Gastroenterology Hepatology

Liver disease in pregnancy

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How can I be sure that the patient has liver disease in pregnancy?

The patient who is pregnant or recently pregnant may present with liver disease.

Depending on the disease, a constellation of symptoms can be found. Presentations include abnormal liver tests, pruritus, nausea, vomiting, jaundice, right upper quadrant pain, ascites, and gastrointestinal bleeding.

A tabular or chart listing of features and signs and symptoms

Are there pathognomonic or characteristic features?

The patient has abnormal liver tests.

It is important to recognize that there are anticipated changes in the liver tests during pregnancy, which are normal presentations during pregnancy. For example, during normal pregnancy, serum albumin decreases with expansion of the plasma volume. There is an anticipated increase in blood volume by 50%, peaking in the second trimester and, therefore, it is anticipated that serum albumin will fall with progression of pregnancy. Alkaline phosphatase normally increases two to three times the upper limits of normal as a result of placental contribution and bone mobilization.

Other diseases and conditions with signs, symptoms, or clinical features that mimic liver disease in pregnancy

Other diseases that might mimic liver diseases unique to pregnancy are liver diseases that are present in the general public. In particular, viral hepatitis A and B can present as acute hepatitis in a pregnant woman as these are diseases that are common. Hepatitis C usually does not present as acute hepatitis; however, it is a common viral hepatitis that may have preexisted prior to the pregnancy and was previously undiagnosed. Acute hepatitis E can occur in the pregnant woman who has recently been to endemic areas in Asia, Africa, and Central America.

There is a higher prevalence of hepatitis E in pregnant women and a higher likelihood of unfavorable outcome and fulminant hepatic failure.

What are the signs and symptoms?

Pruritus: Pruritus is a classic symptom for intrahepatic cholestasis of pregnancy.

Nonpregnancy-related causes of pruritus such as dry skin, scabies, and atopic dermatitis can also cause pruritus. Other pregnancy-related causes of pruritus are pruritic urticarial papules and plaques of pregnancy (PUPP) and prurigo of pregnancy, which can cause pruritus but have associated rashes.

Nausea and vomiting: Nausea and vomiting are common in pregnancy but when extreme, these can be hyperemesis gravidarum, which also can cause abnormal liver enzymes.

Nausea and vomiting in the third trimester may be a symptom of acute fatty liver of pregnancy or HELLP (hemolysis, elevated liver enzymes, and low platelet count).

Right upper quadrant and epigastric pain: Right upper quadrant and epigastric pain can be a sign of liver disease but can also be a sign of biliary disease, such as gallstones.

Ascites: Ascites can be difficult to diagnose in the setting of the gravid abdomen, but differentiation requires good history and evaluation of the size of the abdomen in relationship to its anticipated size at the specific stage of the pregnancy.

New onset of ascites can occur in women who have decompensation of their prior chronic liver disease or in women who develop Budd-Chiari (hepatic vein thrombosis). The hypercoagulable state of pregnancy can predispose to hepatic vein thrombosis. Budd-Chiari typically occurs at the end of the third trimester and even more commonly in the postpartum period. Twenty-five percent of patients have coexisting hypercoagulable states, such as factor V Leiden, antithrombin II, protein C and S deficiency, or antiphospholid antibodies. In addition to ascites, hepatomegaly and pain may be present.

Other complications of chronic liver disease in patients with preexisting cirrhosis are esophageal variceal bleeds due to the increase in portal pressures during the third trimester of pregnancy.

How can I confirm the diagnosis?

For liver diseases specific to pregnancy, the most important determinant of which type of liver disease is present is to determine the patient's stage of pregnancy (i.e., in which trimester is the patient?)

Diseases to suspect include:

  1. 1st trimester: hyperemesis gravidarum

  2. 2nd trimester: intrahepatic cholestasis of pregnancy (usually from week 25 and later)

  3. 3rd trimester: acute fatty liver of pregnancy and HELLP syndrome

Diseases that are not specific to pregnancy (i.e., diseases that can be present whether or not individual is pregnant) are preexisting liver diseases that flare during pregnancy or common liver diseases, such as viral hepatitis, which can occur at any stage of pregnancy.

Hyperemesis gravidarum

What tests should be ordered first?

  • – CBC and platelets

  • – AST (aspartate aminotransferase)

  • – ALT (alanine aminotransfer

  • – Bilirubin

  • – Alkaline phosphatase

  • – Albumin

  • – Total protein

  • – Basic panel

  • – INR (international normalized ratio), and

  • – Urinalysis. If not, the rise in AST, ALT is directly correlated with severity of nausea and vomiting.

What tests should be used to confirm the initial tests?

For hyperemesis gravidarum, other biochemical abnormalities could include hypophosphatemia and hypomagnesium due to excessive vomiting.

Liver biopsy is not indicated and should not be performed; however, if performed, it will only show nonspecific changes, such as perhaps mild steatosis.

Intrahepatic cholestasis of pregnancy

What test should be ordered first?

  • – CBC and platelets

  • – AST

  • – ALT

  • – Bilirubin

  • – Alkaline phosphatase

  • – Albumin

  • – Total protein

  • – Basic panel

  • – INR, and

  • – Urinalysis

What tests should be used to confirm the initial tests?

Fasting serum bile acids (>10 micro-mol/L).

Acute fatty liver of pregnancy

What tests should be ordered first?

  • – CBC and platelets

  • – AST

  • – ALT

  • – Bilirubin

  • – Alkaline phosphatase

  • – Albumin

  • – Total protein

  • – Basic panel

  • – INR, and

  • – Urinalysis

What tests should be used to confirm the initial tests?

Serum lactic acid and ammonia levels are present in severe disease. Increased serum uric acid may be present. Imaging tests with CT and ultrasound may show nonspecific changes in the liver, such as heterogeneity, but often there are no findings as the fat is microvesicular. Ascites, if present, may be seen by imaging studies.

Exclusion of other liver diseases such as viral hepatitis A, B, C, and E should be performed with hepatitis A IgM, hepatitis B surface antigen and hepatitis B core IgM, hepatitis B DNA levels, and hepatitis C PCR (polymerase chain reaction), as well as hepatitis E PCR (if available).

Exclusion of hepatic vein thrombosis and gallbladder disease should be performed with imaging studies, such as ultrasound with Doppler, MRI, or CT scan.

What test is useful if the diagnosis is still in doubt?

A liver biopsy is definitive to confirm the diagnosis but may not be possible due to the urgency of disease and coagulopathy.

HELLP

What tests should be ordered first?

  • – CBC and platelets

  • – AST

  • – ALT

  • – Bilirubin

  • – Alkaline phosphatase

  • – Albumin

  • – Total protein

  • – Basic panel

  • – INR, and

  • – Urinalysis

What tests should be used to confirm the initial tests?

LDH (lactate hydrogenase)

Exclusion of other liver diseases such as viral hepatitis A, B, C, and E should be performed with hepatitis A IgM, hepatitis B surface antigen and hepatitis B core IgM, hepatitis B DNA levels, and hepatitis C PCR, as well as hepatitis E PCR (if available).

A CT scan or MRI may be helpful in detecting hepatic hematomas and ruptures, which are severe complications of HELLP. These should be performed if patients have severe abdominal pain or should pain suggests these conditions or if there is abdominal distention.

What other diseases, conditions, or complications should I look for in patients with liver disease in pregnancy?

Hyperemesis gravidrum

Major risk factors

  1. Preexisting diabetes

  2. Multiple gestation

  3. Multiparity

  4. Hyperthyroidism

  5. Psychiatric illness

  6. Molar pregnancy

  7. High BMI

Commonly encountered complications

Dehydration, ketosis, and weight loss

List of complications

  1. Dehydration

  2. Renal failure

  3. Malnutrition

  4. Vitamin deficiency

  5. Instruction

Intrahepatic cholestasis of pregnancy

Major risk factors

  1. Patients with prior intrahepatic cholestasis of pregnancy on prior pregnancies

  2. Women who have developed cholestasis with oral contraceptives

  3. Women with family histories of intrahepatic cholestasis of pregnancy

  4. Disease is more common in Scandinavia and South America.

Disease that may occur with cholestasis of pregnancy

Patients may develop jaundice with progression of cholestasis usually 1 to 4 weeks after onset of pruritus.

Commonly encountered complications

Pruritus can be very debilitating and cause sleep disturbance, irritability, and other psychological consequences.

List of complications

  1. Jaundice (uncommon but if present, usually arises about 1-4 weeks after onset of pruritus)

  2. Sleep disturbances

  3. Excoriation from scratching

  4. Diarrhea and steatorrhea can be associated with severe cholestasis.

  5. Increased risk of infant prematurity, perinatal death, fetal distress, and still birth. Risk of fetal complications is correlated with serum bile acids. Risks increases when bile acid concentrations >40 micro-mol/L.

Acute fatty liver of pregnancy

Major risk factors

Women who carry the fetus with defects in fatty acid beta oxidation and long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD deficiency).

Other risk factors

  1. Twin pregnancies

  2. Nulliparity

Disease that may occur with acute fatty liver of pregnancy

There may be associated disseminated intravascular coagulation.

About 50% of patients have signs of preeclampsia.

Commonly encountered complications

Transient polyuria and polydipsa may occur due to central diabetes insipidus.

Hepatic encephalopathy can occur and is a poor prognostic sign.

List of complications

  1. Acute liver failure

  2. Maternal and fetal mortality

  3. Diabetes insipidus

  4. Hepatic encephalopathy

HELLP

Major risk factor

Presence of preeclampsia.

Other risk factors

  1. Advanced maternal age

  2. Multiparity and white ethnic background

Diseases that occur with HELLP

Hypertension and proteinuria are common.

Commonly encountered complications

  1. Hepatic infarct

  2. Hematoma

  3. Rupture

List of complications

  1. Preeclampsia

  2. Hypertension

  3. Proteinuria

  4. Hepatic infarct

  5. Hepatic hematoma and rupture

What is the right therapy for the patient with liver disease in pregnancy?

Hyperemesis gravidarum

What treatment options are effective?

Supportive care with intravenous rehydration and antiemetics. Often, hospitalization is required to achieve this.

Options, lifestyle, and other estimates of efficacy

Careful attention to nutrition should be paid. In particular, supplementation of vitamins, such as thiamine, may be required if oral intake is inadequate.

Intrahepatic cholestasis of pregnancy

Delivery of the infant, if possible. Otherwise, proceed with symptomatic treatment, ursodeoxycholic acid, and monitoring of fetus.

Ursodeoxycholic acid: 10-15 mg/kg improves pruritus and liver function tests.

  1. Symptomatic treatment of pruritus. If cholestyramine 10-12 g/day is used, be wary of vitamin K deficiency.

  2. Enhanced fetal surveillance usually with weekly nonstress tests starting at week 34 or after onset of diagnosis.

  3. Delivery of infant as soon as possible. Delivery is recommended with evidence of fetal lung maturity.

Acute fatty liver of pregnancy

  1. Prompt delivery is essential once diagnosis is certain.

  2. Delivery of the infant should be performed as soon as possible.

  3. Steroid treatment may be helpful to accelerate fetal lung maturity.

  4. Liver transplantation for fulminant hepatic failure may be needed if there is no recovery after delivery.

HELLP

Prompt delivery of the infant if possible.

Prompt delivery is warranted if at more than 34 weeks of gestations, there is evidence of fetal distress or evidence of maternal end-organ damage such as DIC (disseminated intravascular coagulation), renal failure, and abruptio placentae.

Management of hypertension and prophylaxis for seizures.

What is the most effective initial therapy?

Hyperemesis gravidarum. Supportive care, rehydration.

Intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid.

Acute fatty liver of pregnancy. Delivery.

HELLP. Delivery.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

Hyperemesis gravidarum. Supportive care, rehydration, and treatment of nausea and vomiting.

Intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid (10-15 mg/kg or 1 g/day) (Category B) and delivery as soon as possible.

Acute fatty liver of pregnancy. Prompt delivery of the infant is recommended; however, the limiting factor is the maturity of the fetus. Steroid treatment may be considered in the appropriate patient candidates to accelerate lung maturation in the fetus.

HELLP. Prompt delivery of the infant is recommended; however, this also can be limited by fetal lung immaturity, warranting steroid treatment. In addition, management usually requires hospitalization in an intensive care unit with treatment of hypertension, DIC, and seizure prophylaxis (IV magnesium sulfate). Platelet transfusions are indicated if there is signficant maternal bleeding.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Intrahepatic cholestasis of pregnancy. Hydroxyzine may improve pruritus but is ^ ^considered category C in pregnancy, so it has some risks. Cholestyramine may also improve pruritus but is also category C in pregnancy. It has the additional problems of potentially worsening the steatorrhea associated with intrahepatic cholestasis of pregnancy and also worsening vitamin K deficiency, which may be problematic during delivery.

HELLP and acute fatty liver in pregnancy. Liver transplantation may be warranted if there is no improvement or worsening of liver failure after delivery in HELLP and acute fatty liver of pregnancy.

Listing of these, including any guidelines for monitoring side effects

N/A

How should I monitor the patient with liver disease in pregnancy?

How should I monitor complications of liver diseases in pregnancy?

Intrahepatic cholestasis of pregnancy. The patient may develop steatorrhea and fat-soluble vitamin deficiency, particularly vitamin K. Perinatal outcome is affected by this disease, and monitoring of both fetal health and bile acid levels is important as the latter may be important in predicting fetal outcome.

HELLP. Maternal morbidity and mortality are high. Serious complications include DIC (21%), aburption placenta (6%), acute renal failure (7%), pulmonary edema (6%), subcapsular liver hematoma (0.9%), and retinal detachment (0.9%). If there is evidence of marked elevations of transaminases higher than the 1000 range or severe abdominal pain, an imaging study should be performed to rule out hepatic infarction and hepatic rupture. Perinatal morbidity and mortality also are very high and thus fetal monitoring, as well as assessment for rapid delivery of the fetus, are critical.

Acute fatty liver of pregnancy. Assess the patient for onset of acute fulminant hepatic failure, including worsening coagulopathy, hypoglycemia, and jaundice. There are potential for complications of gastrointestinal bleeding, acute renal failure, pancreatitis, and DIC. In addition, the development of hepatic encephalopathy portends a poor prognosis.

Monitoring recommendations

HELLP and acute fatty liver of pregnancy. These disease require continued monitoring of liver function after delivery as they can worsen even after delivery and, if conditions worsen, liver transplantation should be considered.

Acute fatty liver of pregnancy. There is a strong association in mothers with acute fatty liver of pregnancy and infants with the LCHAD (long-chain 3-hydroxyacyl-CoA dehydrogenase) defect and thus there is a recommendation for testing nfants for the most common mutation, G1528C.

There is an increased risk for recurrence of acute fatty liver of pregnancy in women who have had it previously and thus subsequent pregnancies need to be monitored by specialists in high-risk pregnancies.

What is the Evidence?

Bacq, Y, Zarka, O, Bréchot, J-F. "Liver function tests in normal pregnancy: a prospective study of 103 pregnant women and 103 matched controls". Hepatology. vol. 23. 1996. pp. 1030-4.

(A good study: examines the changes in liver function tests that occur normally during pregnancy.)

Jamjute, P, Ahmad, A, Ghosh, T, Banfield, P. "Liver function test and pregnancy". J Matern Fetal Neonatal Med. vol. 22. 2009. pp. 274-83.

(Review details approaches to the interpretation of abnormal liver function tests in pregnancy.)

Jarvis, S, Nelson-Piercy, C. "Management of nausea and vomiting in pregnancy". BMJ. vol. 342. 2011. pp. d3606.

(A review of the clinical management of nausea and vomiting in pregnancy, including hyperemesis gravidarum.)

Glantz, A, Marschall, HU, Mattsson, LA. "Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates". Hepatology. vol. 40. 2004. pp. 467-74.

(A study of 45,485 pregnancies in Swen, where intrahepatic cholestasis of pregnancy was diagnosed in 693 (1.5%) patients. It found that fetal complications did not arise until serum bile acid levels rose above 40 micromole/L, suggesting that serum bile acids may have prognostic value in intrahepatic cholestasis of pregnancy.)

Glantz, A, Marschall, HU, Lammert, F, Mattsson, LA. "Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid". Hepatology. vol. 42. 2005. pp. 1399-1405.

(A randomized double-blind placebo-controlled trial of 130 women with severe intrahepatic cholestasis of pregnancy who received either ursodeoxycholic acid (1g/day), dexamethasone, or placebo for 3 weeks. Ursodeoxycholic acid was the only treatment that improved the biochemical markers of IP and improved pruritus, as well as decreased serum bile acids.)

Kondrackiene, J, Beuers, U, Kupcinskas, L. "Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy". Gastroenterology. vol. 129. 2005. pp. 894-901.

(A randomized controlled study of 84 women with intrahepatic cholestasis, who were randomized to receive either ursodeoxycholic acid (8-10 mg/kg) or cholestyramine 8 g daily for 14 days. Ursodeoxycholic acid was more effective in reducing pruritus and decreasing LFTs than cholestyramine. In addition, babies were delivered significantly closer to term by patients on ursodeoxycholic acid.)

Baxter, JK, Weinstein, L. "HELLP syndrome: the state of the art". Obstet Gynecol Serv. vol. 59. 2004. pp. 838-45.

(A clinical review of the HELLP syndrome.)

Knight, M, Nelson-Piercy, C, Kurinczuk, JJ. "UK Obstetric Surveillance System (UKOSS). A prospective national study of acute fatty liver of pregnancy in the UK". Gut. vol. 57. 2008. pp. 951-6.

(One of the largest population-based cohort of women with acute fatty liver disease described. Fifty-seven women in the UK were diagnosed between February 2005 and August 2006 in an estimated cohort of 1,132,964 delivering women. The incidence measurements were lower and outcome better than previously described.)

Su, GL. "Pregnancy and liver disease". Curr Gastroenterol Rep. vol. 10. 2008. pp. 15-21.

(A general review of liver disease in pregnancy.)

Keller, J, Frederking, D, Layer, P. "The spectrum and treatment of gastrointestinal disorders during pregnancy". Nat Clin Pract Gastroenterol Hepatol. vol. 5. 2008. pp. 430-43.

(A general review of gastrointestinal disease in pregnancy, including liver disease.)
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