature, estrogen resistance, 141
Tangier disease, 159
R TELESTAR, 92
Rabson-Mendenhall syndrome (RMS), 86–88 Telotristat ethyl, 90
Receptor activator of nuclear factor κ-B ligand Testicular adrenal rest tumors (TARTs), 68
(RANK-L), 7, 104 Testicular volume (TV), 134, 135
Receptor for AGE (RAGE), 82 Testosterone, 132–135, 137, 138
Reddish hair, 161 Thomas Addison (1793-1860), 179
Renin-angiotensin-aldosterone axis, 11, 129 Thyroid acropachy (TA), 34, 35
Renin-angiotensin-aldosterone system Thyroid hormone resistance syndromes
(RAAS), 36, 106 Goiter, 42
Resting energy expenditure (REE), 38, 140 short stature, 42, 43
Retinal detachment (PDR), 83 thyroid hormone receptor alpha
Reverse cholesterol transport pathway, (THRA), 43
156, 157 thyroid hormone receptor beta (THRB), 43
Rhizopus species, 81 Thyrotoxic periodic paralysis (TPP), 35
Rickets, 116, 117 Triglycerides (TAGs), 154
200 Index
Trousseau’s sign, 109 VIPoma

Tuberous xanthomas, 152 biochemical abnormalities, 95
Tumor-induced osteomalacia (TIO), 119 chronic diarrhea, 95
Tumor-necrosis-factor-alpha (TNF-α), 134 clinical features, 94
Turner’s syndrome (TS) effects, 95
diabetes mellitus, 130 pathophysiology, 94
endocrinopathies, 130
hypertension, 129
lymphedema, 129 W
melanocytic nevi, 130 Watery diarrhea, hypokalemia, hypochlorhy-
sexual infantilism, 130 dria or achlorhydria (WDHA)
short stature, 127, 128 syndrome, 94
webbed neck, 129 Webbed neck (pterygium colli), 129
Type A insulin resistance, Weber and Rinne tests, 115
see Rabson-Mendenhall Wolfram syndrome (DIDMOAD), 171
syndrome (RMS)
Type 1 diabetes mellitus (T1DM), 80
Type 2 diabetes mellitus (T2DM), 80 X
Type I hyperlipoproteinemia, 156 Xanthelasmas, 153
Type IIa hyperlipoproteinemia, 157 Xerosis, 86
Type IIb hyperlipoproteinemia, 158 X-linked hypophosphatemia (XLH), 119
Type III hyperlipoproteinemia, 158 X-linked hypophosphatemic rickets (XLHR)
Type IV hyperlipoproteinemia, 158 dental abscesses, 119
Type V hyperlipoproteinemia, 158 FGF-23, 119, 120
short stature, 117, 118
X-linked hypophosphatemia, 119
V 46,XX testicular disorder, 138
Vaginal dryness, 139–141 XXY genotype, 138
Vasculopathy, 84
Vasoactive intestinal peptide (VIP), 95
Vellus (nonpigmented or nonsexual) Z
hair, 144 Zollinger-Ellison syndrome (gastrinoma), 95

Endocrine Pathophysiology: A Concise Guide To The Physical Exam Andrea Manni Akuffo Quarde

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Endocrine Pathophysiology: A Concise Guide To The Physical Exam Andrea Manni Akuffo Quarde

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Endocrine

A Concise Guide to the Physical

ISBN 978-3-030-49871-9 ISBN 978-3-030-49872-6 (eBook)

© Springer Nature Switzerland AG 2020

To my wife, Rosemary, for her support

To my beloved parents, for being inspiring

To my wife Anisa and children Stephanie

Hershey, PA, USA Andrea Manni

Hershey, PA, USA Andrea Manni

1 Pituitary Gland Signs�������������������������������������������������������������������������������� 1

2.1.2 Bradycardia ���������������������������������������������������������������������������� 28

3.4 Familial Glucocorticoid Deficiency���������������������������������������������������� 61

5.2 Hypoparathyroidism �������������������������������������������������������������������������� 109

6.6 Complete Androgen Insensitivity������������������������������������������������������� 142

8.7.6 Frederick Banting (1891–1941)���������������������������������������������� 180

Andrea Manni MD – Professor of Medicine, Chief of the Division of

Akuffo Quarde MD, PgD (Clinical Trials) – Endocrinologist, Sanford Health

1. Understand the metabolic effects of growth hormone in both hormone

1.1 Cushing’s Disease

1.1.1 Proximal Myopathy

© Springer Nature Switzerland AG 2020 1

11β -HSD1 11β -HSD2

Fig. 1.1 The cortisol-to-cortisone shunt – the role of 11beta-hydroxysteroid dehydrogenases in

Table 1.1 Comparison of the isoforms of 11β HSD

In both ACTH-dependent and ACTH-independent Cushing’s syndrome, there is

1.1.2 Fat Maldistribution

fatty acid synthesis. This is a novel mechanism underlying the distribution of

1.1.3 Striae and Skin Atrophy

1.1.4 Facial Plethora

External root sheath

Blood capillary with

Associated Endocrinopathies/Differentials of Hirsutism

1.1.7 Fragility Fractures

1. Decreased bone formation occurs because of increased glucocorticoid-mediated

2. Osteocytes which act as mechanoreceptors are also subject to apoptosis in the

Fig. 1.3 Clinical features

Questions You Might Be Asked on Clinical Rounds

1.2.1 Acanthosis Nigricans

1.2.2 Frontal Bossing and Prognathism

1.2.3 Acrochordons and Other Skin Manifestations

Table 1.2 Mechanisms underlying other manifestations of acromegaly

1.2.4 Colonic Polyps

1.2.5 Tinel’s Sign (Carpal Tunnel Syndrome)

Questions You Might Be Asked on Clinical Rounds

1. Co-secretion of growth hormone and prolactin by the tumor may occur in

1.3.2 Gynecomastia and Galactorrhea

1.3.3 Bitemporal Hemianopsia

Questions You Might Be Asked on Clinical Rounds

How does hyperprolactinemia cause hirsutism?

• Prolactin receptors are present on dermal papilla cells and keratinocytes.

1.4 Adult Growth Hormone Deficiency

1.4.1 Abnormal Body Composition

Questions You Might Be Asked on Clinical Rounds

Triglyceride-rich White adipose tissue

Prandial period (storage of fat) Fasting period (mobilization of fat)

+ INS = Facilitated by insulin - INS = Inhibited by insulin

1.5 Growth Hormone Insensitivity (Laron-Type Dwarfism)

1.5.1 Short Stature

1. The role of growth hormone in stimulating chondrocytes in the proliferative zone

Hershey, PA, USA Andrea Manni

Hershey, PA, USA Andrea Manni

1 Pituitary Gland Signs�� 1

2.1.2 Bradycardia �� 28

3.4 Familial Glucocorticoid Deficiency�� 61

5.2 Hypoparathyroidism �� 109

6.6 Complete Androgen Insensitivity�� 142

8.7.6 Frederick Banting (1891–1941)�� 180

1.1 Cushing’s Disease

1.1.1 Proximal Myopathy

1.1.2 Fat Maldistribution

1.1.3 Striae and Skin Atrophy

1.1.4 Facial Plethora

1.1.7 Fragility Fractures

1.2.1 Acanthosis Nigricans

1.2.2 Frontal Bossing and Prognathism

1.2.3 Acrochordons and Other Skin Manifestations

1.2.4 Colonic Polyps

1.2.5 Tinel’s Sign (Carpal Tunnel Syndrome)

1.3.2 Gynecomastia and Galactorrhea

1.3.3 Bitemporal Hemianopsia

1.4 Adult Growth Hormone Deficiency

1.4.1 Abnormal Body Composition

1.5 Growth Hormone Insensitivity (Laron-Type Dwarfism)

1.5.1 Short Stature

1.5.3 Small Genitalia

1.6 Central Diabetes Insipidus

1.6.1 Dehydration due to Polyuria and Polydipsia

2.1 Hashimoto’s Thyroiditis

2.1.1 Queen Anne’s Sign

2.1.3 Pericardial and Pleural Effusions

2.1.4 Dry Skin

2.1.7 Proximal Myopathy

2.2 Graves’ Disease

2.2.1 Thyroid Eye Disease

2.2.2 Pretibial Myxedema

2.2.3 Thyroid Acropachy

2.2.5 Periodic Paralysis

2.2.6 Thyroid Bruit and Thrill

2.2.10 Change in Body Composition (Weight Loss)

2.3 Euthyroid Goiter with Thoracic Outlet Syndrome

2.3.1 Pemberton’s Sign

2.4 Resistance to Thyroid Hormone

2.4.2 Short Stature

2.5 Medullary Thyroid Cancer

2.5.2 Cervical Mass

3.1 Primary Adrenal Insufficiency

3.1.1 Postural Hypotension

3.2 Primary Hyperaldosteronism

3.2.2 Muscle Weakness

3.2.3 Atrial Fibrillation