INFLAMMATORY

BOWEL DISEASES (IBD)

 INFLAMMATORY BOWEL DISEASES
Definition

o Immune-mediated chronic intestinal conditions

o Aetiology still undefined
o Common cause for seeking medical gastro consultation

• ULCERATIVE COLITIS
• CROHN’S DISEASE
• INDETERMINATE COLITIS (10-15%)
 INFLAMMATORY BOWEL DISEASES
Epidemiology

ULCERATIVE COLITIS CROHN’S DISEASE

Incidence (North America) per PY 2.2-14.3:100,000 3,1-14,6:100.000
Age of onset 15-30; 60-80 15-30; 60-80
Ethnicity Jewish>non-Jewish white> African >America< Hispanic>Asian
Male/female ratio 1:1 1.1-1.8:1
Smoking May prevent disease May cause disease
OR 0.58 (0.45-0.75)
Oral contraceptives Increased risk OR 1.4
Appendicectomy Protective Not protective
Monozygotic twins 6% concordance 58% concordance
Dizygotic twins 0% concordance 4% concordance
 INFLAMMATORY BOWEL DISEASES
Epidemiology

• IBD is a familial disease in 5-10% of patients, but sporadic cases can

also occur
• First degree relative lifetime risk: 10%

• Additional evidence association with certain genetic syndromes

(Turner’s syndrome, IPEX syndrome, hypogammaglobulinemia…)
 INFLAMMATORY BOWEL DISEASES
Epidemiology

In genetically predisposed individuals both exogenous factors (intestinal

microbiota) and endogenous host factors (intestinal epithelial barrier,
innate ad adaptive immunity) interact to cause a state of dysregulated
mucosal immune function that is further modified by environemental
factors (smoking, entheropathogens)
ULCERATIVE COLITIS
 ULCERATIVE COLITIS
Definition

Ulcerative colitis
• Mucosal disease involving the RECTUM and extending
proximally to involve all or part of the colon
• Diffuse (non-segmental) mucosal disease (NO SKIP
AREAS)
20% 35-40% • Always biopsy normal mucosa! (miscroscopic
inflammation)
• PROCTOSYGMOIDITIS: rectum, rectum+sigmoid colon 40-
50%
1% 40-50% • LEFT COLITIS: disease beyond the left colon, but not
whole colon 30-40%
• PANCOLITIS: 20% (in 10-20% of these patients backwah
ileitis extending to 2-3 cm into the terminal ileum)
RECTUM CAECUM
• RECTUM SPARING UC: very rare, associated to PSC
 ULCERATIVE COLITIS
Epidemiology

• More prevalent than Crohn’s disease

• North America and Northern EU have the highest prevalence and incidence
• Incidence higher in developed countries (urban > rural areas)
• Bimodal peak of incidence (15-30 and 50-70 years)
• M=F (although slightly predominant in men)

ENVIRONMENTAL FACTORS
• Smoking: OR 0.58 (0.45-0.75)
• Acute GI infections (Salmonella, Shigella, Campylobacter) double the risk of UC
• Appendicectomy: OR 0.31 (0.25-0.38)
• Breastfeeding: OR 0.56 (0.38-0.81)
 ULCERATIVE COLITIS
Genetic factors

• HLA DRB1*0103 disease susceptibility, extensive disease, risk of

colectomy (OR 84, 9-785)

• GWAS studies have revolutioned the field of polygenic disease

• 47 susceptibility loci (20 overlapping with Crohn’s disease, eg IL-23,
IL-10, JAK-2)

• Specific loci for UC: hepatocyte nuclear factor-4alpha, CDH1, laminin-

beta1, E-Cadherin (defective barrier function)
ULCERATIVE COLITIS
Pathophysiology
 ULCERATIVE COLITIS
Clinical presentation

• Diarrhoea (also nocturnal)

• Rectal bleeding
• Passage of mucus
• Tenesmus
• Urgency
• Abdominal pain (severe disease)
• Weight loss (severe disease)
• Fever (severe disease)
• Anorexia (severe disease)
• Extraintestinal manifestations
• Increased CRP, ESR, anemia
• Increased fecal calprotectin (correlated with histologic inflammation and predicts
relapses)
 ULCERATIVE COLITIS
Clinical presentation

• EXTRAINTESTINAL MANIFESTATIONS
• Can predate the onset of GI symptoms in 10% of patients

HEPATOBILIARY
• PRIMARY SCLEROSING CHOLANGITIS ( 5% UC; 50-75% PSC have IBD)
• Intraepathic and extraepathic bile ducts inflammation and fibrosis biliary cirrhosis and hepatic
failure
• P-ANCA +ve
• Traditional gold standard diagnostic: endoscopic retrograde cholangiopancreatography (ERCP)
• Magnetic resonance cholangiopancreatography (MRCP)
• 10-15% lifetime risk of developing cholangiocarcinoma and increased risk of colon cancer
• Therapy: ursodeoxycholic acid
 ULCERATIVE COLITIS
Clinical presentation

• EXTRAINTESTINAL MANIFESTATIONS
RHEUMATOLOGIC
• Peripheral seronegative arthitis (10-15%): asymmetric, polyarticular, migratory, large joints +++
• Ankylosing spondylitis (10% CD>UC; HLA-B27+)
• Sacroileitis
DERMATOLOGIC
• Erythema nodosum (10% UC)
• Pyoderma gangrenosum (up to 12% UC)
• Psoriasis (5-10% IBD patients)
OCULAR
• Conjunctivitis, anterior uveitis/iritis, episcleritis (ocular pain, photophobia, blurred vision…)
 ULCERATIVE COLITIS
Clinical presentation

• EXTRAINTESTINAL MANIFESTATIONS

METABOLIC BONE DISORDERS

• Low bone mass 3-30% of IBD patients

THROMBOEMBOLIC DISORDERS
• IBD patients carry an increased risk of venour and arterial thrombosis
 ULCERATIVE COLITIS
Diagnosis

• COLONOSCOPY+ MULTIPLE BIOPSIES!!!!!!

• Full blood count
• CRP, ESR
• Fecal calprotectin
• Stool coltures and parasites, Clostidium toxin
• Liver function
 FECAL CALPROTECTIN

• cytosol of neutrophil granulocytes

• Most sensible marker for IBD diagnosis

• Cut-off still unclear (150? Mcg/g)

• Not specific to differentiate between different types of inflammation

• Good correlation with endoscopic pattern

• Diagnosis, clinical follow-up, therapy adjustment in IBD patients

 ULCERATIVE COLITIS
Endoscopic features

BACKWASH ILEITIS: inflammation of 2-3

cm of the distal ileum in pts with
pancolitis (+ rectal sparing). Highly
associated with PSC.
 MAYO ENDOSCOPIC SCORE for UC

MILD (+1) SEVERE (+3)

MODERATE (+2)

Erythema Diffuse ulcerations

Friability Purulent exudate
Easy bleeds Profuse bleeding
Loss of vascular pattern Pseudopolyp formation
More granularity
Spontaneous bleeding
 ULCERATIVE COLITIS
Microscopic features

• Histological findings correlate with endoscopic appearance and clinical course

• Inflammation limited to mucosa and superficial submucosa (deeper layers unaffected)
• DISTORSION AND ATROPHY OF CRYPTHS with neutrophil inflammationCRYPTH ABSCESSES
• Mucin depletion (depleted Goblet cells)
• Diffuse mixed inflammation, lymphoplasmacytosis of the lamina propria
• Superficial erosions
CLASSIFICATION OF ULCERATIVE
COLITIS
SCORES TO EVALUATE CLINICAL
ACTIVITY OF UC
SCORES TO EVALUATE CLINICAL ACTIVITY
OF UC
SCORES TO EVALUATE CLINICAL
ACTIVITY OF UC

- <2: remission
- 2-4 mild activity
- 5-7 moderate activity
- > 7 severe activity
ULCERATIVE COLITIS
Assessment of clinical severity
 ULCERATIVE COLITIS
Natural history

• Alternating periods of remission and relapse

• Risk factors for relapse
• Short period (<2 yrs) from diagnosis to first flare
• Fever or weight loss at diagnosis
• Active disease in the first year
• EXTENT OF THE DISEASE
• pts with more severe disease have a more extensive disease
• Predictor of colectomy (extensive colitis 3.5x risk than proctitis only)
• Increased risk of colorectal cancer (pancolitis; disease duration>10 years)

• Mortality in UC is not increased than in the general population

 ULCERATIVE COLITIS
Management of mild to moderate UC (AGA guidelines)

Mesalamine
Budesonide: extensively metabolized in
first pass, resulting in a low bioavailability and
systemic effects

Oral therapy
Local rectal therapy (enemas, suppositories)
 ULCERATIVE COLITIS
Management of moderate to severe UC (AGA guidelines)
Corticosteroids (oral or iv)
Mesalamine
azatioprine

In adult outpatients with moderate to severe UC,

the AGA recommends using biological therapy:
• Anti-TNFα: infliximab, adalimumab,
golimumab
• Anti- integrin α4β7: vedolizumab
• JAK1, JAK3 inhibitor:tofacitinib
• Anti IL-12, IL-23: ustekinumab
 ULCERATIVE COLITIS
Complications

• COLORECTAL CANCER
• TOXIC MEGACOLON
• MASSIVE HEMORRAGE
• STRICTURES
• PERFORATION
• SYSTEMIC COMPLICATIONS
 ULCERATIVE COLITIS
Complications

• COLORECTAL CANCER
• LONG-STANDING DISEASE (cumulative risk 2% after 10 years, 8% after 20 years, 18% after 30 years)

• DISEASE EXTENT (pancolitis: risk 14.8 greater than general population; left colitis: intermediate;
proctitis/proctosigmoiditis: no risk)

• SCLEROSING CHOLANGITIS (X4 THAN THOSE WITHOUT annual follow-up)

• FAMILY HISTORY OF CCR (x2)

• For surveillance histological extent is more important than endoscopic extent

• Endoscopic follow-up every 2-3 years ± chromoendoscopy

• If low dysplasia repeat colonoscopy with chromoendoscopycolectomy?

• If high dysplasia colectomy

 ULCERATIVE COLITIS
Complications

• TOXIC MEGACOLON
• Severe form of paralytic ileus with distension of the colon and systemic toxicity
CLINICAL PICTURE
• Inability to have a bowel movement or pass gas
(diarrhoea is not a sign of improvement!)
• Abdominal distension
• Fever
• Hearth rate >100 bpm
• Sensory disturbance
RISK FACTORS
• GI infections
• Dehydratation and electolyte imbalance
• Iatrogenic causes
• DRUGS: oppioids, antidiarrheal drugs, spasmolytic
agents, benzodiazepines
• Colonscopy, barium enema
 ULCERATIVE COLITIS
Complications

• TOXIC MEGACOLON: DIAGNOSIS

• Clinical picture+ abdomen RX RAY

cm
> 6
 ULCERATIVE COLITIS
Complications

• TOXIC MEGACOLON: THERAPY

• FASTING!!!!!!!
• Electrolyte and fluid replacement
• Iv. Antibiotics
• SURGERY!!!
• Rectal probe ?
CROHN’S DISEASE
 CROHN’S DISEASE
Definition and macroscopic features

• Chronic inflammatory disease of the GI tract with symptoms evolving in a

intermittent and relapsing manner
• Can affect any part of the GI
• CD is segmental (skip areas in the midst of affected intestine) and
transmural disease
• Rectum is often spared (differently from UC)
• Small bowel+colon: 40-55%
• Small bowel involvement alone: 30-40%
• Colitis alone: 15-25%
• Perianal disease
CROHN’S DISEASE
MONTREAL CLASSIFICATION
 CROHN’S DISEASE
Epidemiology

• Incidence in Northern EU 10.6/100.000

• Prevalence EU 322 per 100.000, USA 214 per 100.000

• Bimodal peak of incidence (15-30 and 50-70 years)

• No gender specific distribution

 CROHN’S DISEASE
Etiopathogenesis

• Still undefined
• Complex interplay between genetic predisposition, environmental factor and
altered gut microbiota dysregulated innate ad adaptive immune responses

ENVIRONMENTAL FACTORS
• Smoking: OR 1.76 (1.35-2.23)
• Oral contraceptives, NSAIDS (?)
• Appendicectomy: OR 0.31 (0.25-0.38)
• Infections: measles? Mycobacterium paratubercolosis ?
• Breastfeeding, living on farms, childhood contacts with animals inconsistently
associated with reduced risk of CD
 CROHN’S DISEASE
Genetic factors

• FIRST DEGREE FAMILY HISTORY FOR CD!!! (RR x15 general

population)

GWAS studies
• More than 200 alleles
• 37 susceptibility loci (NOD2, ATG16L1, LRRK2, IRGM, IL23R, HL, STAT3,
JAK2, Th17 pathways)

• These genes are associated to bacterial sensing and innate immunity

 CROHN’S DISEASE
NOD2/CARD15- Innate immune defects

• NOD-like receptors are innate immune proteins that mobilise the

host defence against fragments of bacterial peptidoglycan by
initiating the NF-k-beta and MAPK-signalling protective
cytokines.
• Chromosome 15 (locus IBD1) associated to CD.
• Double dose of allelic variant of NOD2: x40 risk of CD than patients
without the allelic variant
 CROHN’S DISEASE
Etiopathogenesis

• Dysbiosis

• Barrier function defects

• Innate immune defects

• Abnormal immune response

Th1 driven to undefined
antigens (luminal?)
• TNF-alpha, IL1, IL2 are
essential for granuloma
formation, expression of MHC
II molecules on epithelial cells
and adesion molecules on
endothelial cells

• Immune cell homing to the

intestinal mucosa
Lancet 2017
 CROHN’S DISEASE
Clinical presentation

• Diarrhoea (also nocturnal)

• Abdominal pain (also acute abdomen)
• Occlusive symptoms
• Rectal bleeding
• Weight loss
• Fever (abscesses!)
• Malabsorption syndrome (small bowel CD with ulcerative jejuno-ileitis)
• Perianal disease
• Extraintestinal manifestations
• Increased CRP, ESR, anemia
• Increased fecal calprotectin
 CROHN’S DISEASE
Clinical presentation

• EXTRAINTESTINAL MANIFESTATIONS
RHEUMATOLOGIC
• Peripheral seronegative arthitis (10-15%): asymmetric, polyarticular, migratory, large joints +++
• Ankylosing spondylitis (10% CD>UC; HLA-B27+)
• Sacroileitis
DERMATOLOGIC
• Erythema nodosum (15% CD)
• Pyoderma gangrenosum (up to 12% UC), less commonly in CD
• Psoriasis (5-10% IBD patients)
OCULAR
• Conjunctivitis, anterior uveitis/iritis, episcleritis (ocular pain, photophobia, blurred vision…)
 CROHN’S DISEASE
Clinical presentation

• EXTRAINTESTINAL MANIFESTATIONS

METABOLIC BONE DISORDERS

• Low bone mass 3-30% of IBD patients
THROMBOEMBOLIC DISORDERS
• IBD patients carry an increased risk of venour and arterial thrombosis
UROLOGIC
• Nephrolitiasis (10-20% calcium oxalate stones) in CD following small-bowel
resection (increased absorption of dietary oxalatehyperoxaluria)
• In pts with ileal dysfunction/resection non-absorpbed fatty acids bind to dietary
calcium and leave oxalate unbounddelivered to the colon where it is
absorbedhyperoxaluria).
 CROHN’S DISEASE
Diagnosis

• COLONOSCOPY+ MULTIPLE BIOPSIES!!!!!!

• Full blood count
• CRP, ESR
• Low albumin and vitamin deficiencies (extensive small bowel
involvement)
• Fecal calprotectin
• Stool coltures and parasites, Clostidium toxin
• Liver function
• Anti-Saccaromyces Cerevisiae antibodies (ASCA)?
• Cross sectional imaging (CT-enterography, MR-enterography,
ultrasonography)
 CROHN’S DISEASE
Endoscopic features

• Segmental inflammation

• Aftoid and serpiginous ulcers

interspersed with nodular
oedematous mucosa
(cobblestone pattern)
ILEOSCOPY

Stenosis
Distorted lumen
Linear ulcers
"Cobblestone" pattern
 CROHN’S DISEASE
Microscopic features

• Chronic focal, patchy, discontinuous and transmural inflammatory infiltrate

• Goblet cells preserved
• Glandular architecture preserved
• Cryptic abscesses may be present, but rarerely
• Transmural lymphoid aggregates and pyloric gland metaplasia are common
• Epithelioid granuloma (15% mucosal specimens, 70% surgical specimens)
CROHN’S DISEASE
MR-enterography

• Extent of disease
• Fistulas
• Strictures
• Complications
• Response to therapies
 IMAGING DIAGNOSIS OF CD
SMALL BOWEL ENEMA BOWEL SONOGRAPHY
 wall thickness
Stenotic lumen
Unstratified wall

SENS SPEC
Stricture 100 91
Fistula 87 90
Abscess 100 92
Gasche et al, Gut 1999
 CROHN’S DISEASE
Clinical patterns

• INFLAMMATORY
• PENETRATING FISTOLOUS
• FIBRO-STENOTIC
• The site of disease, age at diagnosis and clinical pattern influence
clinical manifestations and the prognosis
CROHN’S DISEASE

- < 150: remission

- 151-219: mild activity
- 220-450: moderate activity
- > 450: severe activity
 CROHN’S DISEASE
Therapy

CORTICOSTEROIDS (prednisone or budesonide)

• Induction of remission mild to moderate disease activity
• Budesonide for ileal disease, prednisone for all the others
• Not good for maintaining remission

ANTIBIOTICS
• Fistulas, abscesses
 CROHN’S DISEASE
Therapy

Anti-TNF THERAPY (Infliximab, Adalimumab, certolizumab pegol)

• Induction of remission in patients refractory to steroids/thiopurines
or as first line in severe disease
• Perianal disease
• Risk of opportunistic infections

Iv. VEDOLIZUMAB (monoclonal ab blocking a4b7 integrin)

• Refractory and luminal CD
 CROHN’S DISEASE
Therapy

IMMUNOSUPPRESSANTS
• Thiopurines (ie. azathioprine, mercaptopurine) or metothrexate ONLY
for maintenance
• Increased risk of cancers (lymphoma) , particularly in young men (<35
yrs) and old people
NUTRITIONAL SUPPORT
SURGERY
• Complications (abscesses, malignancies)
• Strictures and obstructive symptoms unresponsive to medical
treatment
 CROHN’S DISEASE
Complications
• Different definitions of complications of CD
• Risk factors: ileal or ileocolonic disease; extensive small-bowel disease; severe
upper GI disease; perianal disease; early stricturing or penetrating phenotype;
young age at diagnosis; smoking

 Abscesses, strictures, fistulas

 Occlusion
 Perforation
 Short bowel syndrome (post multiple surgeries)
 Haemorrage
 Systemic complications
 Intestinal and extraintestinal malignancies
 (Toxic megacolon)
 CROHN’S DISEASE
Complications
Intestinal malignancies

Lancet 2017
 CROHN’S DISEASE
Complications
Extra-Intestinal malignancies

Lancet 2017