Pregnancy and Liver Disease

Normal Anatomic and Physiologic Changes During Pregnancy

• 1.

  What are the structural and functional hepatic adaptations during pregnancy?

  Liver size and histologic characteristics do not change. Maternal blood volume and cardiac output increase significantly, without a corresponding increase in hepatic blood flow, with a net decrease in fractional blood flow to the liver. An enlarging uterus makes venous return via the inferior vena cava progressively more difficult toward term. Blood is shunted via the azygous system with possible development of esophageal varices.

• 2.

  Does liver function change during pregnancy?

  Hepatic function remains normal during pregnancy, but the normal range of laboratory values changes because of hormonal changes and an increase in blood volume with subsequent hemodilution. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGTP), bilirubin, and prothrombin remain within normal limits. Total alkaline phosphatase (AP) is elevated. The placenta is a major source of AP; levels return to normal within 20 days after delivery. Estrogen increases the synthesis of fibrinogen, as well as other coagulation proteins (factors VII, VIII, IX, and X). Also attributed to estrogen’s effects are significant increases in serum concentrations of major lipid classes (triglycerides, cholesterol, and low- and very-low-density lipoproteins). These levels may be twice the normal limit of nonpregnant women of the same age. Serum albumin decreases slightly, contributing to the approximately 20% decline in serum protein concentration. Plasma concentrations of other serum proteins (ceruloplasmin, corticosteroids, testosterone, serum binding protein for thyroxine), as well as vitamin D and folate, also increase during pregnancy.

Diseases During Pregnancy

• Coincident occurrence of liver disease (viral hepatitis, alcoholic hepatitis, gallstone disease, autoimmune hepatitis)

• Intrahepatic cholestasis of pregnancy (IHCP)

• Acute fatty liver of pregnancy (AFLP)

• Hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome)

• 3.

  Can gestational age differentiate between different liver diseases in pregnancy?

  Yes. Hyperemesis gravidarum presents in the first trimester of pregnancy. Patients have severe nausea and vomiting, and approximately one-half have associated elevations of bilirubin, AST, or ALT. Cholestasis of pregnancy, viral hepatitis, and abnormal liver chemistries caused by cholelithiasis may present at any point in gestation, from the first to the third trimester. AFLP and preeclamptic liver disease (HELLP, hepatic infarct, and hepatic rupture) are specifically encountered in the third trimester of pregnancy. Both herpes simplex virus and hepatitis E virus are exacerbated in pregnancy and usually present in the third trimester. The presentation may be a mild elevation in transaminases or severe hepatic failure. Budd-Chiari syndrome presents from the second half of pregnancy to 3 months postpartum.

Coincident Occurrence

• 4.

  Can we assume the presence of chronic liver disease in a pregnant patient with angiomas and palmar erythema on physical examination and small esophageal varices detected endoscopically?

  No. Spider angiomas and palmar erythema are common and appear in approximately two thirds of pregnant women without liver disease. Small esophageal varices are present in approximately 50% of healthy pregnant women without liver disease because of the increased flow in the azygous system.

• 5.

  What is the most common cause of jaundice in pregnancy?

  Viral hepatitis is the most common cause of jaundice during pregnancy.

• 6.

  How severe is the course of viral hepatitis acquired during pregnancy?

  • Hepatitis A, B, and C run a similar course in pregnant and nonpregnant patients.

  • Hepatitis E runs a different course in pregnancy. It is fulminant in up to 20% of patients, compared with less than 1% of nonpregnant women. The fatality rate is 1.5% during the first trimester, 8.5% during the second trimester, and up to 21% during the third trimester compared with 0.5% to 4% in nonpregnant women. Fetal complications and neonatal deaths are increased if infection is acquired in the third trimester of pregnancy.

  • Herpes simplex hepatitis can be fulminant in pregnancy and associated with high mortality rates. Patients present in the third trimester with fever, systemic symptoms, and possibly vesicular cutaneous rash. Associated pneumonitis or encephalitis may be present. Liver biopsy is characteristic, showing necrosis and inclusion bodies in viable hepatocytes, along with few or no inflammatory infiltrates. Response to acyclovir therapy is prompt; there is no need for immediate delivery of the baby.

• 7.

  What signs and symptoms suggest the diagnosis of Budd-Chiari syndrome?

  The clinical triad of sudden onset of abdominal pain, hepatomegaly, and ascites, near term or shortly after delivery. Ascitic fluid shows a high protein content in approximately one half of cases. Biopsy typically shows centrilobular hemorrhage and necrosis, along with sinusoidal dilation and erythrocyte extravasation into the space of Disse. Hepatic scintigraphy and computed tomography (CT) typically show compensatory hypertrophy of the caudate lobe resulting from its separate drainage into the inferior vena cava. Doppler analysis of portal and hepatic vessels and magnetic resonance imaging (MRI) establish hepatic vein occlusion.

• 8.

  Is the serum ceruloplasmin level a good diagnostic marker in pregnant women at term who are suspected of having Wilson disease?

  No. Ceruloplasmin levels increase gradually during pregnancy, reaching the maximum at term. Because of this, in a patient with Wilson disease who usually has a low level of ceruloplasmin, the level may increase misleadingly into the normal range (greater than 20 mg/dL) during pregnancy.

• 9.

  Can we maintain a woman with Wilson disease on therapy during pregnancy?

  Absolutely. Therapy must continue during pregnancy; otherwise, the mother is at risk for hemolytic episodes associated with fulminant hepatic failure. Agents approved by the U.S. Food and Drug Administration (FDA) are d-penicillamine, trientine, and zinc. Evidence indicates that penicillamine and trientine (tissue copper-chelating agents) are teratogenic in animal studies, and there are reports of penicillamine effects in humans, including cutis laxis syndrome or micrognathia, low-set ears, and other abnormalities. According to the current consensus, penicillamine and trientine are safe in doses of 0.75 to 1 g/day during the first two trimesters; the dosage should be reduced to 0.5 g/day during the last trimester and in nursing mothers. Zinc therapy is an attractive alternative with a different mechanism of action; it induces synthesis of metallothionein, which sequesters copper in enterocytes, blocking its absorption. No teratogenic effects have been reported in animals or humans. The recommended doses are 50 mg three times/day for patients with 24-hour urinary copper values greater than 0.1 mg and 25 mg three times/day for patients with lower urinary copper values. Close monitoring of urinary copper and zinc levels is suggested; the zinc dose should be adjusted accordingly.

Intrahepatic Cholestasis of Pregnancy

• 10.

  What is the most common liver disorder unique to pregnancy?

  IHCP is the most common disorder unique to pregnancy.

• 11.

  What is the major clinical manifestation of IHCP?

  Severe pruritus with onset in the second or, more commonly, third trimester (more than 70% of cases).

• 12.

  What biochemical changes are noted in IHCP?

  Serum bile acids, often measured as cholylglycine, increase by 10- to 100-fold. Serum levels of AP rise by seven- to tenfold, along with a modest rise in serum levels of 5′-nucleotidase (confirming the hepatic source of AP). AST, ALT, and direct bilirubin also rise. No evidence of hemolysis is found. GGTP is usually normal, as is prothrombin time (PT) and international normalized ratio (INR).

• 13.

  What is the expected clinical and biochemical course after delivery for patients with IHCP?

  Pruritus should improve promptly after delivery (within 24 hours). Jaundice is rare and, if present, may persist for days. Biochemical abnormalities may persist for months.

• 14.

  What is a possible cause for abnormal bleeding in a postpartum woman previously diagnosed with IHCP? What is the treatment?

  Malabsorption of liposoluble vitamins, including vitamin K, especially in patients treated with cholestyramine for pruritus. The INR corrects with parenteral administration of vitamin K.

• 15.

  What is the effect of IHCP on the fetus?

  Fetal distress requiring cesarean section develops in approximately 30% to 60% of cases. Prematurity occurs in approximately 50% of cases and fetal death in up to 9% of affected pregnancies. All of these effects are more likely if the disorder begins early in pregnancy.

• 16.

  What is the therapy for IHCP?

  Alleviating pruritus is the main goal. Therapeutic agents include:

  • Ursodeoxycholic acid, 15 mg/kg/day; up to 24 mg/kg/day studied with good results

  • Cholestyramine, 4 g four or five times/day (bile acid–binding resin)

  • Hydroxyzine hydrochloride (Atarax) or pamoate (Vistaril) (antihistamines); Atarax 25 to 50 mg every 6 hours as needed, Vistaril 15 to 30 mg every 6 hours as needed

  • Phenobarbital, 100 mg/day (choleretic and centrally acting sedative)

  • Phototherapy with ultraviolet B light as directed by a dermatologist

  Vitamin K before delivery is highly recommended to minimize the risk of postpartum hemorrhage. Mother and fetus should be observed closely. Elective induction is recommended at 36 weeks (severe cases) or 38 weeks (average cases) if the fetal lungs have matured.

• 17.

  Can IHCP recur?

  Yes. Approximately 40% to 70% of subsequent pregnancies show evidence of mild intrahepatic cholestasis. The same pattern can be seen with use of estrogen-containing contraceptives.

• 18.

  What atypical signs and symptoms make the diagnosis of IHCP doubtful?

  Fever, hepatosplenomegaly, pain, jaundice preceding or without pruritus, and pruritus after delivery or before 21 weeks of pregnancy, especially with a singleton pregnancy, should prompt the search for an alternate diagnosis.

• 19.

  What biochemical changes suggest an alternate diagnosis?

  • Normal AST and ALT levels

  • Elevated AP and GGTP (i.e., biliary disease)

  • Predominantly unconjugated hyperbilirubinemia (i.e., hemolysis)