Liver Disease in Pregnancy

Function

The Liver During Normal Pregnancy

The liver, like other organs, undergoes various physiological and anatomical changes during pregnancy. An understanding of these changes can help one to differentiate the physiological changes from the pathological ones. These changes can be broadly classified into the following categories:

• Physical Findings: During Pregnancy, the gross examination of the liver is relatively unchanged; however, skin findings such as spider angiomata (vascular spider) and palmer erythema can be seen. These physical findings are especially prominent in the latter half of the pregnancy, especially in Caucasian women. It should be noted that such findings might be hard to appreciate because of the expanding uterus.
• Laboratory Findings: Most of the liver biochemical tests remain within normal limits during pregnancy with a few exceptions. Serum alkaline phosphate (ALP) increases markedly (up to four times the normal) in the third trimester which results from the increased levels of placental alkaline phosphate. Conjugate increase in serum gamma-glutamyl transpeptidase along with serum alkaline phosphate usually indicates a pathological process as the level of serum gamma-glutamyl transpeptidase is usually slightly reduced during normal pregnancy. Other liver biochemical tests such as serum alanine transferase (ALT), aspartate aminotransferase (AST), and total and free bilirubin typically remain within normal limits, and any increased value should warrant further evaluation. Furthermore, hemodilution, a well-known phenomenon during pregnancy, results in a decrease in serum albumin which worsens as pregnancy progresses. Total cholesterol, triglyceride, fibrinogen, and ceruloplasmin are few other laboratory findings that are noticeably augmented during pregnancy.
• Radiographic Findings: Ultrasonography examination during pregnancy usually reveals a normal biliary tree. The only striking ultrasonographic findings are increased fasting gallbladder volume and residual volume post contraction.

Issues of Concern

Approach to Hepatobiliary Disease in Pregnancy

As in other liver diseases, a systematic approach is needed while treating liver diseases associated with the pregnant state. A basic workup includes a detailed history, clinical examination, and laboratory and radiographic tests. The history should include prior pregnancy and associated liver complications, intravenous drug use, transfusions, the term of pregnancy, and oral contraceptive use. Although not unique to pregnancy, the patient should be evaluated for clinical findings such as nausea, vomiting, jaundice, generalized pruritus, polyuria, and polydipsia in the absence of diabetes, and abdominal pain. Generally, liver diseases during pregnancy can be classified into three categories: those unique to pregnancy, those unrelated to pregnancy, and lastly, those preexisting the pregnancy.[5][6][7][8]

Liver Disease Unique to Pregnancy

The liver diseases that are only seen during pregnancy can include multi-organ diseases such as HELLP syndrome or diseases that are specific to the liver such as acute fatty liver of pregnancy. Following are the most common liver diseases that are unique to pregnancy:[9][10][11]

Hyperemesis Gravidarum: Hyperemesis gravidarum (HG) is a form of morning sickness where the patient experiences severe nausea and vomiting, usually in the first trimester. It can be seen in up to 1.5 % of pregnant women. Although there is no universal definition, HG is primarily diagnosed by the presence of intractable nausea and vomiting accompanied by weight loss (greater than 5% of pre-pregnancy weight) and ketonuria. The exact pathogenesis of HG is unclear, but it has been associated with age less than 20 years, obesity, diabetes mellitus, nulliparity, Helicobacter pylori infection, hormonal changes during pregnancy, and abnormal gastrointestinal motility. The diagnosis of HG is made clinically and often requires hospitalization. The primary liver manifestation includes elevation of both ALT and AST. This is especially true for ALT, where the levels can go as high as 1,000 International Units/L but are usually less than 250 International Units/L. Transient hyperthyroidism may be seen in up to 60% of the patients due to the thyroid stimulating property of human chorionic gonadotropin. Treatment usually involves bowel rest, antiemetics medications, intravenous fluids, and correction of electrolytes abnormalities if present. In some instances, thiamine administration should be considered if vomiting has persisted for prolonged periods. Complications are rare but include esophageal rupture, retinal hemorrhage, spontaneous pneumomediastinum, Wernicke encephalopathy, and central pontine myelinolysis. This condition typically does not recur in future pregnancies.

Intrahepatic Cholestasis of Pregnancy: Intrahepatic cholestasis of pregnancy (ICP) is a reversible cholestatic disease of the second or third trimester. Although it usually manifests in the third trimester, it can start as early as the second or third month of pregnancy. The prevalence of the disease varies geographically, and it is seen in up to 1.5 % of pregnancies in the United States. The pathogenesis of ICP is not well understood but most likely multifactorial. The hormonal changes, the use of high dose oral contraceptive (high estrogen state causes cholestasis), the geographic variability, and the genetic susceptibility are all likely triggers for alteration of the transport of sex steroids across the canalicular and hepatic membranes and ICP. At least ten different MDR3 mutations have been associated with ICP, of which the ABCB4 variant has been reported to be associated with a severe form of ICP.  ICP is rare in Asian or Black women.

ICP is a diagnosis of exclusion and is characterized by the presence of pruritus and abnormal LFTs. Pruritus is the hallmark symptom of ICP, and jaundice is rare but follows after two weeks of pruritus if present. Pruritus is usually more dominant on the palms and soles, and it is worse during night time. Patients with ICP do not experience symptoms such as encephalopathy or abdominal pain, and if present, these symptoms should initiate a further evaluation to rule out other causes of liver diseases. The key laboratory findings in ICP include an increase in total and fasting serum bile acid concentration. In some cases, this may be the only laboratory abnormality. Other laboratory abnormalities include elevated ALT (rarely exceeding 250 International Units/L but viral hepatitis must be ruled out), ALP, direct and total bilirubin serum concentrations. Although routinely not done, the levels of chenodeoxycholic acid and cholic acid are also elevated such that the ratio of cholic acid to chenodeoxycholic acid greater than 42% is usually indicative of ICP. Steatorrhea is usual and prothrombin time may be prolonged due to Vitamin K malabsorption, which can be exacerbated by cholestyramine therapy. Ultrasonography should be done in all cases of suspected ICP to rule out the biliary obstruction. Liver biopsy is rarely necessary, but the presence of focal and irregular cholestasis is characteristic.

ICP normally resolves 4 to 6 weeks after delivery and is usually benign to the mother but recurs with subsequent pregnancies. However, poor fetal outcomes such as prematurity, respiratory distress syndrome, and intrauterine demise have been associated. Delivery is recommended at 38 weeks, or at 36 weeks if cholestasis is severe. Vitamin K should be given at least 6 hours before delivery to minimize the risk of post-partum hemorrhage. Treatment includes administration of ursodeoxycholic acid (10 to 20 mg/kg/day) which modifies the bile acid pool, relieves pruritus, and improves liver biochemical tests as well as the fetal outcome. Other treatments such as cholestyramine and hydroxyzine can be tried if the first line of treatment fails, however, they are not as effective as ursodeoxycholic acid. Fetal outcomes are better with ursodiol. If pruritus and alkaline phosphatase elevation do not resolve after pregnancy, alternate conditions such as primary biliary cholangitis and familial cholestatic disorder (MDR3 mutations are also present in progressive familial intrahepatic cholestasis) should be considered. A cholestatic response to a trial of small doses of estrogen therapy after delivery, if present, is a predictor of poor tolerance to oral birth control pills.

HELLP Syndrome: HELLP syndrome is a severe and rare variant of preeclampsia, which is defined as elevated blood pressure seen after 20 weeks of gestation in the presence of proteinuria or end-organ dysfunction if proteinuria is absent. The pathogenesis of HELLP is not well understood but likely involves abnormal development of placental vasculature and new defects in maternal vascular endothelial cells, resulting in poor perfusion to various organs. In preeclampsia, there is generalized vasospasm, resulting in increased systemic vascular resistance and pressor responses to endogenous vasoconstrictors. Vascular endothelial damage results in platelet and fibrin deposition in sinusoids, causing hepatocellular necrosis and hemorrhage in zone 1. The finding of zone 3 necrosis and hemorrhage, if present, is due to shock in severe pre-eclampsia. In mild cases of preeclampsia, there is a mild elevation of serum AST/ALT/alkaline phosphatase as well as minor signs of disseminated intravascular coagulation (DIC) with thrombocytopenia. Jaundice is rare, but if present, is terminal and hemolytic in etiology with serum total bilirubin often not exceeding 6 mg/dL.

The clinical presentation of HELLP syndrome is highly variable. The patient might be asymptomatic or may present with symptoms such as right upper quadrant abdominal pain, enlarged liver, nausea, vomiting, jaundice, or confusion. The laboratory findings are significant for intravascular hemolysis, schistocytes on peripheral smear, elevated LFTs (usually ALT), and low platelet count. Serum aminotransferases are more than ten times elevated, and unconjugated hyperbilirubinemia may be present due to hemolysis. The diagnostic criteria such as Tennessee or Mississippi classifications should be used to diagnose and to grade HELLP syndrome as it has prognostic value. HELLP caries up to 5% maternal mortality rate in comparison to fetus mortality rate which can be as high as 30%. Like ICP, prematurity remains the most common risk associated with fetal outcomes. Treatment of HELLP depends on gestation age. Supportive management with anti-hypertensive medicines, administration of magnesium sulfate should be considered in the mother; however, the cornerstone remains early delivery of the fetus. If gestation age is less than 34 weeks, treatment with steroids for 24 to 48 hours should be considered for fetal maturity before attempting delivery of the fetus.

Acute Fatty Liver of Pregnancy: Acute fatty liver of pregnancy (AFLP) is a rare but serious liver disease of pregnancy. It is caused by microvascular fatty infiltration of the hepatocytes. The pathogenesis of AFLP has been linked to the long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) in the fetus in a setting of the mother with heterozygosity for LCHAD. This leads to the defective beta-oxidation of the fatty acid in the fetal mitochondria. However, the link between how LCHAD in the fetus leads to AFLP in a heterozygous mother is still unclear. The diagnosis of AFLP is made clinically, and liver biopsy is rarely done.

The clinical presentation normally includes nonspecific symptoms of liver disease such as abdominal pain, jaundice, nausea, and vomiting. The differential diagnoses to be considered are viral hepatitis, drug-induced liver injury, HELLP syndrome, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Among those, AFLP and HELLP syndrome have considerable overlap; however, outcomes such as encephalopathy, hyperammonemia, coagulopathy (especially anti-thrombin activity), hypoglycemia, hypoalbuminemia, and renal insufficiency are usually seen in AFLP and can be used to differentiate from HELLP syndrome. Hyperbilirubinemia is predominantly (greater than 90%) conjugated, in contrast to HELLP where it is unconjugated due to hemolysis. The symptoms of vomiting and weakness, along with lactic acidosis, hypoglycemia, and metabolic acidosis, are due to defective oxidative phosphorylation and energy supply in the setting of mitochondrial cytopathy. The elevated serum uric acid level results from tissue destruction and lactic acidosis. Serum GGT is often normal, but if elevated is indicative of viral hepatitis. Other notable laboratory findings include the increased level of the white cell count, platelet count, PT, and PTT. Fibrinogen levels are low, severe bleeding is frequent, but DIC is present in only about 10% of the cases. Although not needed for diagnosis, radiological workup will show signs of fatty liver, but the absence of fatty liver does not exclude the diagnosis. Liver biopsy, if performed via the transjugular route, will show microvesicular and macrovesicular steatosis and the microvesicular change may be apparent only when fresh sections are stained with oil red O. Other changes include ballooned hepatocytes with dense, central nuclei, cholestasis, and changes of cell inflammation/necrosis.

AFLP is an obstetric emergency, as such emergent delivery of the fetus is indicated irrespective of the gestational age. The route of delivery can be cesarean or vaginal depending upon the fetus and the maternal status. If hypoglycemia or coagulopathy is present, it should be reversed before delivering the fetus. Children may be at risk of hypoglycemia, dilated cardiomyopathy, progressive neuromyopathy and sudden infant death syndrome. AFLP carries high mortality rate for both fetus and mother if not recognized promptly. The mother should be informed of the small but increased risk of recurrence of AFLP in future pregnancies.

Liver Disease Unrelated to Pregnancy

Pregnant women, like any individual, are susceptible to liver diseases that can affect the general population. However, compared to general population, certain liver diseases in pregnancy carry higher mortality and morbidity which can be seen in diseases such as hepatitis E.

Viral Hepatitis: The prevalence, incidence, and outcome of Hepatitis A, B, and C are the same in the pregnant population as compared to the general population. Immunoprophylaxis should be given to the newborn at the time of birth if perinatal transmission risk is present, especially in the setting of acute hepatitis B infection. Pregnant women who are in close contact with individuals carrying hepatitis A or B virus should receive immunoglobulin and vaccination promptly. Indications for treatment of hepatitis B in pregnancy are not different from the pre-pregnant state. In order to reduce the risk of transmission of hepatitis B infection to the infant, mothers who are not already on treatment may be given antiviral therapy with tenofovir disoproxil fumarate at 28 to 30 weeks of gestation, if the HBV viral load is greater than 200,000 International Units/mL. The risk of transmission of hepatitis C from mother to infant is minimal. Routine C-section is not recommended in any of these cases. Hepatitis E, which is usually a self-limiting infection, has adverse outcome during pregnancy. If it occurs during the third trimester, hepatitis E carries a maternal mortality rate of up to 30% (fetal mortality up to 50%) and is associated with fulminant liver failure. Maternal-to-fetus transmission of hepatitis E can occur and is a potential cause of acute hepatitis in a newborn. Hepatitis E infection is most commonly seen in the endemic region such as northern Africa and sub-continental countries; however, a recent increase in the non-endemic region has been linked to zoonotic transmission and increased travel to endemic areas. Pregnant women during the third trimester should be counseled on the risk associated with traveling to the endemic areas. Treatment of hepatitis E is usually supportive. Herpes simplex virus (HSV) type II has been reported in pregnant women, most likely due to the defective cell-mediated immunity that is prevalent in pregnancy. Serum aminotransferases can be severely elevated, mimicking AFLP, but without jaundice (anicteric hepatitis). Herpetic lesions may be present on the vulva or cervix. Imaging studies may show multiple, low-density areas of necrosis. Liver biopsy shows intranuclear, Cowdry A inclusions and extensive hepatocellular necrosis. Acyclovir is the treatment of choice and mortality is high.

Vascular Liver Disease: In the pregnant state, the increased level of serum estradiol results in an increase in the procoagulant factors and a decrease in the anticoagulant factors. Furthermore, a decrease in aPTT, PT, and thrombin time has been associated with pregnancy. These changes during pregnancy increase the risk for thrombosis which can potentially lead to diseases such as portal vein thrombosis or Budd-Chiari syndrome (BCS). Although pregnancy is a risk factor, BCS usually occurs in the presence of other thrombotic risk factors such as protein S deficiency (most common for BCS in pregnancy) and factor V Leiden mutation. A comprehensive workup should be done in a pregnant woman diagnosed with BCS to rule out other thrombotic diseases. Treatment is usually low molecular weight heparin as oral anticoagulants are contraindicated because of teratogenicity. Other invasive treatments such as TIPS, thrombolysis, or percutaneous transluminal angioplasty can be considered in a case of severe BCS.

Biliary Tract Disease: There is an increased risk of gallstones during pregnancy as the gallbladder’s motility slows down and the volume goes up during normal pregnancy. Gallstones and biliary sludge can be seen in ultrasound in asymptomatic pregnant women which usually resolve postpartum; however, a tiny fraction (0.8%) of women can develop acute cholecystitis within one year postpartum. Acute cholecystitis can also be seen during pregnancy. Initial management includes antibiotics and intravenous fluids. Generally, cholecystectomy is performed after delivery. However, prompt laparoscopic cholecystectomy should be done in patients who are non-responsive to conservative management. Other diseases such as choledocholithiasis/cholangitis and gallstone pancreatitis should be managed a usual. ERCP and sphincterotomy may be done from the second trimester onwards.

Preexisting Liver Disease During Pregnancy

Pregnant women with chronic liver disease are rarely seen in a clinical scenario given that most patients are either in a pathological anovulatory state or have passed the child-bearing age. However, the following situations are frequently encountered:

Cirrhosis: Pregnancy in the cirrhotic patient has been reported without any adverse effects on the liver; however, it is not unusual to see cirrhosis complications such as hepatic encephalopathy/coma, ascites, and declining liver function including worsening jaundice in a cirrhotic pregnant patient. Since there is an increase in effective circulatory volume during pregnancy, a pregnant woman remains at high risk for worsening of preexisting portal hypertension. A cirrhotic pregnant woman should undergo upper endoscopy before pregnancy or during the second trimester of pregnancy for evaluation and possible treatment of varices. Although variceal bleeding has been reported during pregnancy, it is still unclear whether or not if the incidence is higher in pregnant patients versus non-pregnant patients. A cirrhotic pregnant woman with portal hypertension can be managed prophylactically with nonselective beta-blocker (which is safe throughout pregnancy) or by banding of varices before or during pregnancy; however, the newborn should be observed for side effects such as bradycardia and low sugar level resulting from the beta-blocker administration. The presence of the ascites in a pregnant woman is usually associated with poor fetal outcomes. The general mode of delivery in a cirrhotic pregnant woman is vaginal unless indicated otherwise. All pregnant mothers with chronic liver disease should be managed in a high-risk pregnancy unit with inputs from an obstetrician, a hepatologist, and preferably close to a liver transplant center.

Autoimmune Hepatitis: Autoimmune hepatitis is seen more frequently in younger women, and therefore, knowing the management of pregnancy in an autoimmune hepatitis patient is crucial. Autoimmune hepatitis is characterized by high serum gamma globulin concentration and increased levels of ALT. It can either present in the asymptomatic form, acute liver failure, or chronic liver failure and is associated with infertility (anovulation); however, women generally recover their fertility after successful treatment of autoimmune hepatitis. The usual treatment includes prednisone and azathioprine. Successful treatment of autoimmune hepatitis before pregnancy usually leads to uneventful pregnancy as the activity of autoimmune hepatitis is generally decreased during pregnancy. Prednisone alone can be used for autoimmune hepatitis during pregnancy. Azathioprine is labeled as category D drug, but it can still be used during pregnancy at a lower dose. The placenta is a relative barrier to azathioprine and metabolites. Breastfeeding is allowed even if mothers are taking corticosteroids or azathioprine. Besides adequate treatment, autoimmune hepatitis is still associated with added risk of maternal death, fetal loss, and prematurity.

Wilson Disease: Wilson disease, like most other liver diseases, is associated with infertility which typically resolves after treatment. The usual treatment of Wilson disease is a chelating drug such as D-penicillamine, trientine, and zinc. It is important to emphasize that patients with Wilson disease should have an uninterrupted treatment during pregnancy as untreated Wilson disease is associated with poor maternal-fetus outcomes such as miscarriages, stillbirth, and prematurity. The chelating agent usually has a variable degree of teratogenicity, with zinc being the safest chelating agent during pregnancy. Generally speaking, the dose of chelating agents is lowered in the first and third trimesters to lower the teratogenic risk. D-Penicillamine or trientine can be still used but at a lower dose and with a teratogenic risk. This is particularly true for D-penicillamine, where the fetus carries a risk for transient goiter hypothyroidism. Breastfeeding should be avoided if mothers are taking D-penicillamine.

Clinical Significance

Liver disease during pregnancy can be very complicated to manage and as such requires a multi-specialist approach. It is important to identify the underlying etiology as it will direct the proper treatment. Given the various overlap for many liver diseases that are unique during pregnancy, a broad differential diagnosis and in-depth understanding are essential for prompt and correct management. 

Other Issues

Liver Transplantation and Consultation to Hepatologist

Safe pregnancy has been reported in women post-liver transplantation; however, it is advisable to wait for at least a year before attempting pregnancy. This is to provide enough time post-liver transplant for immunosuppressive agents to reach safer profiles. Patients with renal dysfunction in the setting of a liver transplant are associated with poor maternal-fetus outcomes. Increased surveillance for general and opportunistic infection should be done in this population during pregnancy. Breastfeeding should be avoided while taking immunosuppressive medications. Although liver transplant during pregnancy (in a condition such as HELLP or AFLP) has been reported, it is a very high-risk procedure that is usually managed with pregnancy termination as maternal survival and support are the priority.

Early consultation and involvement of a hepatologist are recommended to manage the liver disease during pregnancy. Pregnant women with liver disease should be educated on the potential risk and complications that may happen during pregnancy. Detailed counseling about the mode of delivery and future pregnancy risk should also be discussed with the patient.

Enhancing Healthcare Team Outcomes

Managing liver disease in pregnancy requires a multispecialty approach involving specialty-trained gastrointestinal nurses and specially trained providers. There are numerous causes of liver dysfunction during pregnancy and it is important to involve the internist and gastroenterologist early in the course. The patient needs to be monitored closely as there are two lives at stake. An interprofessional approach will result in the best outcome.[Level V]