Liver Disease In Pregnancy

I. Problem/Condition.

Development of physical exam findings associated with liver disease and changes in liver biochemical profile are normal in pregnancy. These normal changes include development of spider angiomas and palmar erythema with decrease in albumin and increase in alkaline phosphatase. Although any liver disease can occur during pregnancy, several liver disorders are unique to the pregnant patient. These liver disorders include hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, pre-eclampsia/eclampsia, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, and acute fatty liver of pregnancy.

Liver diseases unique to pregnancy are estimated to complicate 3% of all pregnancies. Although rare, HELLP and acute fatty liver of pregnancy are severe diseases necessitating early recognition and intervention due to significant morbidity and accounting for 18% maternal and 23% fetal mortality.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Any pregnant patient who has abnormal liver enzymes not associated with normal pregnancy such as elevation in alanine aminotransferase, aspartate aminotransferase, or bilirubin should undergo evaluation. The differential diagnoses for these pregnancy associated liver disorders include non-alcoholic steatohepatitis, acute or chronic viral hepatitis, drug or toxin mediated hepatitis, autoimmune hepatitis, Wilson’s disease, Budd-Chiari syndrome, and biliary disease.

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B. Describe a diagnostic approach/method to the patient with this problem.

The first in step differentiating these liver disorders unique to pregnancy is identification of the trimester of pregnancy.

Hyperemesis gravidarum typically occurs in patients in the first or second trimester of pregnancy. Liver involvement in this illness usually manifest as elevated aminotransferases. The laboratory abnormalities resolve when the vomiting symptoms from the hyperemesis gravidarum also resolve.

Intrahepatic cholestasis of pregnancy is a reversible condition that typically occurs in the second to third trimester. The diagnostic laboratory abnormality is an elevated serum bilirubin. Pre-eclampsia and eclampsia causing elevation in aminotransferases or hepatic rupture or infarction can occur during the third trimester. Patients typically have other symptoms which classically define preeclampsia and eclampsia: hypertension and proteinuria.

HELLP and acute fatty liver of pregnancy are considered to be illnesses on a continuum with preeclampsia and eclampsia. HELLP syndrome is a variant of severe preeclampsia that occurs in up to 12% of patients with preeclampsia. However, one does not have to have preeclampsia or eclampsia to have either HELLP or acute fatty liver of pregnancy. The classic symptoms that are also associated with HELLP are evidence of hemolysis and low platelets. Unlike the other liver disorders unique to pregnancy, acute fatty liver of pregnancy is a common cause of liver failure in pregnancy and is a medical and obstetric emergency.

Patients being considered to have one of the above disorders should undergo an extensive drug and toxin history to rule out this as cause of liver enzyme abnormality. Laboratory studies should evaluate for acute or chronic viral hepatitis. Ultrasound of the liver and biliary tree with doppler evaluation should be done to evaluate for biliary disease or venous obstruction. If no etiology is defined after this initial evaluation, serologies to evaluate for autoimmune hepatitis or Wilson’s disease should be considered. Ultimately, a liver biopsy can also be considered.

1. Historical information important in the diagnosis of this problem.

The history should investigate for any exposures to new drugs, toxins, or risk factors for hepatitis such as travel, unprotected intercourse, intravenous (IV) drug use, and blood transfusions. Also, past medical history and family history review should investigate for other liver disorders that are a part of the differential diagnoses. Risk factors for the liver diseases specific to pregnancy are variable but special attention should be paid to complications noted in patient’s prior pregnancies.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.


3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Laboratory workup includes an acute hepatitis viral panel as well as lab to fulfill diagnostic criteria for these unique liver disorders. A right upper quadrant ultrasound is required to rule out biliary disease or thrombosis.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Hyperemesis Gravidarum is considered a diagnosis when pregnant patients have intractable nausea and vomiting that results in dehydration, weight loss, and ketosis. Serum aminotransferases can be raised up to 20 times the upper limits of normal without significant elevation of bilirubin. Other electrolyte abnormalities can occur secondary to vomiting and malnutrition such as hypokalemia, hypophosphatemia, hypomagnesemia. In addition, hyperthyroidism can be an associated problem in more than half of patients. There are no specific abdominal ultrasound findings. Associated fulminant hepatic failure has never been reported.

Intrahepatic cholestasis of pregnancy should be considered as a diagnosis if patients are in their second trimester of pregnancy, complaining of pruritus, and have elevated bilirubin and aminotransferases. Pruritis especially occurs at night and often involves the palms and soles. Aminotransferases may be elevated 2-10 fold. Alkaline phosphatase levels may not be helpful due to higher physiological levels in late pregnancy, however, an elevated fasting serum bile acids level (> 10 micromole/L [μmol/L]) confirms the diagnosis.

HELLP is the combination of microangiopathic hemolysis, increased liver enzymes, and low platelets. Laboratory evaluation will show thrombocytopenia and anemia with elevated LDH and low haptoglobin. Peripheral blood smear will show schistocytes. Liver enzyme abnormalities are usually a mild to moderation elevation in amiotransferases and only slight increase in bilirubin levels. The Mississippi Triple-class HELLP System further classifies the severity of the disorder as shown by the diagnostic criteria in Table 1. Class 1 is defined by severe thrombocytopenia (platelets ≤50,000/micromole [μmol]), evidence of hepatic dysfunction (AST and/or ALT ≥70 units/Liter [U/L]), and evidence suggestive of hemolysis (LDH ≥600 U/L). Class 2 requires similar criteria except thrombocytopenia is moderate (>50,000 to ≤100,000/μL). Class 3 includes patients with mild thrombocytopenia (platelets >100,000 but ≤150,000/μL), mild hepatic dysfunction (AST and/or ALT ≥40 U/L), and hemolysis (LDH ≥600 U/L).

Table 1.
HELLP Class Mississippi Classification
1 Platelet Count = 50,000/μL, AST or ALT = 70 IU/L, Total LDH = 600 IU/L
2 > 50,000/μL Platelet Count = 100,000/μL, AST or ALT = 70 IU/L, Total LDH = 600 IU/L
3 > 100,000/μL Platelet Count = 150,000/μL, AST or ALT = 40 IU/L, Total LDH = 600 IU/L

Swansea diagnostic criteria can be used for the diagnosis of acute fatty liver of pregnancy. It involves identifying six or more of the following features in patients who have no other explanation for their symptoms: vomiting, abdominal pain, polydipsia/polyuria, encephalopathy, high bilirubin > 14 μmol/L, hypoglycemia, hyperuricemia, leukocytosis, ascites or bright liver on ultrasound, elevated aminotransferases, hyperammonemia, renal impairment, coagulopathy, or microvesicular steatosis on liver biopsy.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Liver Disease in Pregnancy.

One has to consider the pregnancy when managing these liver disorders unique to pregnancy. With pre-eclampsia and eclampsia, the liver abnormalities usually resolve with delivery of the fetus. The liver abnormalities with hyperemesis gravidarum follow an indolent course and resolve when the hyperemesis gravidarum symptoms resolve. Care is supportive to ensure the patient has adequate hydration, anti-emetics, nutrition, and has limited to no exposure to hepatotoxins.

The liver abnormalities with intrahepatic cholestasis of pregnancy also follows an indolent course. However, high levels of bile acids can cause fetal distress. In addition, the patient may have debilitating pruritus. Both the pruritus and liver abnormalities can be managed with ursodeoxycholic acid at a dose of 10-15 milligram/kilogram bodyweight, but do not change fetal outcomes. However, fetal distress in this condition may mandate early delivery at which time intrahepatic cholestasis should resolve. This is a benign condition for the mother, but may result in premature births up to 60%, fetal distress in 61%, and intrauterine fetal death have been reported at 1.6% in some studies. No strong evidence recommends early delivery before 37 weeks gestation is beneficial.

Acute fatty liver of pregnancy is a diagnosis that requires aggressive management as these patients have a risk of liver failure. Like eclampsia, prompt delivery is essential. If patients have evidence of synthetic liver dysfunction with encephalopathy, hypoglycemia, or coagulopathy, patients should be transferred to a transplant center for further care. Classification of patients into class 1, class 2 or class 3 HELLP syndrome is important for determining possible initiation of the Mississippi Protocol (See Figure 1) with IV dexamethasone, magnesium sulfate, stringent blood pressure control, and management in an appropriate intensive care or hospital labor and delivery setting. Goals of therapy are to further prevent the progression of HELLP syndrome from class 2 and class 3, minimize the development of new maternal morbidity after initial diagnoses, shorten the disease course and length of hospitalization, minimize perinatal morbidity and mortality, and prevent maternal mortality. Utilization of the triple classification system enables physicians to asses show well patients are being managed. Results from a retrospective cohort study using the Mississippi Protocol suggest it may be more beneficial than other approaches, however, a large well-constructed randomized and blinded clinical trial using assessment by HELLP classification is needed to validate these findings.

Figure 1.

Mississippi Protocol for HELLP syndrome. Indicators of treatment and regimen.

In a few severe cases of acute fatty liver of pregnancy, plasmapheresis was used with faster improvement in liver function and reduced length of ICU and hospital stay. Plasmapheresis within 6 hours after delivery has been used in a few severe cases to remove ammonia, endotoxins, bilirubin, and inflammatory cytokines from the circulation that are not well cleared due to liver dysfunction. Removal of renin angiotensin and other vasoactive factors may also improve renal function. Plasmapheresis should be considered in advanced cases of acute fatty liver of pregnancy, however, there are no randomized controlled studies that have evaluated the role of plasmapheresis on morbidity and mortality.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.


IV. What's the evidence?

Ahmed, KT, Almashhrawi, AA, Rahman, RN. “Liver diseases in pregnancy: Diseases unique to pregnancy”. World J Gastroenterol. vol. 19. Nov 21, 2013. pp. 7639-7646.

Martin, JN, Brewer, JM, Wallace, K. “Hellp syndrome and composite major maternal morbidity: importance of Mississippi classification system”. . vol. 26. 2013. pp. 1201-1206.

Geenes, V, Williamson, C. “Intrahepatic cholestasis of pregnancy”. World J Gastroenterol. vol. 15. 2009 May 7. pp. 2049-2066.

Joshi, D, James, A, Quaglia, A. “Liver disease in pregnancy”. . vol. 375. 2010. pp. 594-605.

Seyyed Majidi, MR, Vafaeimanesh, J. “Plasmapheresis in acute Fatty liver of pregnancy: an effective treatment”. Case Rep Obstet Gynecol. vol. 2013. 2013. pp. 615975