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

of deliveries  There are 2 liver diseases which are specific to pregnancy
 Acute fatty liver of pregnancy  Intrahepatic cholestasis of pregnancy

 Liver disease occurs in approximately 3%

 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 pre-

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 F-oxidation pathway F Also occurs more frequently in women whose fetuses have a deficiency of long chain 3-hydroxyacyl-CoA (enzyme 3-hydroxyacyldeficiency 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) 28-

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
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

 The right upper quadrant is generally

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 DDIC

 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 falsefalsenegatives  decreased attenuation over the liver is consistent with fatty infiltration

 MRI
 fatty infiltration can be visualized with T2T2weighted 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 1,000pregnancies  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 20during 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 5-

 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 8 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, meconuimmeconuim-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 60 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 3-

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 Bilirubin Transaminases Acute Hepatitis B Acute Fatty Liver Intrahepatic Cholestasis HELLP >1000 >5 Coagulopathy Histology Other Features Potential for perinatal transmission Coma, renal failure, hypoglycemia Pruritis, increased bile acids HTN, edema, thrombocytop enia 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, Management, http://gastroresource.com/GITextbook/en/Default.htm  Up to date