Hepatobiliary Disease in Pregnancy

Tannys Vause Academic Half Day May 11, 2005

Objectives
Review normal liver function during pregnancy Discuss etiology, diagnosis and management of
acute fatty liver in pregnancy Discuss etiology, diagnosis and management of intrahepatic cholestasis in pregnancy Review differential diagnosis for liver dysfunction in pregnancy

Approach to Liver Disease in Pregnancy

Liver disease occurs in approximately 3%
of deliveries There are 2 liver diseases which are specific to pregnancy
Acute fatty liver of pregnancy Intrahepatic cholestasis of pregnancy

Liver dysfunction may also be seen in

patients with hepatitis and as a result of HELLP syndrome

The Liver in Normal Pregnancy

Physical Examination
Skin - palmar erythema and spider angiomas are usually signs of chronic liver disease, but can
be normal findings in pregnancy secondary to high estrogen levels

Liver In the third trimester, the enlarging uterus

displaces the liver superiorly and posteriorly a palpable liver is abnormal

The Liver in Normal Pregnancy

Hemodynamics
cardiac output increases until the second trimester, then plateaus until delivery absolute hepatic blood flow remains unchanged, as the percentage of cardiac output to the liver decreases

The Liver in Normal Pregnancy

Liver function tests
Albumin decreases secondary to hemodilution Alkaline Phosphatase 2-4 times normal in the third trimester increases secondary to placental ALP Alkaline phosphatase may remain elevated for up
to six weeks after delivery

The Liver in Normal Pregnancy

Liver function tests
ALT slightly higher in second trimester but still within
normal range

AST unchanged LDH unchanged

The Liver in Normal Pregnancy

Liver function tests
Bilirubin Total and Free are lower throughout pregnancy Conjugated is lower during T2 and T3 Bile acids unchanged Coagulation Factors PTT/INR - unchanged Fibrinogen - slightly elevated

The Liver in Normal Pregnancy

Serum lipids
Total cholesterol and triglycerides increase markedly during pregnancy

The Liver in Normal Pregnancy

Ultrasound
biliary tract is usually normal

Pathology
standard and ultrastructural examination of the liver during normal pregnancy reveals no specific abnormalities

Acute Fatty Liver in Pregnancy

Acute Fatty Liver of Pregnancy

Affects 1 in 6,692 15,900 pregnancies In 1975, maternal survival was 72%, with
neonatal survival slightly lower maternal mortality of 18% fetal mortality of 23% improved outcomes have been attributed to early recognition of the disorder followed by prompt delivery association with nulliparity, twin gestations, male fetus and pre-eclampsia or eclampsia

Etiology
Remains unknown Similar histologically and clinically to
Reyes syndrome and Jamaican vomiting sickness These diseases are characterized by microvesicular fatty infiltration of hepatocytes without inflammation or necrosis

Etiology
Presentation is also similar to those
people with metabolic defects in the intramitochondrial -oxidation pathway Also occurs more frequently in women whose fetuses have a deficiency of long chain 3-hydroxyacyl-CoA (enzyme deficiency is similar to that in Reyes)

Clinical Manifestations
Generally occurs in the second half of
pregnancy Mean gestational age is 34.5 weeks (range 28-39 weeks)

Clinical Manifestations
The duration of prodromal symptoms and
signs is variable Often presents with nausea and vomiting, followed by severe abdominal pain and headache

Clinical Manifestations
The right upper quadrant is generally
tender, but the liver is not enlarged to palpation Within a few days, jaundice appears, and the patient becomes somnolent and eventually comatose Hematemesis and spontaneous bleeding result when the patient develops hypoprothrombinemia and DIC

Clinical Manifestations
Oliguria, metabolic acidosis, and
eventually anuria occur in approximately 50 percent of patients Diabetes insipidus may also accompany the disease, but may not manifest itself until postpartum These patients may respond to dDAVP after delivery

Clinical Manifestations
If the disease is allowed to progress, labor
begins and the patient delivers a stillborn infant Uteroplacental insufficiency may be the cause of fetal distress and fetal death in these patients.

Clinical Manifestations
During the immediate postpartum period,
the mother becomes febrile, comatose and, without therapy, dies within a few days DIC, renal failure, profound hypoglycemia, and occasionally pancreatitis are the most often cited immediate causes of death

Lab Investigations
Serum transaminases
elevated, but usually below 500 IU/L

Coagulation factors
INR increases before PTT because of vitamin K dependent clotting factors made in the liver fibrinogen decreases, D-dimer increases with DIC

Bilirubin
mildly elevated

Lab Investigations
Serum ammonia - elevated Serum glucose - decreased

Further Investigations
Liver Biopsy
liver biopsy not advised for diagnosis in most cases due to coagulopathy if biopsy is necessary, FFP can be administered to correct coagulpathy pericentral microvesicular fatty change minimal inflammatory cell infiltration or hepatic necrosis periportal areas are usually preserved

Histology

Further Investigations
CT
diagnosis can occasionally made using CT, however there are a large number of falsenegatives decreased attenuation over the liver is consistent with fatty infiltration

MRI
fatty infiltration can be visualized with T2weighted images

Management
Once diagnosis is made, delivery should
be carried out as soon as possible Need to ensure patient is stable
invasive hemodynamic monitoring correct coags IV fluids containing adequate glucose if ammonia levels are elevated, treat with lactulose

Management
Vaginal delivery is preferable May use cervical ripening agents if needed C/S can be performed if it appears vaginal
delivery cannot be carried out in a timely fashion or if patient is deteriorating

Management
If coagulopathy is corrected, regional
anesthesia is preferable because it allows adequate assessment of LOC GA should be avoided if possible because of hepatotoxicity of some anesthetic agents Narcotic doses need to be adjusted as metabolized by the liver

Management
If delivery is carried out before hepatic
encephalopathy and renal failure develop, patients recover rapidly

Recurrence Risk
Little risk of recurrence in subsequent
pregnancies

Intrahepatic Cholestasis of Pregnancy

Background
Incidence of 1 in 1,000-10,000
pregnancies Uneven incidence worldwide High incidence in Chile and Sweden Seems to have a seasonal variation, peaking in November

Pathogenesis
Cause is unknown Evidence suggests both genetic and
hormonal factors play a role
Genetic could explain familial cases and a higher incidence
in some ethnic groups heterozygous mutations in the MDR3 gene has been found in a large consanguineous family likely autosomal dominant

Pathogenesis
Hormonal
Estrogens estrogens are known to cause cholestasis in both
experimental and clinical conditions ICP occurs mainly in the third trimester, when estrogens reach their peak also more common in twin pregnancies, which have higher circulating estrogen levels

Pathogenesis
Hormonal
Progesterone administration of progesterone may be a risk factor
for ICP the formation of large amounts of progesterone metabolites may result in saturation of the hepatic transport system utilized for biliary excretion

Clinical Manifestations
Generally occurs in second and third
trimesters Usually begins with pruritis at night Pruritis is often generalized, but predominates on palms and soles of feet Progresses to continuous pruritis

Clinical Manifestations
May have excoriations due to scratching Abdominal pain is uncommon Occasionally may have dark urine and
pale stool

Clinical Manifestations
~2 weeks after start of symptoms,
jaundice develop in 50% Accounts for 20-25% of cases of jaundice during pregnancy Jaundice is usually mild, but persists until delivery Symptoms usually abate about 2 days after delivery

Differential Diagnosis for pruritis without a primary skin lesion

cholestasis xerosis (dry skin) medications uremia iron deficiency leukemia HIV

polycythemia lymphoma thyroid disorders diabetes visceral malignancies multiple sclerosis

Lab Investigations
ALP
increases 5-10 fold

Serum total bile acids

may increase to more then 10x normal

Total bilirubin
mildly increased

AST, ALT
may increase to >1,000 U/L

Lab Investigations
GGT
normal or slightly elevated

Coagulation factors
INR usually normal may be increased scondary to Vitamin K deficiency
due to cholestasis or due to the use of bile acid sequestrants

Diagnosis
Fasting serum bile acids must be more
then 3 times the upper limit of normal Clinical symptoms must also be present for diagnosis Need to exclude other causes of jaundice and pruritus including viral hepatitis, primary biliary cirrhosis and biliary tract disease

Diagnosis
Ultrasound
reveals no biliary duct dilation, hepatic parenchyma appear normal

Liver Biopsy
rarely necessary for diagnosis histologically shows: centrilobular areas reveal dilated bile canaliculi these changes tend to regress after pregnancy

Management
Treatment focuses on reducing symptoms Benadryl, hydroxyzine and other
antihistamines may help only slightly Antihistamines may aggravate respiratory difficulties in preterm babies

Management
Cholestyramine
anion binding resin that interrupts the enterohepatic circulation, reducing reabsorption of bile acids dose 8-16 g/day in three to four divided doses may take up to 2 weeks to work, so should start as soon as pruritis is noted check INR qweekly, as affects vitamin K absorption may cause bloating and constipation

Management
Ursodeoxycholic acid (UDCA)
increases bile flow causes significant decrease in pruritus and decrease liver function studies dose 500 mg BID

Management
Delivery
In most cases, delivery should be accomplished by 38 weeks If cholestasis is severe, delivery should be considered at 36 weeks if fetal lung maturity is documented

Outcomes
Perinatal Outcome
Main complications are prematurity, meconuim-stained amniotic fluid and intrauterine demise Probability of fetal complications is directly related to bile acid levels Fetal complications are generally not seen until bile acid levels are >40 mmol/L (further studies need to be done to validate this level)

Outcomes
Perinatal Outcome
Antepartum FHR testing and fetal surveillance should be undertaken May induce labour at term, or when amniotic fluid studies indicate FLM

Outcomes
Maternal Outcome
Maternal prognosis is good Pruritis usually begins to resolve around 2 days postpartum There are generally no hepatic sequelae Recurs in 60-70% of subsequent pregnancies Recurrent episodes are variable in severity

Outcomes
Maternal Outcome
May be at increased risk for gallstones OCP administration rarely results in recurrent cholestasis, however LFTS should be checked after 3-6 months

Differential Diagnosis
When patients present with signs of liver
disease, appropriate workup needs to be undertaken to determine the cause Generally a combination of clinical manifestations and lab results can help diagnose a patient Rarely is invasive testing ie. liver biopsy necessary for diagnosis

Differential Diagnosis of Liver Disease in Pregnancy

Serum Transaminases Acute Hepatitis B Acute Fatty Liver Intrahepatic Cholestasis HELLP >1000 Bilirubin Coagulopathy Histology Other Features Potential for perinatal transmission Coma, renal failure, hypoglycemia Pruritis, increased bile acids HTN, edema, thrombocytop enia >5 Hepatocellular necrosis Fatty infiltration Dilated bile canaliculi Variable periportal necrosis

<500

<5

<300

<5, mostly direct <5

>500

Summary
Need to be familiar with the normal liver
during pregnancy in order to determine what is abnormal Acute Fatty Liver
Need to have a high suspicion for acute fatty liver as outcomes can be poor Management of acute fatty liver is delivery as soon as diagnosis is made and patient is stabilized

Summary
Intrahepatic cholestasis
Intrahepatic cholestasis is usually identified by pruritis and diagnosis is confirmed with increased serum bile acids Treatment is mainly symptomatic, with antihistamines, cholestyramine and ursodeoxycholic acid Delivery should be pursued at 38 weeks, or earlier if FLM is confirmed Fetal monitoring is crucial, as there is a higher incidence of stillbirth

References
Gabbe: Obstetrics Normal and Problem Pregnancies, 4th ed., 2002 First Principles of Gastroenterology: The Basis of Disease and
an Approach to Management, http://gastroresource.com/GITextbook/en/Default.htm Up to date