Managing the Spectrum of Liver Diseases in Pregnancy

Pregnancy directly affects the physiology of the liver and liver disorders can negatively affect pregnancy. Some of these conditions can be fatal for both the mother and the fetus. Therefore, it is important to determine the underlying cause of abnormal liver function, allowing prompt treatment to reduce morbidity and mortality.

Pregnancy itself causes changes in physiology and laboratory results. Alkaline phosphatase (ALP) increases via an isoenzyme of placental origin and does not reflect liver disease. Albumin decreases and transaminases may remain normal or decrease slightly. During pregnancy, both abdominal ultrasound and magnetic resonance imaging can be performed. There may be rare occasions when the use of computed tomography (CT) of the abdomen is required, which involves exposure of the fetus to ionizing radiation. Health professionals should carefully consider the rationale for this image and discuss it with the woman.

Hyperemesis gravidarum (HG) consists of severe, prolonged nausea and vomiting with a triad of dehydration, electrolyte imbalance, and weight loss of more than 5% of body weight. The cause of HG is unknown, but it is associated with an increase in the hormone beta-human chorionic gonadotropin (βHCG) secondary to pregnancy itself, and women with multiple pregnancies or trophoblastic disease (with larger volumes of placental tissue) are more likely to see affected.

It usually occurs in the first trimester and affects 0.3% to 3.6% of pregnancies. Risk factors include increased body mass index, preexisting diabetes, asthma, psychiatric disorders, hyperthyroidism in a previous pregnancy, or previous HG. Symptoms resolve by week 20 in 90% of women.

Initial investigations include urine dipstick (with ketone quantification), voiding midstream, urea and electrolytes, complete blood count, blood glucose (exclude diabetic ketoacidosis in preexisting diabetes), and pelvic ultrasound. In refractory cases or in women with a history of previous admission, check thyroid function, liver function, calcium, phosphorus and amylase.

Liver function is impaired in up to 40% of women with HG, most commonly elevated transaminases, but bilirubin and amylase may also be slightly elevated. The pathogenesis of liver dysfunction in HG is not completely understood.

Biochemical abnormalities resolve with resolution of vomiting. Alternative diagnoses (eg, viral hepatitis) should be considered if there are persistent liver abnormalities. Treatment is usually supportive and includes rehydration with electrolyte correction, antiemetics, thromboprophylaxis with low molecular weight heparin for hospitalization, and thiamine supplementation in some cases. Corticosteroids can also be used for refractory hyperemesis.

Gestational intrahepatic cholestasis (IGC) is characterized by pruritus with elevated bile acids in the absence of a skin rash. Pruritus usually affects the palmar aspect of the hands and the plantar aspect of the feet, but it can affect any part of the body. IGC most often affects women in the second half of their pregnancy.

Adverse outcomes associated with IGC include preterm birth, distress, and stillbirth. A complete history (including drug history) and examination should be performed. Laboratory findings include elevated serum bile acids >10 μmol/L (most complications occur at levels >40 μmol/L), elevated transaminase levels, and gamma-glutamyl transferase (GGT). It is important to note that the upper limit of transaminases, GGT and bilirubin in pregnancy is 20% lower than the range without pregnancy.

Normal liver function does not exclude the diagnosis . Liver function tests should be repeated every 1 to 2 weeks if pruritus is persistent. Additional testing may include viral screening for hepatitis A, hepatitis B, hepatitis C, Epstein-Barr virus, and cytomegalovirus; hepatic autoimmune screening (anti-smooth muscle and anti-mitochondrial antibodies); and a liver ultrasound. Ursodeoxycholic acid (10-15 mg/kg) is recommended to relieve pruritus and improve liver function.

One large trial (PITCCHES) looked at the benefit of ursodeoxycholic acid in pregnancy and did not show an overall benefit in reducing stillbirth, preterm birth or admission to the neonatal unit, but there is likely to be some benefit for certain groups of pregnant women and doctors may try the use of ursodeoxycholic acid. CIG resolves after delivery. Obstetric management may include bringing forward delivery in severe cases to minimize the risk of late fetal death.

Preeclampsia is a multiorgan disease characterized by hypertension and proteinuria after 20 weeks of gestation that can affect the renal, hepatic, hematological and central nervous systems. It affects 5% to 10% of pregnancies. Clinical features include headache, visual disturbances, peripheral edema, epigastric pain, and vomiting.

Altered liver enzymes are present in up to 30% of cases up to 10 times the upper limit of normal, while bilirubin concentrations are rarely increased. Treatment of hypertension includes labetalol, hydralazine, and modified-release nifedipine. Intravenous magnesium sulfate is used for the prophylaxis and treatment of seizures. Preeclampsia is the leading cause of iatrogenic preterm birth.

Hospitalization is indicated for blood pressure (BP) >160/110 mmHg, with a goal of BP ≤135/85 mmHg. Consider admission for BP of 140/90 – 159/109 mmHg if there are concerns about maternal or fetal well-being. An obstetric evaluation (including fetal monitoring) should be performed. Obstetric management may include termination of pregnancy in severe cases due to deterioration of maternal or fetal condition.

Liver dysfunction usually normalizes within 2 weeks after delivery. Hypertension may persist for a few weeks after delivery, therefore postnatal follow-up is crucial. Platelet count, transaminases, and serum creatinine are recommended 48 to 72 hours after delivery.

5 to 10% of women with preeclampsia develop hemolysis, elevated liver enzymes, and plateletopenia (HELLP). HELLP syndrome usually appears in the second or third trimester, but can also develop after childbirth (in up to 30% of cases). It can be classified as mild, moderate or severe based on alanine aminotransferase (ALAT), lactate dehydrogenase (LDH) and platelet count. Risk factors include advanced maternal age, multiparity, and white ethnicity.

It is important to note that hypertension and proteinuria are only present in approximately 85% of cases. Laboratory tests should include complete blood count, liver function, and coagulation tests (including fibrinogen, prothrombin time, and partial thromboplastin time). The prothrombin time remains normal unless there is evidence of disseminated intravascular coagulation or severe liver damage. Treatment for hypertension is the same as that for preeclampsia, but immediate delivery is usually indicated. HELLP syndrome usually resolves after childbirth; however, if there is evidence of hepatic or renal failure, admission to intensive care may be warranted.

Acute fatty liver of pregnancy (AFLP) is a rare disorder that constitutes a medical and obstetric emergency, which can lead to liver failure due to fatty infiltration of hepatocytes. It usually occurs in the third trimester and its incidence is 1/7,000 to 1/16,000 pregnancies. Risk factors include nulliparity and twin pregnancies.

Symptoms include malaise, nausea, vomiting, polyuria, polydipsia, abdominal pain, jaundice, and encephalopathy. Hypoglycemia is a sign of poor prognosis . Common biochemical changes include renal dysfunction, elevated transaminases, prothrombin time, serum uric acid, and bilirubin. Elevated serum ammonia concentration and lactic acidosis are indications of serious illness.

Management is supportive and, if diagnosed prenatally, includes termination of pregnancy. Liver transplant is justified in cases of failure to recover liver function and severe hepatic encephalopathy. After delivery, resolution may take up to 4 weeks.

Box. Swansea diagnostic criteria for the diagnosis of acute fatty liver of pregnancy.

Drug-induced liver disease occurs during pregnancy in about 3% of women and is a leading cause of liver failure. It can be direct, due to an immunological reaction or indirect. The most common agents include antibiotics and antihypertensives. Treatment consists of stopping the responsible agent and monitoring liver function.

For viral hepatitis (such as hepatitis B), it is recommended to reduce mother-to-child transmission; Antiviral therapy is recommended for viral levels > 200,000 IU/mL. Tenofovir, entecavir and lamivudine can be used during pregnancy and breastfeeding.

Cirrhosis and portal hypertension are associated with a risk of variceal bleeding. Physiological changes in pregnancy lead to an increase in plasma volume due to compression of the inferior vena cava. This leads to an increase in portal pressures and can lead to new varicose veins or an increase in their size. Women with known varicose veins should undergo endoscopy in the second trimester for surveillance and consideration of variceal ligation. Propranolol should be used for the prophylaxis of variceal bleeding during pregnancy.

Nonalcoholic fatty liver disease (NAFLD) can be considered a high-risk complication as it is associated with hypertensive disorders in pregnancy, gestational diabetes, postpartum hemorrhage, and preterm birth. Pre-pregnancy counseling and postpartum follow-up are recommended, especially because it is a manifestation of metabolic syndrome.

Autoimmune hepatitis can recur during pregnancy in 20% of women and disease activity should ideally be monitored before conception. Disease flares may increase the risk of adverse fetal outcomes, such as prematurity and preeclampsia. The condition can be treated with corticosteroids and azathioprine, which are safe during pregnancy.

Wilson’s disease is a rare autosomal recessive condition that alters copper metabolism in the liver, reflected by increased levels of ceruloplasmin in both the brain and liver. If left untreated, this condition can lead to miscarriage, but if treated, successful pregnancies are possible. Chelating copper before pregnancy and not stopping drug therapy during pregnancy is thought to help improve pregnancy outcomes.

Liver diseases in pregnancy can be difficult to manage due to various presentations, ranging from subtle liver biochemical changes to liver failure. Early detection, appropriate follow-up, and involvement of experienced clinicians within the multidisciplinary team can help improve outcomes for these women and their babies.