Pregnancy-associated liver diseases

Liver diseases unique to pregnancy include intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy (AFLP), hyperemesis gravidarum, and HELLP syndrome. The diagnostic evaluation of abnormal liver chemistries is similar in pregnant and nonpregnant individuals; it includes diagnostics for transaminitis and abdominal ultrasound to assess for causes of abnormal liver chemistries unrelated to pregnancy (e.g., viral hepatitis) and for findings associated with conditions unique to pregnancy. Intrahepatic cholestasis of pregnancy manifests in the second or third trimester and is characterized by jaundice, pruritus, and elevated serum bile acid levels. AFLP most commonly manifests in the third trimester. Diagnosis of AFLP is supported by clinical features (e.g., vomiting, jaundice, encephalopathy) and imaging findings (hyperechoic liver, ascites); biopsy is rarely needed. Management of pregnancy-associated liver disease is multidisciplinary. Treatment of intrahepatic cholestasis of pregnancy involves ursodeoxycholic acid, and timing of delivery is based on the degree of serum bile acid elevation. Management of AFLP involves supportive care and immediate delivery to reduce risks to the pregnant individual and fetus.

This article covers intrahepatic cholestasis of pregnancy and AFLP. Hyperemesis gravidarum and HELLP syndrome are detailed separately.

Causes of abnormal liver chemistries in pregnancy ^[1][2]

• Normal physiology ^[3]
• Liver disease unrelated to pregnancy
• Liver diseases unique to pregnancy ^[4]
  • Hyperemesis gravidarum ^[2]
  • Intrahepatic cholestasis of pregnancy
  • Acute fatty liver of pregnancy
  • HELLP syndrome

Mildly elevated ALP is normal in pregnancy. Pregnant patients with elevated transaminase and/or bilirubin levels should be evaluated for hepatocellular and biliary disease. ^[1][5]

Management of abnormal liver chemistries in pregnancy ^[1][2][5]

• Initial evaluation of abnormal liver chemistries is similar in pregnant and nonpregnant individuals.
  • Hepatocellular injury pattern: Perform diagnostics for transaminitis.
  • Cholestatic injury pattern: Obtain abdominal imaging.
    • Ultrasound is the preferred imaging modality throughout pregnancy.
    • If additional imaging is needed, MRI without gadolinium is recommended. ^[2]
• If liver disease unique to pregnancy is suspected , refer to specialists to guide further diagnostic evaluation and management.
• Treatment is based on the cause of abnormal liver chemistries and may include supportive care, pharmacological treatment, and early delivery.

For patients with pregnancy-related liver disease, a multidisciplinary care team approach (e.g., gastroenterology, maternal-fetal medicine) is important for minimizing maternal and fetal morbidity and mortality. ^[2]

Intrahepatic cholestasis of pregnancy most commonly manifests in the second or third trimester with pruritus and elevated serum bile acid levels. ^[4]

Epidemiology

• Most common pregnancy-associated liver disease ^[1]
• Occurs in ∼ 0.4–10% of pregnancies ^[2]

Etiology ^[2][5]

• Genetic predisposition
• Increased estrogen and progesterone during pregnancy
• Certain drugs (e.g., antibiotics)

Clinical features ^[2][5]

• Pruritus
• Jaundice ^[1]
• Steatorrhea (uncommon)

Diagnostics ^[1][2][4]

• ↑ Total serum bile acid levels (> 10 mcmol/L): confirmatory ^[1][2][3]
• ↑ ALT, ↑ AST ^[2]
• Normal or mildly elevated bilirubin
• ↑ GGT, ↑ ALP ^[3]

Elevated total serum bile acid level (> 10 mcmol/L) in a patient with pruritus in the second or third trimester (without other causes of pruritus) is diagnostic for intrahepatic cholestasis of pregnancy. Elevated transaminases are not required for diagnostic confirmation. ^[2]

Management ^[2][4]

• Pharmacological treatment
  • First line: ursodeoxycholic acid (off-label) (reduces bile acid levels and pruritus) ^[1][2][4]
  • Alternative or adjunctive therapies (e.g., for refractory pruritus): first-generation antihistamines, S-adenosylmethionine, cholestyramine, rifampicin ^[1][2][4]
• Prenatal care
  • Perform antepartum fetal surveillance. ^[4]
  • Consider repeat serum bile acid levels to help guide timing of delivery. ^[4]
  • Administer corticosteroids for fetal lung maturity if preterm delivery is anticipated. ^[1]
• Peripartum management: Deliver at 36–39 weeks' gestation based on severity. ^[4]
  • Bile acid levels ≥ 100 mcmol/L: Deliver at 36 weeks' gestation.
  • Bile acid levels between 10 and 100 mcmol/L: Deliver between 36 and 39 weeks' gestation.
  • Consider earlier delivery (e.g., between 34 and 36 weeks' gestation) for patients with:
    • Severe intractable pruritus
    • Worsening liver dysfunction
    • History of stillbirth due to intrahepatic cholestasis of pregnancy
  • Perform continuous fetal monitoring during labor.
• Postpartum management ^[4]
  • Complete resolution typically occurs postpartum.
  • For patients with persistent symptoms 4–6 weeks postpartum:
    • Repeat laboratory testing
    • Refer to specialist (e.g., hepatology, gastroenterology) for further evaluation

Early initiation of therapy with ursodeoxycholic acid may reduce the risk of preterm birth and stillbirth. ^[4]

Cholestyramine can cause significant adverse effects (including increased risk of neonatal intracranial hemorrhage) and should be used with caution. ^[2][4]

Complications ^[2][5]

• Intrauterine fetal demise (1.2% after 37 weeks) ^[4]
• Fetal growth restriction
• Premature labor; and increased preterm birth rates
• Meconium-stained amniotic fluid
• Neonatal respiratory depression
• Recurrence in subsequent pregnancies (60%–90%) ^[4][6]

Acute fatty liver of pregnancy is an idiopathic, rare, life-threatening obstetric emergency most commonly arising in the third trimester, characterized by extensive fatty infiltration of the liver, which can result in acute liver failure ^[1][5]

Epidemiology

• 1–3 cases per 10,000 pregnancies ^[7]

Etiology

• Risk factors ^[1][5]
  • Multiple pregnancy
  • Male fetus
  • Low BMI
• Pathophysiology: dysfunction of fatty acid β-oxidation ^[5]

Clinical features ^[1][3][5]

• Sudden onset of jaundice
• RUQ pain, nausea, and vomiting
• Polyuria and polydipsia
• Clinical features of complications (e.g., hepatic encephalopathy, ascites, bleeding diathesis)
• Preeclampsia (present in ∼ 50% of patients) ^[3]

Diagnostics ^[1][3][5]

• Diagnostics for transaminitis are similar to diagnostics in nonpregnant adults.
• Ultrasound is the preferred initial imaging modality to exclude alternative diagnoses (e.g., liver hematoma). ^[1]
• Liver biopsy is rarely necessary but may be considered for: ^[5]
  • Diagnostic uncertainty (e.g., atypical presentation) that affects management ^[2]
  • Persistent postpartum liver dysfunction
• Swansea criteria: a set of clinical, imaging, and/or histological findings commonly used to evaluate for AFLP
  • The presence of ≥ 6 features suggests AFLP.
  • Limitations include low specificity for distinguishing from other causes of acute liver failure in severe disease and limited sensitivity for detecting early disease. ^[2][5]
• Diagnostic testing may show findings associated with complications (e.g., thrombocytopenia in patients with DIC). ^[1][2]

Rule out causes of acute liver injury that are unrelated to pregnancy (e.g., acute viral hepatitis, autoimmune hepatitis, drug-induced liver injury, Wilson disease). ^[5]

Differential diagnoses

• HELLP syndrome
• Preeclampsia with severe features
• Other causes of acute liver failure

It is often difficult to differentiate between AFLP, HELLP, and preeclampsia with severe features, and these conditions can also coexist. Renal failure, hyperuricemia, and hypoglycemia are more common and severe in AFLP than in HELLP and severe preeclampsia. ^[5]

Management ^[5][7]

• Deliver immediately regardless of gestational age. ^[1]
• Consult specialists as needed (e.g., hepatology, critical care, maternal fetal medicine).
• Provide supportive care and management of complications (see "Management of acute liver failure").
• Perform diagnostic testing for fatty acid metabolism disorders in the newborn.

Complications ^[5]

• Acute liver failure ^[9]
• Encephalopathy
• Disseminated intravascular coagulation
• Ascites, pulmonary edema
• Acute renal failure
• Pancreatitis
• Infection
• Maternal death (∼ 2%)
• Fetal demise (∼ 10–20%)

Prognosis ^[5]

• Clinical improvement is typically seen within 4 days of delivery.
• Laboratory abnormalities may persist for > 1 week.