Liver Diseases in Pregnancy
Christian G. Stevoff and Andres T. Blei
Table Of Contents
Christian G. Stevoff, MD
Andres T. Blei, MD
THE LIVER DURING NORMAL PREGNANCY
PREEXISTENT LIVER DISEASES IN PREGNANCY
LIVER DISEASES DEVELOPING DURING PREGNANCY
Liver diseases in pregnancy encompass a diverse range of problems. Some of these disorders are unique to the gestational state, whereas others may reflect a preexisting condition that has been unmasked or exacerbated by pregnancy. Knowledge of the spectrum of disease is important because some of these entities require specific or urgent management. Because not all changes to the liver during pregnancy are pathologic, familiarity with interpretation of liver function tests is necessary to direct a proper workup of abnormalities, especially those found incidentally on automated biochemical screening. The goals of this chapter thus encompass discussion of physiologic hepatic changes associated with the pregnant state, preexistent liver disease in pregnancy, liver diseases arising during pregnancy, and a problem-oriented approach to diagnosis and treatment. Several reviews have been published recently.1,2
|THE LIVER DURING NORMAL PREGNANCY|
There are no histologic changes in the liver during normal pregnancy.3 However, a mild cholestatic state can be shown in the later stages of pregnancy with specialized testing such as the reduced transport maximum for bromosulphthalein, bilirubin tolerance testing, or by slight elevation in serum postprandial cholyglycine.4,5 The hormonal changes that accompany pregnancy may account for the mildly cholestatic state. Estrogens change the permeability of the biliary canalicular membrane, reducing both bile salt-dependent and bile salt-independent fractions of bile flow.6,7 Effects of sex hormones likely mediate smooth muscle relaxation in the biliary tree, leading to increased gallbladder volume and decreased contractility.8 Bile lithogenicity also may be increased because of the effects of sex hormones on the relative concentrations of cholesterol, phospholipids, and bile acids with an increase in cholesterol synthesis and excretion into bile.9,10 Despite these physiologic abnormalities, symptomatic cholestasis is not a typical feature of normal pregnancy.
There is a 40% increase in blood volume in pregnancy, which is maximal in the third trimester. Cardiac output increases until the second trimester and then may decrease or plateau during the third trimester. Despite these systemic hemodynamic changes in pregnancy, absolute hepatic blood flow is unchanged. This relative decrease in hepatic blood flow is an intriguing observation in view of the generalized hyperdynamic state of pregnancy.11 This relative reduction may impair the clearance of substances requiring adequate hepatic perfusion.
Most liver “function” tests detected on automated panels do not truly evaluate a specific hepatic function. Even those that qualify as such do so partially, since other factors may influence their serum concentrations. Bilirubin levels may reflect liver uptake and metabolic transformation. Serum albumin may reflect its synthetic function but also may be related to nutrition. Serum transaminases, alkaline phosphatase (AP), and γ-glutamyl transferase (GGT) are markers of hepatic injury. Furthermore, the source for an elevated aspartate transaminase or lactate dehydrogenase may reside in other tissues, such as skeletal muscle.
A recent series comparing liver test results of 103 pregnant patients with 103 control subjects12 showed differences in liver chemistries during pregnancy. AP was significantly higher and also above the normal range in the third trimester. This represents AP of placental, not canalicular, origin. Similarly, alanine transaminase and 5%-nucleotidase were mildly elevated but still within the normal range compared with that of control subjects. Aspartate transaminase and total bile acids were not significantly different from those of control subjects. Conversely, total and indirect bilirubin were lower in all trimesters, and direct bilirubin and GGT were lower in the second and third trimesters (Table 1).
A marked increase in serum triglycerides and, to a lesser extent, cholesterol also may be seen. This effect is due in part to increased production of very low-density liproprotein in pregnancy.
Physical examination of the liver does not show major changes. The enlarging uterus often causes the liver to shift upward under the rib cage, relatively hidden from examination. The liver is impalpable during a normal pregnancy, and its detection should raise the possibility of underlying disease. Spider angiomas and palmar erythema, classic cutaneous signs of liver disease, may be features of an uncomplicated pregnancy and usually disappear after delivery.
|PREEXISTENT LIVER DISEASES IN PREGNANCY|
Cholestasis can be defined physiologically as a decrease in bile flow. The differential diagnosis of biliary stasis, schematically divided into intrahepatic and extrahepatic types, progresses from biliary structures within the liver (bile canaliculi, ductules, and ducts) to the extrahepatic tree. Both share symptoms, such as jaundice and generalized pruritus. Right upper quadrant pain is more suggestive of extrahepatic biliary obstruction. Elevations of AP, 5%-nucleotidase, or GGT are common. Bilirubin rises according to the extent of impairment of bile flow. For the differential diagnosis of cholestasis in pregnancy, ultrasonography is the test of choice. It should be remembered that dilation of the common bile duct or intrahepatic ducts may be intermittent in the presence of an intraluminal stone.
Factors that favor the genesis of cholelithiasis in pregnancy have already been discussed. A review of the literature suggests surgical management of cholecystitis should be reserved only for complicated or unremitting cases, since more than 90% of acute cholecystitis in pregnancy resolves spontaneously.13 Opposite views have been expressed.14 Laparoscopic cholecystectomy is considered a safe option, especially in the second trimester after organogenesis and before uterine enlargement, causing difficulties with laparoscopic technique.15
Pregnancy may worsen features of underlying intrahepatic cholestatic disorders, a reflection of the underlying hormonal changes discussed previously. Jaundice may worsen in primary biliary cirrhosis, but this does not necessarily reflect a worsening of the overall disease process. The Dubin-Johnson syndrome, one of the familial conjugated hyperbilirubinemia, may show exacerbation during the second or third trimester.16 In one case of Alagille's syndrome, a familiar disorder of intrahepatic cholestasis, worsening of pruritus, was noted in the third trimester.17 A common theme in all these disorders is their clinical expression in the latter part of pregnancy, when the hormonal change that affects biliary function is at its peak.
Chronic hepatitis is a clinicopathologic syndrome with several etiologies. Autoimmune hepatitis is a disease seen predominantly in women.18 Adult-acquired hepatitis B and C progress to chronic hepatitis in 5% to 10% and 75% to 85% of cases, respectively.19,20 Other etiologies include Wilson's disease, continued use of some drugs such as nitrofurantoin or α-methyldopa, and α1-antitrypsin deficiency. Secondary amenorrhea is a common feature of chronic liver disease, and thus such patients infrequently become pregnant.
The clinical course of chronic viral hepatitis usually remains stable in the pregnant state; however, changes in viral replication occur. In the case of hepatitis C, recent studies document a decrease in serum alanine transaminase and an increase in serum hepatitis C virus (HCV)-RNA during pregnancy,21 with a postpartum return to prepregnancy values. In the case of hepatitis B, changes in the immune status after delivery could account for the subsidence of viral replication.22 Treatment with interferon is contraindicated during pregnancy.
There is no consensus regarding the course of autoimmune hepatitis in pregnancy. Although some reports have described a worsening of liver disease, others have described no change or even improvement in histology and biochemistry.23 Steroid therapy may be continued safely. Azathioprine, used at the low doses required for autoimmune hepatitis, can be continued. The risk of azathioprine-induced teratogenesis is quite low at these doses, but a higher than normal fetal loss can be expected in this disease.24
Wilson's disease is a rare genetic disorder of copper accumulation and toxicity, caused by a defect in an enzyme that is part of the pathway of biliary copper excretion.25 In the absence of specific therapy, patients have a relentless, deteriorating course. Copper accumulation in specific tissues such as liver, brain, cornea, and kidney is the basis for its symptomatology. The disease may first manifest during pregnancy.26 A positive diagnosis may be difficult during this stage, since serum ceruloplasmin levels (traditionally below normal in this disease) may rise as a nonspecific effect of pregnancy on plasma proteins.27 Every effort should be made to exclude such a treatable disease, preferably with serum-free copper or hepatic copper determination.25 Patients treated with D-penicillamine or trientene (copper chelators) have carried their pregnancy to term successfully, although some evidence of prematurity with penicillamine has been reported.26,28 Although it generally is recommended that these drugs be discontinued when pregnancy is discovered in many other diseases, doing so in Wilson's disease may lead to fulminant hepatic failure and death.25,29 Therefore, patients with Wilson's disease discovered to be pregnant should continue therapy.
Although little is known about the course of α1-AT deficiency-related liver disease in pregnancy, there are several cases of healthy offspring being carried to term. Occasionally, it is the lung disease that is the limiting factor for healthy pregnancy.30,31
Another rare cause of chronic hepatitis is erythropoietic protoporphyria, a disorder that may cause photosensitive cutaneous reactions and hepatic dysfunction. There have been reports of a lessening of the severity of cutaneous reactions to light, possibly secondary to lower circulating erythrocyte protoporphyrin burden in pregnancy.32,33 Little is known of the hepatic aspects of this disease in pregnancy.
In the United States, alcoholic cirrhosis is the most common type of cirrhosis encountered in general practice. Women may have this disease develop after substantially less alcohol intake than men.34 It is uncommon to encounter patients with decompensated cirrhosis who become pregnant, since amenorrhea is a common occurrence. Alcohol itself disrupts reproductive function, as seen in experimental animals.35 Women found to have alcoholic cirrhosis should be counseled as to the dangers of fetal alcohol syndrome if they continue to consume alcohol through pregnancy.
Prenatal care is very important for the cirrhotic patient, as potential problems may be averted. The frequency and severity of complications during pregnancy are related to the severity of the cirrhosis.36 Early termination of pregnancy should be considered if severe hepatic decompensation exists.37 However, pregnancy generally is considered safe in patients with well-compensated cirrhosis.36 If portal hypertension is suspected clinically, upper endoscopy should be part of routine prenatal workup to assess for the presence of esophageal varices. The absence of varices does not preclude development later in pregnancy but makes their occurrence less likely. The role of prophylactic beta-adrenergic blockers or endoscopic band ligation has not been studied systematically, although band ligation has been used safely in bleeding pregnant patients.38 The patient should be aware that in the absence of liver transplantation, a mother with severe cirrhosis has a very poor chance of raising the child to adulthood.39 If transplantation is to be undertaken, pregnancy should be delayed until after transplant.
The medication regimen used for the complications of cirrhosis should be tailored according to the patient. Spironolactone, shown to be associated with fetal genital malformations, should be discontinued. Beta-adrenergic blockers have been associated with fetal growth restriction40 but may be worth the risks in women with large esophageal varices with red wales, findings that increase the likelihood of hemorrhage.
Variceal hemorrhage is a common complication in pregnant cirrhotic patients. Up to 24% of all pregnancies in patients with cirrhosis will be complicated by variceal bleeding, and 78% of those with known varices will bleed.41,42 Variceal bleeding occurred in 14% of pregnant women with noncirrhotic portal hypertension in India.43 The combination of increased blood volume and inferior vena cava compression makes bleeding especially likely in the second and third trimesters. Maternal mortality is much higher from variceal bleeding in the cirrhotic patient than in the noncirrhotic patient.44 In addition to hemodynamic stabilization, management of acute variceal hemorrhage in the pregnant patient includes endoscopic intervention. There have been no cases of placement of transjugular intrahepatic portasystemic shunt in the pregnant patient, a procedure done under radiographic guidance. Surgical shunting has been reported but should be reserved for refractory life-threatening bleeding after medical and endoscopic therapies have failed.45,46 Although the Valsalva maneuver during delivery may acutely increase portal pressures, cesarean delivery is not routinely recommended because of the increased risk associated with surgical procedures in the cirrhotic patient.47
Splenic artery rupture occurs in 2.6% of pregnant patients with cirrhosis, with up to 69% occurring in the third trimester.48,49 Left upper quadrant pain or syncope may precede hemorrhagic shock. Because fetal and maternal mortalities are 80% and 70%, respectively, a high index of suspicion and rapid intervention are essential.
Hepatic adenomas are observed most often in women taking oral contraceptives.50 The tumors may grow during pregnancy and rupture, endangering the life of the mother and fetus.51 The mechanism of growth is related to the effects of sex hormones. Similarly, focal nodular hyperplasia and hepatic hemangiomas may grow during pregnancy, a mechanism likely related to the increase in blood volume. In patients with known histories of these tumors, a baseline ultrasound examination early in pregnancy is prudent. Adenomas should be resected before pregnancy.
Acute hepatic vein thrombosis (Budd-Chiari syndrome) can be a life-threatening condition and has been reported in both pregnancy52 and the postpartum state.53 There are many known causes, but the hypercoagulable state of pregnancy may be a contributing factor. However, an additional underlying hypercoagulable state should always be investigated. Budd-Chiari syndrome has been reported with the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome54 and with factor V Leiden mutation.55 Right upper quadrant pain, hepatomegaly, and hepatic dysfunction are hallmarks of this disease. Urgent consultation with a hepatologist should always be obtained as soon as this life-threatening condition is diagnosed.
Hepatocellular carcinoma occurs very rarely in pregnancy.56 Typically, patients have been treated by termination of pregnancy, followed by appropriate surgical treatment, chemotherapy, or ablative therapy. There has been a report of a healthy pregnancy taken to term after resection of hepatocellular carcinoma without chemotherapy.57
A single case of pregnancy complicated by symptomatic adult polycystic liver disease has been reported.58 Multiple transcutaneous cyst aspirations were performed to alleviate pain. The mother and fetus did well, with labor induced at 35 weeks' gestation.
|LIVER DISEASES DEVELOPING DURING PREGNANCY|
Intrahepatic Cholestasis of Pregnancy
Intrahepatic cholestasis of pregnancy (ICP) predominantly affects women in the third trimester, although symptoms also may become manifest in the second trimester. In general, ICP is a rare disorder, affecting 1 in 1000 to 10,000 pregnancies worldwide.59 However, there is a much higher incidence in Scandinavia (1% to 2%) and Chile (14%); in the latter, native Araucanians (24%) are preferentially affected.59,60 This finding, along with the observation that women with ICP are more likely to have a sister or mother with a history of the disorder, suggests a genetic predisposition for the disease.61 Studies of high-prevalence populations have suggested an autosomal-dominant pattern of inheritance.62 The condition recurs in 60% to 70% of subsequent pregnancies63 and is more common in multiple gestation pregnancies. Environmental factors also seem to play a role, with a decreased incidence in Scandinavia in winter months.64
The exact cause of ICP is unknown. Increased levels of estrogen may play a role via altered bile excretion. Estrogen can alter bile excretion in normal subjects, and patients with a history of ICP show an exaggerated response.65 However, because subsequent pregnancies do not necessarily lead to repeat episodes of ICP, there are likely additional factors that play a role in the development of the disease. Some theories include defects in enzymes used for bile acid detoxification in the liver66 and estrogen-induced changes in actin microfilaments necessary for bile acid excretion by the hepatocytes.67
Clinical expression varies from pregnancy to pregnancy, but the main complaint is pruritus typically affecting palms and soles extending to legs and abdomen. There are no skin rashes. Jaundice affects 20% of patients and typically is mild.63 Abdominal pain is unusual, and most patients appear clinically well; however, nocturnal pruritus and insomnia may cause increasing distress to the expectant mother. Anorexia, nausea, and vomiting also may be reported by some patients. Pruritus should resolve within days of delivery and laboratory abnormalities within 2 to 4 weeks.63
Diagnosis is that of exclusion and cannot be made without first ruling out viral hepatitis, drug reaction, or, in severe cases, HELLP syndrome. Pruritus, a primary feature of ICP, is unlikely in these other conditions but also can suggest the possibility of exacerbation of primary biliary cirrhosis. Right upper quadrant ultrasound examination should show no evidence of biliary tract dilation. If present, further investigation is warranted to rule out other structural causes of cholestasis. A potentially complicating factor is the finding that cholelithiasis may occur more frequently in patients with ICP.68 Urinary tract infections also are more likely in cases of ICP, with treatment of urinary tract infection in some patients improving pruritus and biochemical markers.69,70
Bile acid levels are elevated, often to levels 100 times greater than normal.71 The AP levels also may be increased, but the difficulty in evaluating elevated AP levels in pregnancy has already been discussed. Although some patients show significant elevations in GGT and 5%-nucleotidase, levels usually are normal to only mildly elevated.64 Jaundice often is mild, with serum bilirubin levels rarely greater than 10 mg/dL.63 There may be mild transaminase elevations. Liver biopsy, only rarely needed for diagnosis, shows evidence of “bland” cholestasis, with canalicular bile plugs, intracellular bile pigment, and scant evidence of inflammatory reaction. Electron microscopy shows dilated canaliculi, loss of microvilli, and thickening of the pericanalicular filamentous network.73
Several agents such as antihistamines, phenobarbital, and benzodiazepines have been used to control pruritus, but none have shown success in improving the laboratory abnormalities.63 Cholestyramine, 8 to 16 g/day in divided doses, is a commonly used treatment of ICP-related pruritus and has been shown to improve symptoms.74 Care must be taken when using cholestyramine, as adsorption of other medications or fat-soluble vitamin malabsorption is common. Both ICP and cholestyramine can lead to vitamin K deficiency and coagulopathy in both mother and fetus.72 Therefore, parenteral vitamin K administration should accompany cholestyramine therapy. Cholestyramine also may worsen constipation, a common problem in pregnancy.
S-adenosyl- L -methionine (SAMe) has been proposed as a treatment of cholestasis of pregnancy. In one study, it was shown to improve not only pruritus but the biochemical abnormalities of ICP.75 SAMe prevents estrogen-related effects on bile flow and increases detoxification of bile acids by increasing the bioavailability of glutathione.80–83 However, a double-masked evaluation of a 3-week course failed to show benefits.84 Conversely, the use of ursodeoxycholic acid (UDCA) has been evaluated more thoroughly.76–79 UDCA is a hydrophilic bile acid that induces changes in the bile acid pool, substituting for more hepatotoxic hydrophobic compounds. It should be noted that although no adverse fetal effects have been reported in humans receiving UDCA therapy, animal studies have suggested possible cytotoxic and embryotoxic effects.86,87 Further investigation is necessary to determine the risk to the human fetus, since initiation of therapy often occurs after organogenesis has been completed. A recent randomly assigned double-masked evaluation of 1 g UDCA versus placebo showed effectiveness in the control of symptoms as well as improvement in fetal outcome.94 An open comparison between UDCA and SAMe showed benefits of the former.85
Dexamethasone has been shown to improve both pruritus scores and bile acid levels88; however, there has been a report of dramatic worsening of a patient's condition after beginning therapy.89 More investigation into the safety of dexamethasone is necessary before its acceptance for widespread use.
Contrary to earlier beliefs, ICP conveys higher rates of fetal distress, spontaneous preterm delivery, thick meconium, and perinatal morbidity and mortality.90–92 The exact mechanism is not known but likely relates to increased levels of maternal and fetal bile acid levels.93 Reliable predictors of fetal outcome are lacking in ICP. UDCA has been shown to improve bile acid transport across the placenta and decrease endogenous bile acid levels in colostrum, while not adversely affecting bile acid concentrations in meconium.94–97 Larger studies are necessary to determine whether the changes in bile acid concentrations translate into positive effects on fetal morbidity and mortality. Early delivery has been shown to decrease fetal morbidity and mortality and is used frequently once fetal lung maturity has been ensured. Fetal deaths were not predicted by antepartum fetal nonstress testing, suggesting a more acute cause of fetal loss.92,98,99
In general, maternal outcome is good. However, care must be given to minimize the morbidity associated with nocturnal pruritus, nausea, and vomiting in the expectant mother so that excessive malabsorption and subsequent malnutrition are avoided. In addition, the physician should be aware of possible vitamin K deficiency and coagulopathy, especially at the time of delivery.
Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome
A range of hepatic abnormalities have been reported in pre-eclampsia/eclampsia and one of its more severe forms, the syndrome of HELLP.100 It has been estimated that HELLP develops in 20% of cases of severe pre-eclampsia.101 There is a significant degree of overlap in the presentations of HELLP syndrome, hemolytic uremic syndrome, thrombotic thrombocytic purpura, and acute fatty liver of pregnancy (AFLP). Ninety percent of patients experienced fatigue or malaise preceding their seeking medical attention. Half to two thirds report epigastric or right upper quadrant pain. Half report nausea, vomiting, or headache.102–104 The degree of elevation of transaminases reported has been variable.105–107 Jaundice usually is mild, but higher values of bilirubin may be observed.105 In 30% of cases, the full manifestation of HELLP is expressed postpartum.101
In severe pre-eclampsia/eclampsia, vascular endothelial injury promotes the deposition of fibrin in the vessel lumen. Liver biopsy shows periportal fibrin deposits.108 Even in asymptomatic cases, perisinusoidal deposits of fibrinogen may be observed. Fatty infiltration occasionally may be seen in the periportal region.109 In more dramatic cases, the periportal fibrin deposits may extend and result in either subcapsular hematomas or overt hepatic rupture.110 In the latter, abdominal pain and shock quickly ensue, and emergent laparotomy with packing of the affected area is mandatory. Both maternal and fetal survival are endangered. In the case of the mother, disseminated intravascular coagulation, abruptio placentae, and acute renal failure may develop. In a group of 152 women with HELLP syndrome, the risk of obstetric complications in subsequent pregnancies was high, but recurrence of HELLP was low.111
Acute Fatty Liver of Pregnancy
Acute fatty liver of pregnancy (AFLP) is a unique disease of the pregnant state. Although it typically manifests in the third trimester, its appearance in the late second trimester has been reported. It never develops after delivery, although some patients may go undiagnosed until after childbirth. Its presentation may range from mild biochemical abnormalities to fulminant hepatic failure. It is an important diagnosis to establish in view of urgent therapeutic decisions that may be indicated.
The incidence of AFLP has been estimated to range from approximately 1 per 7000 deliveries to 1 per 16,000.112,113 AFLP is more likely to occur with twin gestations.114,115 Although once believed to not recur in subsequent pregnancies, there have been several reports of recurrence of the condition in some women.114,116,117 Women in whom AFLPs have developed should be monitored closely for recurrence in the third trimester of subsequent pregnancies.
Advances in both adult and neonatal intensive care as well as earlier recognition have allowed a great reduction in the mortality once associated with AFLP. The maternal mortality rate, greater than 90% in 1970,114 has been decreased to less than 10% with prompt intervention and delivery. Similarly, fetal mortality has been reduced significantly from approximately 50% before 1985.114,118
Presenting symptoms include nausea or vomiting, epigastric pain, anorexia, or jaundice. Jaundice typically is mild and may be absent completely with early diagnosis. Headaches are common, and altered sensorium may be noted on presentation as well. Approximately half of the patients with AFLP show clinical signs of pre-eclampsia, namely hypertension, proteinuria, and peripheral edema.114 Pruritus usually is not a feature of AFLP and may suggest another cholestatic process such as ICP.113,114
Laboratory test results show mild hyperbilirubinemia without gross evidence of hemolysis. Serum transaminases rarely are elevated above 300 IU/mL. A marked prolongation of the prothrombin time, unresponsive to vitamin K, signals hepatic insufficiency and the severity of the case. Leukocytosis and thrombocytopenia may be present. Any patient in whom thrombocytopenia develops in the third trimester should be evaluated closely for AFLP. A decrease in the serum fibrinogen and a rise in fibrin split products may signal the presence of disseminated intravascular coagulation. Hyperuricemia, rarely present, may be caused by tissue destruction and a decrease in renal function. Hyperammonemia may be detected on arterial blood specimens.
Histologically, there is little evidence for widespread necrosis, although scattered areas of necrosis may be present.119 On hematoxylin-eosin stain, the hepatic cells are enlarged and contain clear vacuoles that do not displace the nucleus and give the cytoplasm a foamy appearance. This characterized the disorder within the microvesicular fat disorders, together with such entities as Reye's syndrome, carnitine deficiency, Jamaican vomiting sickness, and certain drug toxicities.120 These pathologic abnormalities resolve rapidly after delivery.115
Radiographically, fatty infiltration of the liver is reflected by increased echogenicity on ultrasound, decreased attenuation on computed tomography (CT) when compared with the spleen, or prior studies.121,122 Increased T1-weighted signal on magnetic resonance imaging may be observed; however, all radiologic studies exhibit a low sensitivity for the recognition of this disorder, as microvesicular steatosis cannot be detected as well as the more common macrovesicular fatty change, in which imaging is very sensitive.123
Although the exact mechanism of liver injury still is unknown, great advances have been made in understanding the pathophysiology of AFLP. It has been observed that impairment of mitochondrial β-oxidation may lead to microvesicular steatosis.124 Furthermore, it has been shown that mothers giving birth to children with a deficiency of a specific mitochondrial oxidative enzyme, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD), have a higher incidence of AFLP, pre-eclampsia, and HELLP syndrome.125 This enzyme is part of the mitochondrial trifunctional protein, which comprises LCHAD, long-chain 2,3-enoyl-CoA hydratase, and long-chain 3-ketoacyl-CoA thiolase. Several mutations of this enzyme have been associated with AFLP and HELLP syndrome, the most common of which is substitution of glutamine for glutamate at residue 474 (Glu474Gln).126 It is inherited in an autosomal-recessive fashion. Heterozygous mothers with homozygous fetuses appear to be at significantly increased risk for AFLP and HELLP. It is hypothesized that excessive concentrations of a toxic fetal metabolite cross the placental barrier and cause maternal hepatic injury. Additionally, maternal mitochondrial oxidation of fatty acids is decreased during late pregnancy, likely secondary to ultrastructural changes in the mitochondria induced by elevated levels of sex hormones.124 This may further predispose the pregnant patient to this condition.
AFLP is an obstetric emergency. It does not resolve spontaneously, and delayed delivery exposes the mother and fetus to increased risk of death. Early delivery is therefore crucial in the management of AFLP. If no fetal or maternal distress exists, vaginal delivery may be attempted; however, cesarean delivery is warranted in the acute setting.127 Other treatment is mainly supportive, with the level of care being set by the degree of hepatic dysfunction. Differential diagnosis of fulminant hepatic failure in pregnancy includes herpetic hepatitis and, in endemic areas, hepatitis E infection. Fulminant hepatic failure requires intensive care monitoring before and after delivery, with special attention being paid to respiratory status, prevention of infection and gastrointestinal tract hemorrhage, and, in advanced coma, management of intracranial hypertension. In extreme cases, liver transplantation has been performed.128,129 For the surviving mother, complete recovery is expected. However, because of the associated fatty acid oxidation defect in the child, closer monitoring is warranted. Confirmation of fatty acid β oxidation defects in the child may be obtained by cultured skin fibroblasts.130 Without dietary management, mortality of children with fatty acid oxidation disorders is very high.131
In the future, the spectrum of fatty oxidation-related disorders will expand. Another fetal deficiency, hepatic carnitine palmitoyltranferase I, may be present with AFLP in the mother.132
Acute Viral Hepatitis
Viral hepatitis acquired during pregnancy is a common cause of altered liver biochemistry and jaundice in pregnancy. This section addresses the risk to the mother. Risk of hepatitis to the offspring is addressed in the section on problem-oriented approaches.
Hepatitis A virus infection leads to an acute and self-limited hepatitis. Very rarely, fulminant hepatitis may develop secondary to hepatitis A and often is related to a poor nutritional state, advanced maternal age, or coexistent hepatitis B infection.34 Chronic carrier state of hepatitis A is not known to occur. Management in pregnancy is supportive and not different from management of hepatitis A infection in the nonpregnant patient. Serum hepatitis A virus immunoglobulin M should be checked in all patients suspected of having hepatitis A infection and may persist for up to 6 months after acute infection. Travelers to endemic areas should be immunized for hepatitis A. The vaccine appears to be safe in pregnancy.134
Hepatitis B virus (HBV) infection in adults leads to chronic hepatitis in approximately 5% of those exposed.135 Pregnancy neither conveys a higher risk of chronic infection nor a worse clinical course of hepatitis.136 Conversely, pregnancy course and outcome are not adversely affected by the presence of active HBV infection, except in cases of fulminant hepatitis.137 Cessation of viral replication has been observed after delivery.22 Hepatitis B testing may yield evidence of infection through “classic” antibody patterns and should be confirmed by checking for the presence of HBV DNA in serum. Hepatitis D (delta hepatitis), an RNA virus that requires hepatitis B surface antigen (HBsAg) to replicate, may coinfect or superinfect persons with acute hepatitis B or hepatitis B carriers. This signals an unfavorable prognosis for the patient but is no worse in pregnancy than in the nongravid patient. Fulminant hepatitis occurs in fewer than 1% of patients with hepatitis B. Vaccination of patients is associated with a weak antibody response, especially in obese mothers with advanced age.138
Hepatitis C is an RNA virus that causes chronic infection in 75% to 85% of those exposed. The clinical course is not affected by pregnancy nor is the course of pregnancy affected by the presence of the virus.139 However, viral replication appears to increase with a lowering of serum aminotransferases.222 Postpartum, values return to prepregnancy levels. Unlike hepatitis B, there have been few reports of HCV causing fulminant hepatitis. When suspected, anti-HCV antibody should be measured and confirmed with serum HCV-RNA if positive. No vaccination currently is available for hepatitis C prophylaxis.
Hepatitis E virus, unlike hepatitis A, B, or C, does convey an acute risk to both mother and fetus.140 There is a high probability of patients having fulminant hepatitis develop when the virus is acquired in the third trimester, and 20% mortality rate of the mother has been described. Even in noncomplicated cases, there is a higher rate of abortion and intrauterine death reported.141 The route of spread is fecal-oral, and epidemics have occurred in India, Pakistan, southeast Asia, Africa, Mexico, and China. Sporadic cases are rare in women who have not traveled to these areas. Chronic carrier state does not exist. Confirmation of infection may be obtained by stool or serum. A vaccine currently is undergoing clinical testing.
Clinically, acute viral hepatitis may mimic other acute hepatitides, such as drug-induced hepatitis and hepatic ishemia, which may occur in the event of left ventricular failure. A careful history should be obtained. The most important differential diagnosis is that of AFLP, which, in cases of fulminant hepatic failure, ultimately may require a liver biopsy. Distinction is important because management of the two entities is entirely different. An aggressive strategy with early delivery is warranted for AFLP, and an expectant attitude should be the initial approach in acute viral hepatitis. AFLP is a disease of the third trimester not associated with conspicuous jaundice; rarely are transaminase levels above 300 IU/mL. Conversely, lack of serologic viral markers does not exclude the diagnosis of viral hepatitis. Tests for cytomegalovirus, Epstein-Barr virus, and rubella should be ordered to further clarify the diagnosis. Prompt interaction between obstetrician and hepatologist clearly is warranted.
Abnormal Transaminases in Normal Women
Despite cost-containing efforts used broadly in today's medical environment, many asymptomatic patients still consult with unsuspected abnormalities of serum transaminases. In nonpregnant subjects, this is most likely because of hepatic fatty infiltration or hepatitis C. A systematic series screening pregnant women for asymptomatic elevations of transaminases has not been reported.
Patients should be questioned about alcohol intake and use of medications. Aspartate aminotransferase (AST) and γ-glutamyl transferase (GGT) are nonspecific markers and should not be used to assess alcohol intake. Muscle source of transaminases needs to be considered as well. Physical examination should be complete to avoid misdiagnosis of pre-eclampsia. If this is noncontributory, the initial laboratory workup during pregnancy should be limited to repeat tests to confirm the abnormality. Hepatitis A, B, and C serologies should be checked, as well as antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and anti-liver-kidney-microsomal antibody if necessary to evaluate for autoimmune hepatitis. Hepatic ultrasound examination with Doppler flows can be obtained to investigate the possibility of chronic parenchymal disease or portal hypertension.
Liver diseases in pregnancy are more conspicuous in the second and third trimesters. Even if clinically stable, a complete liver panel should be repeated periodically. It is important to be aware of clinical changes suggestive of a more serious picture such as AFLP or overt pre-eclampsia, since prompt intervention is imperative in either of these conditions. Liver tests should be followed after delivery with a wide differential diagnosis if abnormalities persist.
Acute Right Upper Quadrant Pain
Sudden onset of right upper quadrant abdominal pain should alert the clinician to several important diagnoses, the most important of which is cholelithiasis. The pregnant state results in the production of lithogenic bile, and it is not uncommon for the patient, especially the multipara, to develop her first symptoms during pregnancy. A patient with choledocholithiasis or gallstone pancreatitis may exhibit more severe symptoms, and physical findings or biochemical tests may be diagnostic.
Pain associated with biliary colic typically is intermittent and builds to a crescendo. Severe unremitting pain suggests the possibility of a subcapsular hematoma or a ruptured liver, either spontaneous (as seen in HELLP) or complicating a hepatic adenoma. An abdominal CT scan is preferable to ultrasound for diagnostic purposes; however, CT may be relatively contraindicated depending on the stage of pregnancy. If blood is found on peritoneal aspiration, a ruptured splenic artery aneurysm should be considered. Emergency laparotomy may be necessary for such patients.
Parenchymal liver disease also may present as right upper quadrant or epigastric pain, generally because of stretching of the hepatic capsule. The pain is dull, and the liver edge may be tender on examination. Patients with viral hepatitis, AFLP, or pre-eclampsia may present with such symptoms.
Risk of Viral Hepatitis to the Offspring
Hepatitis A infection is transmitted via the fecal-oral route and is only rarely passed vertically. However, there have been isolated reports of perinatal transmission.142 Horizontal transmission from an acutely infected mother who is caring for her newborn is, of course, possible. Therefore, an infant born to a woman who is acutely infected with hepatitis A virus should receive immune globulin.
Hepatitis B virus carries a significant risk of vertical transmission, with most affected infants becoming chronic carriers. Transmission is not affected by route of delivery, and breastfeeding is thought to play a minimal role in transmission, since 95% of cases are acquired intrapartum.143 The likelihood of transmission is related to the timing of onset of acute hepatitis or active viral replication in the mother.
Acute hepatitis B infection in the first two trimesters carries a low risk of transmission to the fetus versus acute infection in the third trimester, which carries a 70% risk of transmission.137 In chronic hepatitis, mothers who are hepatitis B e antigen-positive (HBeAg+ ) have 80% to 90% chance of vertical transmission, with 85% of these becoming chronic carriers.144,145 The high rate of carriage may be because of tolerance induced by HBeAg, which, unlike HBsAg, can cross the placental barrier. The transmission rate in chronic hepatitis also is related to levels of HBV-DNA present in maternal serum. In mothers who are HBeAg- and HBsAg+ , the rate of transmission is 2% to 15% and only 10% to 15% of these infants become carriers.145,146 There have been cases of infected newborns showing fulminant hepatitis from mothers who are HBeAg-, and these likely are caused by a mutant strain of HBV.147
All women should have screening for hepatitis B at the first antenatal care visit.148 If positive, further workup to assess extent of liver disease should be undertaken. In addition, women testing positive for HBV should have serologies and, if appropriate, HBV-DNA levels repeated in the third trimester.
Because 95% of transmission is thought to occur at or near the time of birth, postexposure prophylaxis at birth is a reasonable strategy. Indications include acute infection in the third trimester or chronic infection with positive serology for HBeAg or HBV-DNA.148 Hepatitis B immune globulin (HBIg) should be given within 2 days of birth, preferably within 12 hours.149–151 Recombinant vaccine also should be given at birth, followed by repeat injections at 1 and 6 months after the initial dose.149,150,152 This strategy has been shown to be 85% to 95% effective in preventing neonatal transmission.149,150 If the recombinant vaccine is not given, repeat doses of HBIg at 3 and 6 months have been shown to have further protective effects than a single dose.153,154 In patients who are delivering without knowledge of hepatitis B status and in whom the results will not be known for more than 12 hours postpartum, consideration should be given to empiric coverage of the newborn with HBIg as efficacy falls rapidly after 12 hours.155 Delta superinfection rarely is transmitted vertically and is equally protected by postexposure prophylaxis as is HBV.
Unlike HBV, vertical transmission plays a small role in the transmission of HCV. A large study investigating vertical transmission of HCV has shown a 5.1% rate of HCV-RNA viremia at 1 year in newborns whose mothers were known to have HCV viremia.156 The transmission rate appears to be related to maternal viremia levels. HIV coinfection also confers higher rates of transmission and may do so via immunosuppression on the mother with subsequent increased viremic titers.157,158 Further investigation is necessary to determine whether HCV genotype plays a role in transmission rate. Breastfeeding is not contraindicated, as only very low levels of HCV-RNA are detected in breast milk.159 The administration immune globulin to newborns has not been examined in controlled clinical trials.
A series of eight mothers with hepatitis E virus infection showed that six of their newborns had evidence for clinical hepatitis E infection, two of whom died within 24 hours after delivery.160 Hepatitis E virus is likely transmitted from mother to child commonly, intrauterine, and with increased fetal and neonatal risks.161 Children born to women with known hepatitis E virus infection should be monitored closely after birth for signs of infection. Table 2 summarizes the strategies currently used in neonatal prophylaxis.
ISG, immune serum globulin; HBIg, hepatitis B immune globulin.
Jaundice During Pregnancy: A Differential Diagnosis
Viral hepatitis is the most common cause of jaundice during pregnancy in most populations. The next most frequent is cholestasis of pregnancy, but this may vary with geographic location. An approach to the differential diagnosis of jaundice during pregnancy is offered in Table 3.
HAV, hepatitis A virus; IgM, immunoglobulin M; HBV, hepatitis B virus; HCV, hepatitis C virus; AFLP, acute fatty liver of pregnancy.
Indirect hyperbilirubinemia may be seen in cases of hemolytic anemia, such as pre-eclampsia. In the absence of renal insufficiency, hemolysis rarely produces bilirubin levels greater than 5 mg/dL. Urinary dipstick test results should be negative in the case of indirect bilirubinemia, as only conjugated bilirubin is excreted into the urine.
Pregnancy and Liver Transplantation
Orthotopic liver transplant is being performed at an increasing number of medical centers, many on women of childbearing age. Conception occurring during the first 6 months posttransplant carries a higher risk of allograft rejection.162 All women of childbearing age undergoing liver transplantation should be counseled on the need for contraception several months posttransplant. Pregnant women after transplantation are at higher risk of having pre-eclampsia, hypertension, premature rupture of membranes, preterm delivery, and cesarean delivery than are normal obstetric patients.162 Women who enter pregnancy with renal insufficiency appear to be at particular risk.162 Offspring of such mothers are reported to have normal development.163 Pregnancies have been described in women using various immunosuppressive regimens and generally are thought to carry an acceptable risk if the patient is under the care of experienced transplant physicians to minimize the necessary dose of immunosuppressives.164
38. Dhiman RK, Biswas R, Chawla Y et al: Management of variceal bleeding in pregnancy with endoscopic variceal ligation and N-butyl-2-cyanoacrylate: Report of three cases. Gastrointest Endosc 51: 91, 2000
62. Holzbach RT, Sivak DA, Braun WE: Familial recurrent intrahepatic cholestasis of pregnancy: A genetic study providing evidence of transmission of a sex-linked dominant trait. Gastroenterology 85: 175, 1983
65. Reyes H, Ribalta J, Gonzalez MC et al: Sulfobromophthalein clearance tests before and after ethinyl estradiol administration in men and women with familial histories of intrahepatic cholestasis of pregnancy. Gastroenterology 81: 226, 1981
71. Heikkinen J, Maentausta O, Ylostalo P et al: Changes in serum bile acid concentrations during normal pregnancy, in patients with intrahepatic cholestasis of pregnancy, and in pregnant women with itching. Br J Obstet Gynaecol 88: 240, 1981
72. Acuna R, Gonzalez MC: Hypoprothrombinemia and bleeding associated to treatment with cholestyramine. Rev Med Chile 105: 27, 1977
74. Heikkinen J, Maentausta O, Ylostal OP et al: Serum bile acid levels in intrahepatic cholestasis of pregnancy during treatment with phenobarbital or cholestyramine. Eur J Obstet Gynecol Reprod Biol 14: 153, 1982
75. Frezza M, Centini G, Cammareri G et al: S-adenosylmethionine for the treatment of intrahepatic cholestasis of pregnancy: Results of a controlled clinical trial. Hepatogastroenterology 37: 122, 1990
80. Stramentinoli G, DiPadova C, Gualano M et al: Ethinyl estradiol-induced impairment of bile secretion in the rat: Protective effects of S-adenosyl-L-methionine and its implications in estrogen metabolism. Gastroenterology 80: 154, 1981
81. Boelsterli UA, Rakhit G, Balazs T: Modulation by S-adenosyl-L-methionine of hepatic Na+ K+ ATPase, membrane fluidity, and bile flow in the rat with ethynyl estradiol-induced cholestasis. Hepatology 3: 12, 1983
83. Vendemiale G, Altomare E, Altavilla R et al: S-adenosyl-L-methionine (SAMe) improves acetaminophen metabolism in cirrhotic patients. J Hepatol 9: S240, 1989
84. Ribalta J, Reyes H, Segovia N et al: S-adenosyl-L-methionine in the treatment of patients with intrahepatic cholestasis of pregnancy: A randomized, double-blind, placebo-controlled study with negative results. Hepatology 13: 1084, 1991
85. Floreani A, Paternoster D, Melis A et al: S-adenosyn-L-methionine (SAMe) versus ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy: Preliminary results of a controlled trial. Eur Obstet Gynecol Reproduc Biol 67: 109, 1996
96. Serrano MA, Brites D, Marin JJ et al: Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta. J Hepatol 28: 829, 1998
104. Martin Jr JN, Files JC, Blake PG et al: Postpartum plasma exchange for atypical preeclampsia-eclampsia as HELLP(hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol 164: 1500, 1991
106. Sibai BM, Taslimi MM, el-Nazer A et al: Maternal-perinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia-eclampsia. Am J Obstet Gynecol 155: 501, 1986
111. Sibai BM, Ramadan MK, Friedman SA et al: Pregnancies complicated by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): Subsequent pregnancy outcome and longterm prognosis. Am J Obstet Gynecol 172: 125, 1995
112. Castro MA, Fassett MJ, Goodwin TM et al: Reversible peripartum liver failure: A new perspective on the diagnosis, treatment, and cause of acute fatty liver of pregnancy, based on 28 consecutive cases. Am J Obstet Gynecol 181: 389, 1999
146. Okada K, Kamiyama I, Mayumi M et al: e Antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. N Engl J Med 294: 746, 1976
147. Terazawa S, Kojima M, Mayumi M et al: Hepatitis B virus mutants with pre-core region defects in two babies with fulminant hepatitis and their mothers positive for antibody to hepatitis Be antigen. Ped Res 29: 5, 1991
148. Centers for Disease Control: Hepatitis B: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: Recommendation of the Immunization Practices Advisory Committee (ACIP). MMWR 40:1, 1991
153. Beasley RP, Hwang LY, Chen CL et al: Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 2: 1099, 1983
154. Beasley RP, Hwang LY, Sun TS et al: Efficacy of hepatitis B immune globulin for prevention of perinatal transmission of the hepatitis B virus carrier state: Final report of a randomized double-blind, placebo-controlled trial. Hepatology 3: 135, 1983
156. Conte D, Fraquelli M, Minola E et al: Prevalence and clinical course of chronic hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort of 15,250 pregnant women. Hepatology 31: 751, 2000
163. Rayes N, Neuhaus R, Neuhaus P et al: Pregnancies following liver transplantation: How safe are they? A report of 19 cases under cyclosporine A and tacrolimus. Clin Transplant 12: 396, 1998