Guide
It is not uncommon for liver disease to develop during pregnancy. Liver disease during pregnancy can be caused by conditions specific to pregnancy or by acute or chronic conditions that are already present or occur during pregnancy.
Pregnancy-specific conditions include hyperemesis gravidarum (HG), hypertensive disorders of pregnancy, intrahepatic cholestasis of pregnancy (ICP), and acute fatty liver of pregnancy (AFLP). Hypertensive disorders of pregnancy include preeclampsia/eclampsia, hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Chronic liver diseases that may be affected by or exacerbated by pregnancy include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and nonalcoholic fatty liver disease (NAFLD).
Prompt diagnosis and management of liver disease during pregnancy is important, as it may lead to adverse maternal and fetal outcomes. This review discusses and summarises recent advances in research on liver disease in pregnancy to help physicians better understand the disease and improve patient outcomes.
Liver disease caused by pregnancy-specific conditions
Determining the patient's gestational stage is essential to understand the liver disease caused by pregnancy-specific conditions (Table 1). HG usually occurs in the first trimester. HELLP syndrome and ICP should be considered in the second trimester. With the exception of HG, all disorders may be the cause of liver injury in the third trimester of pregnancy.
Table 1 Liver disease caused by pregnancy-specific diseases
Note: AST, aspartate aminotransferase, ALT, alanine aminotransferase, LDH, lactate dehydrogenase, US, ultrasonography
Pregnancy vomiting
The incidence of HG is between 0.3%~2%, and liver involvement can be seen in 50%~60% of patients, and the clinical manifestations are excessive nausea, vomiting, weight loss and dehydration. Treatment depends on the severity of symptoms and includes intravenous fluids, antiemetics, and vitamin and mineral supplementation. Mothers are encouraged to eat smaller, more frequent meals and eat a high-carbohydrate and low-fat diet. Because elevated liver enzymes resolve spontaneously within about 20 weeks of gestation, maternal and fetal outcomes are excellent.
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Preeclampsia/eclampsia is a part of hypertensive diseases of pregnancy, and preeclampsia is relatively common, with an incidence of 2%~8%. The most common symptoms of preeclampsia/eclampsia are persistent and severe headache, visual disturbances, epigastric pain, vomiting, and peripheral edema. Among them, liver involvement occurs in 20%~30% of cases, which usually manifests as mild to moderate elevation of AST/ALT.
Low-dose aspirin is recommended for preeclampsia/eclampsia prevention in high-risk patients. Antihypertensive drugs and magnesium are used to control hypertensive crises and seizures, respectively. Liver damage associated with preeclampsia/eclampsia is not progressive and does not require specific treatment.
Hemolysis, elevated liver enzymes, and low platelet count syndrome
HELLP syndrome is a part of hypertensive disorders of pregnancy, with an incidence of 0.2%~0.6% and an incidence of 10%~20% in patients with preeclampsia/eclampsia. Epigastric/right upper quadrant pain is the most characteristic symptom of HELLP syndrome, often associated with nausea and vomiting, and should be considered in any pregnant woman with sudden onset of such pain in the second half of pregnancy, particularly when accompanied by nausea and vomiting. Other symptoms include malaise, headache, severe systolic/diastolic hypertension, and proteinuria. The diagnosis and severity grading system for HELLP syndrome is shown in Table 2.
Table 2 Grading system for HELLP syndrome
Note: ELLP, no hemolysis (elevated liver enzymes and low platelet count), EL, elevated liver enzymes, LP, decreased platelet count, N/A, not applicable
HELLP syndrome is a life-threatening condition for both the mother and the fetus. Although emergency delivery is the only treatment, elevated aminotransferases may persist until 48 hours postpartum. Liver rupture, hematoma, and decompensation require urgent treatment including radiological or surgical intervention and liver transplantation, especially if hepatic, renal, and hematologic complications persist up to 72 hours postpartum. If the patient is less than a month old, drug therapy includes low-dose aspirin, intravenous magnesium, and antihypertensive drugs. Mississippi Protocol strongly recommends intravenous corticosteroids, especially high-dose dexamethasone, in combination with magnesium sulfate and systolic blood pressure control.
Intrahepatic cholestasis of pregnancy
ICP refers to the impaired flow of bile in the liver, resulting in retention in the liver and spillage into the bloodstream, and is the most common liver disease specific to pregnancy. Some adverse outcomes, including preterm birth, meconium contamination of amniotic fluid, and fetal death, were associated with ICP. The most common symptom of ICP is moderate to severe pruritus without a rash that begins in the palms and plantars and extends throughout the body. It often worsens at night, disrupting sleep and inducing irritability. Other symptoms include jaundice, epigastric pain, fatigue, and anorexia. A significant increase in serum total bile acid levels was observed, reflecting bile retention.
Treatment focuses on reducing maternal symptoms and preventing fetal distress. The European Society for the Study of the Liver recommends ursodeoxycholic acid (UDCA) 10 to 15 mg/kg/day as first-line therapy. In severe ICP with refractory symptoms, early delivery is the only way to benefit outcomes.
Pregnancy acute fatty liver
AFLP is rare, but it is a potentially fatal emergency that can lead to severe maternal and fetal complications. The disease has a high stillbirth rate, with a maternal mortality rate of about 12%. The early manifestations of AFLP are nonspecific and similar to those of preeclampsia and HELLP syndrome. The most common symptoms include anorexia, nausea and vomiting, and epigastric pain, followed by signs of acute liver failure such as encephalopathy and jaundice. Aminotransferases can rise up to 20 times. Coagulopathy can also be observed in AFLP and HELLP syndromes, caused by decreased AFLP synthesis and increased HELLP consumption.
AFLP usually requires intensive care treatment. In most cases, immediate delivery is first-line treatment, but laboratory and clinical abnormalities may persist up to one week postpartum. Fetuses born to patients with AFLP are at higher risk of liver failure, cardiomyopathy, nonketotic hypoglycemia, myopathy, and neuropathy. In addition, AFLP may recur in subsequent pregnancies.
Liver disease that may develop into pregnancy complications
Chronic liver diseases that may be affected by or exacerbated by pregnancy include AICH, PBC, PSC, and NAFLD.
Autoimmune hepatitis
AIH is a chronic inflammatory liver disease characterized by elevated aminotransferases, the presence of antinuclear or anti-smooth muscle antibodies, elevated IgG, and interfacial hepatitis/plasma-lymphocyte inflammation.
Controlled AIH is not a contraindication to pregnancy, but women with cirrhosis are at highest risk of adverse outcomes and require close monitoring. Regarding pharmacotherapy, no clear relationship has been found between the use of immunosuppressants (corticosteroids and azathioprine) during pregnancy and adverse outcomes. To prevent adverse outcomes that may result from poor disease control, maintenance immunosuppressive therapy is recommended, but mycophenolate mofetil is contraindicated. Hepatitis flare-ups may occur after delivery, so the mother should be closely monitored for at least six months after delivery.
Primary biliary cholangitis and primary sclerosing cholangitis
Both PBC and PSC are chronic cholestatic liver diseases. PBC may progress to cirrhosis and liver failure. Like AIH, PBC occurs predominantly in middle-aged women, but it can also occur in younger women. Pregnancy in patients with PBC without cirrhosis was not associated with an increased risk of adverse maternal or fetal outcomes. However, due to the high risk of potential complications in childbirth, close monitoring of pregnancy and delivery is essential. About half of pregnant women with PBC may experience new or worsening itching and occasionally require antipruritic treatment. UDCA is safe and well tolerated in pregnant women and should not be discontinued. Bezafibrate is often used as a second-line treatment for PBC in Japan and is contraindicated during pregnancy.
PSC mainly affects the extrahepatic and extrahepatic bold ducts. Unlike PBC, PSC is more common in men, with adolescents and young adults being at the highest risk. Although liver enzymes are elevated during pregnancy and postpartum in 20% and 32% of patients, respectively, the clinical course of PSC is not affected by pregnancy. Patients with PSC may present with new pruritus or worsening pruritus.
Although available data are limited, maternal and fetal outcomes are good for pregnant women with PBC and PSC, and close monitoring and treatment of possible pruritus is recommended.
Nonalcoholic fatty liver disease
NAFLD is the most common liver disease in women of childbearing age. Although there are few data on the effects of NAFLD on the mother and fetus, several studies have shown that it has a negative impact on pregnancy outcomes.
Gestational diabetes mellitus (GDM) is the most common metabolic disorder during pregnancy, and its association with NAFLD is likely to be bidirectional. NAFLD in the first trimester is significantly associated with an increased risk of GDM, and prior GDM is also a predictor of postpartum NAFLD. To reduce the burden of NAFLD on the mother and fetus, it is important to control prenatal hyperglycemia, prevent GDM, and avoid excessive weight gain during pregnancy.
文献索引：Sasamori Y, Tanaka A, Ayabe T. Liver disease in pregnancy. Hepatol Res. 2020 Jun 24. doi: 10.1111/hepr.13540.
Source: Yimaitong Hepatology