History

Fact Explanation
Nausea and vomiting Liver diseases in pregnancy are usually categorized into liver disorders that occur only in pregnancy and liver diseases that occur coincidentally in pregnancy. There are five liver disorders that are pregnancy-specific: hyperemesis gravidarum,preeclampsia/eclampsia, syndrome of hemolysis, elevated liver tests, and low platelets (HELLP), acute fatty liver of pregnancy, and intrahepatic cholestasis of pregnancy. Intractable nausea and vomiting can be seen in Hyperemesis gravidarum (HG). And also it is a common symptom of HELLP syndrome, Acute fatty liver of pregnancy (AFLP) [1].
Abdominal Pain Common presenting symptom. Most patients with HELLP syndrome present with right upper quadrant abdominal pain. Patients with AFLP also typically present with a 1 to 2 week history of nausea, vomiting, abdominal pain, and fatigue. Pregnant women with gallstones may present with right upper quadrant pain that may radiate to the flank, scapula, or shoulder .[1].
Pruritus Occurs in Intrahepatic cholestasis of pregnancy (ICP). Maternal complications are much less severe. The classic symptom is pruritus that usually begins in the second or third trimester. It usually occurs in the palms and soles and may progress to the rest of the body, and the pruritus is often worse at night. Pruritus may be severe but is usually relieved within 48 h after delivery of the fetus.[1].
Steatorrhea Also seen in Intrahepatic cholestasis of pregnancy. Steatorrhea usually occurs due to fat malabsorption.[1].
Postpartum hemorrhage Present in case of Intrahepatic cholestasis. Malabsorption may also lead to vitamin K deficiency leading to prolonged prothrombin times and postpartum hemorrhage.[1].
Weight loss Also seen in Hyperemesis gravidarum (HG). Weight loss of 5% or greater, and nutritional deficiency requiring hospital admission.[1].
Headache and visual disturbances Eclampsia involves all features of preeclampsia and includes neurologic symptoms such as headaches, visual disturbances, and seizures or coma.[1].
Cholelithiasis and cholecystitis Cholelithiasis and cholecystitis have been observed to occur with greater frequency in women with Intrahepatic cholestasis of pregnancy.[1].
Maternal and fetal morbidity and mortality AFLP can lead to significant maternal and fetal morbidity and mortality, so prompt diagnosis must be made.Maternal mortality from preeclampsia/eclampsia is rare in developed countries, but may approach 15%-20% in developed countries. Likewise, the fetal mortality rate is rare, occurring in 1%-2% of births. Maternal and neonatal morbidity may include placental abruption, preterm delivery, fetal growth restriction or maternal renal failure, pulmonary edema, or cerebrovascular accident.The reported maternal mortality from HELLP is 1%, and the perinatal mortality rate ranges from 7%-22% and may be due to premature detachment of placenta, intrauterine asphyxia, and prematurity.[1].
Disseminated intravascular coagulopathy (DIC) A late findings of HELLP include disseminated intravascular coagulopathy (DIC).DIC may be present with increased levels of fibrin degradation products and D-dimer, and thrombin-antithrombin complexes.[1].
Placental abruption, and retinal detachment Placental abruption, and retinal detachment are late findings of HELLP syndrome.[1].
Acute renal failure Acute renal failure is a Complication of HELLP syndrome. It can also resulted due to preeclampsia/eclampsia.[1].
Adult respiratory distress syndrome and pulmonary edema The complications of HELLP syndrome include acute renal failure, adult respiratory distress syndrome, pulmonary edema, stroke, liver failure, and hepatic infarction. Pulmonary edema may also resulted due to preeclampsia/eclampsia.[1].
Fatigue and anorexia Fatigue and anorexia seen in most of the liver diseases in pregnancy. It is a common presentation of Intrahepatic cholestasis of pregnancy (ICP). [1].
Reduced fertility ,miscarriage and amenorrhea Seen in Primary biliary cirrhosis (PBC).[1]. It is a chronic cholestatic disease that affects persons in their 30s to 60s. It is suggested that PBC is associated with reduced fertility, amenorrhea, repeated pregnancy loss, endometriosis, and premature ovarian failure as well as worsening liver function during the course of pregnancy.It has been proposed that Wilson disease (WD) may adversely affect fertility due to hormonal fluctuations that can result in amenorrhea. It may also lead to copper deposition in the uterus, resulting in miscarriage due to improper implantation of the embryo[1].
Risk of vertical transmission Hepatitis B infection during pregnancy may lead to vertical transmission to the fetus. Approximately 10%-20% of neonates born to hepatitis B surface antigen (HBsAg)-positive mothers and 90% of those born to both HBsAg- and hepatitis B e antigen (HBeAg)-positive mothers will become infected with HBV. HBV infection early in life usually results in chronic infection, and 25% of these infected persons will die prematurely from cirrhosis and liver cancer.Thus, prevention of vertical transmission is critical.[1].
Low birth weight and small for gestational age Infants of HG mothers were found to have lower birth weights and higher rates of being small for gestational age.[1].
Low-grade fever Pregnant women with gallstones may present with nausea, vomiting, anorexia, fatty food intolerance, and low-grade fever.[1].
Portal hypertension and liver failure Portal hypertension and liver failure may develop as a outcome of primary biliary cirrhosis in pregnancy.[1].
References
  1. LEE NM, BRADY CW. Liver disease in pregnancy World J Gastroenterol [online] 2009 Feb 28, 15(8):897-906 [viewed 29 August 2014] Available from: doi:10.3748/wjg.15.897

Examination

Fact Explanation
Jaundice Jaundice occurs frequently in patients with AFLP. Mild hyperbilirubinemia with mild jaundice can be seen in HG. Jaundice occurs in approximately 10%-25% of patients with Intrahepatic cholestasis and may appear within the first four weeks of the onset of pruritus [1].
Hypoglycemia and hepatic encephalopathy Some women with AFLP experience moderate to severe hypoglycemia, hepatic encephalopathy, and coagulopathy.[1].
Fluid and electrolyte imbalance Commonly seen in Hyperemesis gravidarum (HG). Intractable nausea and vomiting during pregnancy that often leads to fluid and electrolyte imbalance.[1]. Electrolyte disturbances such as hypokalemia and hyponatremia as well as metabolic alkalosis and erythrocytosis may present.[2].
Hypertension Identified in preeclapsia. Preeclampsia is a disorder defined by the triad of hypertension, edema, and proteinuria. In preeclampsia, hypertension is defined as having a systolic pressure greater than 140 mmHg and a diastolic pressure greater than 90 mmHg on at least two occasions that are at least 4 to 6 h apart in a previously normotensive patient.[1]. In acute fatty liver of pregnancy (AFLP) although hypertension can be present, severe hypertension is likely secondary to the reduction in peripheral vascular resistance associated with liver failure.[2].
Proteinuria Seen in preeclampsia. Proteinuria is defined as equal to or greater than 300 mg of protein in a 24 h urine collection or 1+ protein or greater on urine dipstick testing of two random urine samples collected at least 4 to 6 h apart.[1].
Hepatic hemorrhage and infarction The pathogenesis of hepatic damage in HELLP syndrome involves intravascular fibrin deposition and sinusoidal obstruction that can lead to hepatic hemorrhage and infarction.[1].
Neurologic abnormalitie Seen in wilson disease in pregnancy.Wilson disease (WD) is a multisystem autosomal recessive disorder of copper metabolism.Neurologic abnormalities occur in 40%-50% and may include an akinetic-rigid tremor similar to Parkinson’s disease, tremor, ataxia, and a dystonic syndrome.[1].
References
  1. LEE NM, BRADY CW. Liver disease in pregnancy World J Gastroenterol [online] 2009 Feb 28, 15(8):897-906 [viewed 29 August 2014] Available from: doi:10.3748/wjg.15.897
  2. . AHMED KT, ALMASHHRAWI AA, RAHMAN RN, HAMMOUD GM, IBDAH JA. Liver diseases in pregnancy: Diseases unique to pregnancy World J Gastroenterol [online] 2013 Nov 21, 19(43):7639-7646 [viewed 29 August 2014] Available from: doi:10.3748/wjg.v19.i43.7639

Differential Diagnoses

Fact Explanation
Hyperemesis gravidarum (HG) Although nausea and vomiting of pregnancy affect up to 90% of pregnancies, hyperemesis gravidarum (HG) occurs in approximately 1 out of every 200 pregnancies. Women with HG present with severe and persistent vomiting in the first trimester that can cause dehydration, metabolic disturbances, and nutritional deficiencies. HG may result in weight loss and ketonuria. Patients usually are acutely ill with signs of dehydration. Rarely, it can present with jaundice and electrolyte disturbances such as hypokalemia and hyponatremia as well as metabolic alkalosis and erythrocytosis. It seems that the severity of nausea and vomiting correlates well with the degree of liver enzymes elevation. Risk factors for HG include multiple gestations, molar pregnancies, fetal anomalies such as hydrops fetalis and trisomy 21. Not all women with HG develop liver disease. Half of the patients who require hospitalization for HG suffer from liver disease.[1].
Preeclampsia and eclampsia Preeclampsia is a syndrome that is unique to pregnancy. By far, preeclampsia is the most common serious medical disorder in pregnancy with prevalence up to 10%.[1].Preeclampsia is a disorder defined by the triad of hypertension, edema, and proteinuria.Eclampsia involves all features of preeclampsia and includes neurologic symptoms such as headaches, visual disturbances, and seizures or coma. Risk factors for preeclampsia and eclampsia include nulliparity, extremes of maternal age, insulin resistance, obesity, and infection[2].
HELLP syndrome HELLP syndrome is a multisystemic disorder of pregnancy involving hemolysis, elevated liver tests, and low platelets.Most patients present with right upper quadrant abdominal pain, nausea, vomiting, malaise, and edema with significant weight gain. Less commonly associated conditions include renal failure (with increased uric acid), diabetes insipidus, and antiphospholipid syndrome. Other late findings of HELLP include disseminated intravascular coagulopathy (DIC), pulmonary edema, placental abruption, and retinal detachment. Hypertension and proteinuria may be seen.[2].
Acute fatty liver of pregnancy (AFLP) Acute fatty liver of pregnancy (AFLP) is a rare but a serious condition that is unique to pregnancy and happens in the third trimester.Although there were few reports of AFLP starting in the second trimester, it usually presents in the third trimester between the 30th and 38th week of gestation.It is more frequent in primiparous women and can return in subsequent pregnancies. Nonspecific symptoms such as nausea, vomiting, headache, and fatigue can be the initial presentation. Right upper quadrant pain or epigastric pain can occur. Jaundice common and early jaundice may indicate severe disease.Other features such as hypoglycemia, renal failure, coagulopathy, ascites, and encephalopathy were reported frequently. AFLP can result in maternal and fetal demise.[1].
Intrahepatic cholestasis of pregnancy (ICP) ICP usually commences in the third trimester although earlier start in the second trimester has been reported. The most common symptom is pruritus. Severity of pruritus increases at night and can involve the palms and soles. Other symptoms include steatorrhea, malabsorption of fat-soluble vitamins, and weight loss. ICP seems also to increase the incidence of gallstones and cholecystitis.[1].
References
  1. AHMED KT, ALMASHHRAWI AA, RAHMAN RN, HAMMOUD GM, IBDAH JA. Liver diseases in pregnancy: Diseases unique to pregnancy World J Gastroenterol [online] 2013 Nov 21, 19(43):7639-7646 [viewed 30 August 2014] Available from: doi:10.3748/wjg.v19.i43.7639
  2. LEE NM, BRADY CW. Liver disease in pregnancy World J Gastroenterol [online] 2009 Feb 28, 15(8):897-906 [viewed 30 August 2014] Available from: doi:10.3748/wjg.15.897

Investigations - for Diagnosis

Fact Explanation
Liver function tests Liver involvement is seen in about 50%-60% of patients with HG. Most commonly seen are mild serum aminotransferases elevations, but there are reported cases of severe transaminase elevations (alanine aminotransferase (ALT) levels 400 to over 1000 U/L). Mild hyperbilirubinemia also seen. In preeclampsia/eclampsia,abnormal laboratory values include a 10- to 20-fold elevation in aminotransferases, elevations in alkaline phosphatase levels that exceed those normally observed in pregnancy, and bilirubin elevations of less than 5 mg/dL . In HELLP syndrome laboratory findings include hemolysis with increased bilirubin levels (usually less than 5 mg/dL) and lactate dehydrogenase (LDH) levels greater than 600 IU/L, moderately elevated aspartate aminotransferase (AST) and ALT levels (200 IU/L to 700 IU/L). Elevations in aminotransferase levels, which may range from being mildly elevated to approaching 1000 IU/L is also seen in acute fatty liver of pregnancy (AFLP). Elevated total bile acid levels up to 10- to 25-fold,mild aminotransferase elevations seen in ICP patients.There AST and ALT levels rarely exceed two times the upper limits of normal, but may approach 10- to 20-fold elevations in rare cases. Bilirubin levels may be elevated, but are usually less than 6 mg/dL. Serum alkaline phosphatase levels may also be elevated, but this is usually less helpful to follow given typical alkaline phosphatase elevations seen in pregnancy.[1].
Liver biopsy and histology In preeclampsia/eclampsia liver histology generally shows hepatic sinusoidal deposition of fibrin along with periportal hemorrhage, liver cell necrosis, and in severe cases, infarction. These changes are likely due to vasoconstriction of hepatic vasculature. Microvesicular fatty infiltration has also been observed in some cases of preeclampsia, suggesting a possible overlap with acute fatty liver of pregnancy. IN HELLP syndrome, liver histology may show focal hepatocyte necrosis, periportal hemorrhage, and fibrin deposits. In acute fatty liver of pregnancy (AFLP),most definitive test is liver biopsy. Histopathologic findings reveal swollen, pale hepatocytes in the central zones with microvesicular fatty infiltration that can be identified on frozen section with oil red O staining. Electron microscopy may also show megamitochondria and paracrystalline mitochondrial inclusions. Although liver biopsy may be helpful, it is often not done due to the presence of coagulopathy. In ICP, histopathologic findings on liver biopsy include nondiagnostic centrilobular cholestasis without inflammation and bile plugs in hepatocytes and canaliculi. Liver biopsy is usually not required to make the diagnosis of ICP.[1].
Full blood count Low platelets level can be seen in HELLP syndrome. Thrombocytopenia with platelets less than 100 000/mL can be identified.Many cases of acute fatty liver of pregnancy, involve neutrophilic leukocytosis, and as the disease progresses, thrombocytopenia (with or without DIC)[1].
Prothrombin time and activated partial thromboplastin time In early stages, of HELLP syndrome, prothrombin time and activated partial thromboplastin time are normal, but in later phases, DIC may be present with increased levels of fibrin degradation products and D-dimer, and thrombin-antithrombin complexes.[1].
Urinary and Serum protein Elevated urinary protein levels can be seen in preeclampsia. Proteinuria in preeclampsia may resulte, equal to or greater than 300 mg of protein in a 24 h urine collection or 1+ protein or greater on urine dipstick testing of two random urine samples collected at least 4 to 6 h apart. Hypoalbuminemia may occur in AFLP.[1].
Renal function test In AFLP, rising uric acid levels and impaired renal function may also be seen.[1].
Ultrasound and computed tomography In case of acute fatty liver of pregnancy, imaging studies, including ultrasound and computed tomography (CT), are inconsistent in detecting fatty infiltration.[1].
Cholic/chenodeoxycholic acid ratio In ICP,increase in cholic acid and a decrease in chenodeoxycholic acid leading to a marked elevation in the cholic/chenodeoxycholic acid ratio. The glycine/taurine ratio is also reduced. [1].
Erythrocyte sedimentation rate Elevated erythrocyte sedimentation rate seen in Primary biliary cirrhosis (PBC).[1].
Hepatitis B antigen levels Positive HBsAg and HBeAg is seen in some hepatitis B infected mothers.[1].
References
  1. LEE NM, BRADY CW. Liver disease in pregnancy World J Gastroenterol [online] 2009 Feb 28, 15(8):897-906 [viewed 30 August 2014] Available from: doi:10.3748/wjg.15.897

Management - General Measures

Fact Explanation
Delivery of the fetus Approximately about 10% of HG patients, symptoms continue through pregnancy and resolve only with delivery of the fetus.The only effective treatment for preeclampsia also is delivery of the fetus and placenta[1].
Supportive care, anti emetics and intravenous fluid Treatment of HG is primarily supportive. Patients should avoid triggers that aggravate nausea, and eat small, frequent, low-fat meals. Intravenous fluids, thiamine and folate supplementation, and antiemetic therapy may be administered. Promethazine is a first-line agent, but other medications such as metoclopramide, ondansetron, and steroids have also been used. Enteral feeding is effective, and in severe cases, total parenteral nutrition may be used cautiously.[1].
Antihypertensives and Magnesium sulfate Used in preeclampsia. Pharmacological agents used in preeclampsia include antihypertensives such as calcium channel blockers and low-dose aspirin. Magnesium sulfate may be administered if eclampsia develops.[1].
Ursodeoxycholic acid (UDCA) The treatment of choice for ICP is ursodeoxycholic acid (UDCA), which helps to relieve pruritus and improve liver test abnormalities. It is unclear how UDCA works, but it is felt that UDCA conjugates help target and insert key transporter proteins, such as MRP2 (ABCC2) or bile salt export pumps (ABCB11) into the canalicular membranes.Other medications, such as cholestyramine and S-adenosyl-L-methionine, have been associated with improving pruritus and normalizing biochemical profiles, but studies have found UCDA to be superior over cholestyramine and S-adenosyl-L-methionine. UCDA also used i primary biliary cirrhosis and Primary sclerosing cholangitis in pregnancy.[1].
Dexamethasone and antihistamines In Intrahepatic cholestasis of pregnancy, dexamethasone has also been used, but has shown to be much less effective in reducing bile acids and bilirubin and ineffective in relieving pruritus. Antihistamines are frequently used to alleviate pruritus.[1].
Vitamin K and other fat-soluble vitamin supplementation In ICP,vitamin K and other fat-soluble vitamin supplementation should also be administered if fat malabsorption is suspected.[1].
Proper councelling The mother should be counseled, and both the mother and her fetus should be monitored closely during pregnancy.[2].
References
  1. LEE NM, BRADY CW. Liver disease in pregnancy World J Gastroenterol [online] 2009 Feb 28, 15(8):897-906 [viewed 30 August 2014] Available from: doi:10.3748/wjg.15.897
  2. ALMASHHRAWI AA, AHMED KT, RAHMAN RN, HAMMOUD GM, IBDAH JA. Liver diseases in pregnancy: Diseases not unique to pregnancy World J Gastroenterol [online] 2013 Nov 21, 19(43):7630-7638 [viewed 30 August 2014] Available from: doi:10.3748/wjg.v19.i43.7630

Management - Specific Treatments

Fact Explanation
Laparascopic cholecystectomy or ERCP In pregnant women with gall stones,laparascopic cholecystectomy in the second trimester is preferred. Endoscopic retrograde cholangiopancreatography (ERCP) may also be required if there are concerns about choledocholithiasis, and this can be performed safely in pregnancy by shielding the fetus and minimizing fluoroscopy time.[1].
Penicillamine, trientine, and zinc Used in Wilson disease in pregnancy.Penicillamine acts by reducing chelation and enabling excretion of copper in the urine. Trientine works similarly but is less effective than penicillamine. Zinc induces intestinal cell metallothionein that binds to copper and prevents transfer of copper into the blood. Penicillamine has been reported to cause teratogenicity in animals and humans.[1].
Hepatitis B immunoglobulin (HBIG) and hepatitis B vaccine Immunization with hepatitis B immunoglobulin (HBIG) and hepatitis B vaccine at birth can reduce HBV transmission to less than 10% among infants of mothers who are positive for both HBsAg and HBeAg with even less transmission if the mother is HBeAg negative. All infants born to HBsAg-positive mothers should receive a single hepatitis B vaccine and HBIG (0.5 mL) no later than 12 h after birth, and the hepatitis B vaccination series should be completed, with the second vaccination at one or two months of age and the third vaccination at 6 months of age.[1].
References
  1. LEE NM, BRADY CW. Liver disease in pregnancy World J Gastroenterol [online] 2009 Feb 28, 15(8):897-906 [viewed 30 August 2014] Available from: doi:10.3748/wjg.15.897