This chapter should be cited as follows:
Update due

Liver Diseases in Pregnancy

Authors

INTRODUCTION

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 liver disease in pregnancy 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 routine biochemical screening. The goals of this chapter thus encompass discussion of physiologic hepatic changes associated with the pregnant state, the effect of pregnancy on preexistent liver disease, liver diseases specific to pregnancy, and a problem-oriented approach to diagnosis and treatment.

THE LIVER DURING NORMAL PREGNANCY

Physiological changes that occur throughout pregnancy affect portal blood flow, however, normal pregnancy is not accompanied by changes in hepatic function. On physical examination spider angiomata and palmar erythema can often be appreciated. While these can also represent classic cutaneous signs of liver disease, they can be features of an uncomplicated pregnancy and usually disappear after delivery. The liver on physical examination does not change, other than a mild upward shift due to the enlarging uterus, making it more difficult to appreciate. If the liver is palpable below the rib cage in later stages of pregnancy, this should raise the possibility of underlying liver disease.

On liver ultrasonography the biliary tract is usually normal though gallbladder volume may be increased. A mildly cholestatic profile may be present in later stages of pregnancy, possibly due to hormonal changes. Effects of sex hormones likely mediate smooth muscle relaxation in the biliary tree, leading to increased gallbladder volume and decreased contractility.1 Furthermore, estrogens change the permeability of the biliary canalicular membrane, reducing both bile salt-dependent and bile salt-independent fractions of bile flow as well as diminishing hepatic transporter expression.2, 3 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.4, 5 Despite these physiologic abnormalities, symptomatic cholestasis is not a typical feature of normal pregnancy.

On hepatic Doppler ultrasound there are some changes in the hepatic venous flow pattern and portal flow velocity,6 due to hemodynamic changes during pregnancy. Throughout pregnancy there is a 40% increase in blood volume, 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.7 This relative reduction may impair the clearance of substances requiring adequate hepatic perfusion.

Regarding laboratory tests, there are also some changes related to pregnancy. It is important to remark that 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, metabolic transformation or canalicular excretion. Serum albumin may reflect its synthetic function but also may be related to nutrition. Serum aminotransferases, alkaline phosphatase (AP), and γ-glutamyl transferase (GGT) are markers of hepatic injury. However, AP is not specific to liver disease as it is also produced in other organs such as the kidney, intestine, bone, and placenta. Similarly, elevations in aminotransferases or lactate dehydrogenase (LDH) may be due to muscle injury.

A series comparing liver test results of 103 pregnant patients with 103 control subjects showed differences in liver chemistries during pregnancy.8 SpecificallyAP was significantly higher, particularly in the third trimester, however, this represents AP of placental, not canalicular, origin. Similarly, alanine aminotransferase (ALT) and 5'-nucleotidase were mildly elevated but still within the normal range and aspartate aminotransferase (AST) and total bile acids were not significantly different compared with those of control subjects. Conversely, serum albumin levels were significantly lower during all trimesters because of hemodilution. Furthermore, total and indirect bilirubin were lower in all trimesters, and direct bilirubin and GGT were lower in the second and third trimesters (Table 1). In another study 430 women were compared with 85 women with gestational hypertension (GH) and women without GH had aminotransferases below the standard reference range. Interestingly, using a lower reference range (now advocated by some),9, 10 more subtle abnormalities in liver tests could be appreciated in patients with either preeclampsia or pregnancy induced hypertension.11 Such abnormalities were clinically important as they significantly correlated with more maternal complications.11 Aminotransferases may transiently increase in the puerperium and can be affected by mode of delivery.12 Finally, in another study, coagulation tests were obtained from 186 women with uncomplicated pregnancy, and levels of prothrombin time remained unchanged compared to non-pregnant reference intervals.13 While we can appreciate also some alterations of specialized tests that reflect mild cholestasis during pregnancy, these are not performed routinely and are not typically clinically significant.14, 15

A marked increase in serum triglycerides and, to a lesser extent, cholesterol also may be seen. This effect is due in part to increased hepatic secretion of very low-density liproprotein in pregnancy.

Finally, on liver histopathology, no alterations are appreciated during normal pregnancy.16

Table 1. Hepatic chemistries in normal pregnancy

 TestComment
BilirubinNormal; urine bilirubin may be positive in the absence of jaundice
AlbuminDecreased because of hemodilution
Prothrombin timeNormal
Serum bile acidsRemain within normal limits
AminotransferasesUnchanged or lower 
Alkaline phosphataseElevated in third trimester; placental origin
Leucine aminopeptidaseElevated in third trimester; placental origin
5'-nucleotidaseNormal
 γ-Glutamyl transferaseMay not rise with hepatic injury

MANAGEMENT OF LIVER DISEASE OCCURRING DURING PREGNANCY

Abnormal aminotransferases in an otherwise healthy pregnant women

Healthy pregnant women typically do not have elevated aminotransferases and, in fact, levels may decrease in pregnancy.11 However, in normal pregnancy aminotransferases can rise in the puerperium.12 Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal aminotransferases in the general population and thus also seen in pregnancy. This is distinct from fatty liver of pregnancy which is discussed later. In patients with a history of intravenous drug use or a remote history of blood transfusion, hepatitis B or C must be considered. Patients should be questioned about alcohol intake and use of medications as they both commonly cause liver enzyme abnormalities. In the case of alcohol, the enzyme profile can be characteristic. An elevated ratio of AST:ALT >2 can suggest alcoholic hepatitis as can an elevated GGT, however, neither of these is specific. AST is present in other tissues, including red blood cells and muscle, thus such sources need to be considered as well. Physical examination should be complete and include evaluation for stigmata of liver disease such as the presence of multiple spider angiomata (a few angiomata may present in normal pregnancy), palmar erythema, Terry’s or Lindsay’s nails, muscle wasting and ascites. The presence of tattoos should prompt an evaluation for hepatitis C. If the physical exam is noncontributory, and the liver enzyme abnormalities confirmed, a basic evaluation should be undertaken in two tiers, beginning with the most common causes. Initial testing should check for hepatitis A, B, and C as well as antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), quantitative IgG, and anti-liver-kidney-microsomal antibody if necessary to evaluate for autoimmune hepatitis. Wilson’s disease should also be considered and evaluated with serum ceruloplasmin, free copper level and a 24 hour urine copper. A hepatic ultrasound examination with Doppler flow should be performed to identify evidence of portal hypertension, mass lesion or vascular obstruction such as portal vein or hepatic vein (Budd-Chiari) thrombosis. If abnormalities persist and the cause is not forthcoming on this evaluation, then referral to a hepatologist should be considered.

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 in a patient with abnormal serum liver chemistries. It is important to be aware of clinical changes suggestive of a more serious picture such as acute fatty liver of pregnancy (AFLP), overt preeclampsia or the hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, 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 common 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. Cholelithiasis can result in cholecystitis, choledocholithiasis or acute pancreatitis. However, only the latter two should increase liver enzymes or result in jaundice. Pain associated with biliary colic typically is intermittent and builds to a crescendo. Choledocholithiasis can be complicated by severe cholangitis with sepsis or acute pancreatitis. An abdominal MRI with magnetic resonance cholangiopancreatography (MRCP) may be a good adjunct to ultrasound for more detailed evaluation of the bile and pancreatic ducts, though gadolinium is generally avoided in pregnancy. Severe unremitting pain should raise the possibility of a subcapsular hematoma or a ruptured liver, either spontaneous (as seen in HELLP) or complicating a hepatic adenoma. If blood is found on peritoneal aspiration or there is any evidence of shock, a ruptured splenic artery aneurysm should also be considered, since this occurs with increased frequency in pregnancy and requires emergency laparotomy.

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, Budd-Chiari syndrome, AFLP, or preeclampsia may present with such symptoms.


Jaundice during pregnancy: a differential diagnosis

Viral hepatitis is the most common cause of jaundice during pregnancy in most populations. The next most frequent cause is intrahepatic cholestasis of pregnancy (ICP), but this may vary with geographic location. An approach to the differential diagnosis of jaundice during pregnancy is offered in Table 2.

Table 2. Jaundice in pregnancy differential diagnosis

DiseaseAssociated symptomsLaboratory abnormalities

Outcome

Viral hepatitisMalaise, abdominal painAminotransferases + + + + 

A

HAV IgM

Generally good

B

HBV serologies

Transmission likely without prophylaxis

C

HCV Ab, HCV RNA

Low vertical transmission

D

HDV RNA

Low vertical transmission

E

HEV Ab, serum RT-PCR, stool sample less reliable

High fetal wastage, high maternal mortality

Cholecystitis

Epigastric pain, fever, nausea

Ultrasound

Surgery if needed ideally in 2nd trimester

Choledocholithiasis/cholangitis

Epigastric pain, nausea +/− fever

Ultrasound, magnetic resonance cholangiopancreatography

Endoscopic ultrasound, endoscopic retrograde cholangiopancreatography if needed – radiation exposure

Pancreatitis

Epigastric pain

Ultrasound

Endoscopic ultrasound, endoscopic retrograde cholangiopancreatography

Acute fatty liver of pregnancyHeadache, nausea/vomiting, abdominal pain
Variable bilirubin, variable transaminases, increased uric acid, decreased plateletsFetal/maternal death possible without early delivery

Intrahepatic cholestasis of pregnancy

Pruritus in 3rd trimester, steatorrhea, nausea, vomiting

AP increased, increased serum bile acids

Increased fetal wastage, maternal morbidity low

PreeclampsiaEpigastric pain, malaise, fatigue, nausea, vomitingMild jaundice, variable transaminases, decreased plateletsPoor if hepatic rupture

HAV, hepatitis A virus; IgM, immunoglobulin M; HBV, hepatitis B virus; HCV, hepatitis C virus; AFLP, acute fatty liver of pregnancy; RT-PCR, reverse transcriptase polymerase chain reaction; AP, alkaline phosphatase.


Indirect hyperbilirubinemia may be seen in cases of hemolytic anemia, such as preeclampsia. 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.
 


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.

HEPATITIS A

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.17 A chronic carrier state of hepatitis A is not known to occur, however, a relapsing form of hepatitis A does occur. Management in pregnancy is supportive and not different from management of hepatitis A infection in the nonpregnant patient. However, Hepatitis A virus infection during the second and third trimester may be associated with gestational complications such as premature contractions, placental separation, premature rupture of membranes, fetal distress, vaginal bleeding, and preterm labor.18, 19Serum 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.20

HEPATITIS B  

 

Hepatitis B virus (HBV) infection acquired in adulthood leads to chronic hepatitis in approximately 5% of those exposed.21 Pregnancy neither confers a higher risk of chronic infection nor a worse clinical course of hepatitis.22 Conversely, pregnancy course and outcome are not adversely affected by the presence of active HBV infection, except in cases of fulminant hepatitis.23 Cessation of viral replication has been observed after delivery.24 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. Management of acute hepatitis B during pregnancy is mainly supportive, except in the case of fulminant hepatitis, which occurs in fewer than 1% of patients, where lamivudine might be a reasonable option since some case reports have shown its safety and efficacy.25, 26, 27 Vaccination of patients is associated with a weak antibody response, especially in obese mothers with advanced age.28Hepatitis 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.

 

HEPATITIS C

 

Hepatitis C (HCV) is an RNA virus that causes chronic infection in 75–85% of those exposed. The clinical course is not affected by pregnancy nor is the course of pregnancy affected by the presence of the virus.29 However, viral replication appears to increase with a lowering of serum aminotransferases.30, 31 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. Current regimens for the treatment of HCV include ribavirin, which is teratogenic and hence contraindicated during pregnancy. No vaccination currently is available for hepatitis C prophylaxis.

 

HEPATITIS E

 

Hepatitis E virus, unlike hepatitis A, B, or C, does convey an acute risk to both mother and fetus.32 Patients who acquire hepatitis E in the third trimester are at higher risk of acute liver failure and consequently have 20% mortality. Even in uncomplicated cases, there is a higher rate of abortion and intrauterine death reported.33 Furthermore, levels of HEV viral load are higher in the pregnant woman, and also related to the severity of the disease.34The 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. As in the case of hepatitis A, a chronic carrier state does not exist. Confirmation of infection may be obtained by stool or serum. Management of infection remains supportive. A hepatitis E vaccine was recently tested in an endemic area and found to be 95% effective, however, safety and efficacy in pregnancy has not been reported.35, 36

 

Risk of viral hepatitis in the newborn

HEPATITIS A

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.37Horizontal transmission from an acutely infected mother who is caring for her newborn is possible. Therefore, an infant born to a woman who is acutely infected with hepatitis A virus and who presents symptoms in the period from 2 weeks before to 1 week after delivery, may benefit immune globulin.38, 39

HEPATITIS B

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.40 However, recent studies have shown that breastfeeding after standard immunoprophylaxis does not contribute to HBV transmission at all.41 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.23 In chronic hepatitis, mothers who are hepatitis B e antigen-positive (HBeAg+) have 80–90% chance of vertical transmission, with 85% of these becoming chronic carriers.42, 43 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.44, 45In mothers who are HBeAg− and HBsAg+, the rate of transmission is 2–15% and only 10–15% of these infants become carriers.43, 46 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.47

All women should have screening for hepatitis B at the first antenatal care visit.48 If positive, further workup to assess the 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.48 Hepatitis B immune globulin (HBIg) should be given within 2 days of birth, preferably within 12 hours.49, 50, 51 Recombinant vaccine also should be given at birth, followed by repeat injections at 1 and 6 months after the initial dose, or an accelerated vaccine regimen.49, 50, 52 This strategy has been shown to be 85–95% effective in preventing neonatal transmission.49, 50 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.53, 54 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.55Some recent studies have reported that injection of multiple doses of HBIg in carrier mothers with a high degree of infectiousness in late pregnancy, plus standard immunoprophylaxis in the newborn, effectively and safely prevent intrauterine transmission.56, 57, 58Furthermore, several studies have shown that addition of lamivudine in the highly viremic mother during late pregnancy, plus standard immunoprophylaxis in the newborn, significantly reduced mother-to-child transmission.59, 60, 61, 62Moreover, two recent Chinese studies reported that the use of telbivudine during later pregnancy can safely reduce perinatal HBV transmission.63, 64


Delta superinfection rarely is transmitted vertically and is equally protected by postexposure prophylaxis as is HBV.

HEPATITIS C

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.65High maternal viremia levels, maternal peripheral blood mononuclear infection by HCV, membrane rupture of longer than 6 hours and procedures exposing the infant to maternal blood infected are associated with an increased risk of perinatal transmission.66, 67 HIV coinfection also confers higher rates of transmission and may do so via immunosuppression of the mother with subsequent increased viremic titers.68, 69, 70 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.71 The administration immune globulin to newborns has not been examined in controlled clinical trials. 

HEPATITIS E

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.72 Another series of 19 HEV infected pregnant women showed that 15 babies had evidence of vertically transmitted HEV infection at birth, and mortality in the first week was nearly 50%.73Current evidence suggests that, intrauterine transmission of hepatitis E virus from mother to child is accompanied by increased fetal and neonatal risks.33 Children born to women with known hepatitis E virus infection should be monitored closely after birth for signs of infection.71 There is at present no proof of the efficacy of immune globulin prophylaxis for the prevention of HEV.74

Table 3 summarizes the strategies currently used in neonatal prophylaxis.

Table 3. Neonatal prophylaxis

Disease

Prophylaxis

Hepatitis A

0.02 mL/kg immune globulin IM at birth

Hepatitis B

Hepatitis B recombinant vaccine (HBIg) (Recombivax 5 μg IM or Energix-B 10 μg IM) at birth and at 1 and 6 months

Hepatitis C

No proven therapy

Hepatitis E

Undergoing clinical trials

THE IMPACT OF PREGNANCY ON PREEXISTENT LIVER DISEASE

Cholestatic disorders

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 in such cases. Bilirubin rises in accordance with the extent of impairment of bile flow. Ultrasonography is the test of choice for the initial evaluation of cholestasis in pregnancy, being mindful that common bile duct or intrahepatic ductal dilatation may be intermittent in the presence of an intraluminal stone.

In the second and third trimester, cholesterol secretion into bile increases relative to bile acids and phospholipid, promoting the formation of supersaturated lithogenic bile. The prevalence of gallstones increases 5–12% in pregnancy, though only 0.1–0.3% patients become symptomatic. A review of the literature suggests that surgical management of cholecystitis should be reserved only for complicated or unremitting cases, since 73–90% of cases of acute cholecystitis in pregnancy resolve with medical management.75, 76Surgical intervention is necessary at times, however, indications for surgery in the pregnant woman are not yet clearly established. Recent studies have suggested earlier surgical intervention may be associated with less complications compared to conservative management.75, 77, 78 While studies have shown the safety of laparoscopic cholecystectomy in all trimesters, avoiding surgery in the first trimester lessens the risk to the fetus. Optimally surgery is recommended during the second (preferably) or third trimester, noting that as the gravid uterus expands, surgery may become more technically challenging.79, 80, 75, 77, 78 For patients with symptomatic choledocholithiasis, endoscopic retrograde cholangiopancreatography (ERCP) appears to be reasonably safe if the radiation dose is kept to a minimum.75, 81, 82

Pregnancy may worsen or unmask underlying intrahepatic cholestatic disorders, a reflection of the hormonal changes discussed previously. Women with primary biliary cirrhosis (PBC) do not have impaired fertility.83, 84 Overall, pregnancy is well tolerated in patients with PBC and does not adversely affect disease course or pregnancy outcome.85Rarely, jaundice may worsen in pregnant PBC patients, but this does not necessarily reflect a worsening of the overall disease process. Ursodeoxycholic acid (UDCA) therapy during the last trimester of pregnancy appears to be safe and may be beneficial in mothers with cholestasis.86, 87, 88 The Dubin-Johnson syndrome, one of the familial conjugated hyperbilirubinemia disorders, may worsen during the second or third trimester.89 In one case of Alagille's syndrome, a familiar disorder of intrahepatic cholestasis, worsening of pruritus was noted in the third trimester.90 A common theme in all these disorders is their clinical expression in the latter part of pregnancy, when the hormonal change that affects biliary transport and function is at its peak.


Chronic hepatitis

Chronic hepatitis has various etiologies ranging from viral to autoimmune to metabolic. Adult-acquired hepatitis B and C progress to chronic hepatitis in 5–10% and 75–85% of cases, respectively.91, 92 The most common cause of abnormal liver chemistries is non-alcoholic fatty liver disease (NAFLD), attributed largely to the mounting epidemic of obesity. Its aggressive subtype, non-alcoholic steatohepatitis (NASH) is a common indication for liver transplantation. Other etiologies include Wilson's disease, continued use of some drugs such as amiodarone, nitrofurantoin or α-methyldopa, and α1-antitrypsin deficiency. Secondary amenorrhea is a common feature of advanced 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,93, 30, 31 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.24 The risk of vertical transmission and treatment during pregnancy has been discussed previously.

Despite the fact that NAFLD is the most common cause of abnormal liver chemistries, it is rarely appreciated in pregnancy. However, it is known that 29% of women of reproductive age (20–39 years) in USA are obese.94 A recent study reported a cohort of women found to have rising liver chemistry tests during or shortly after pregnancy, attributed to NAFLD.95 In those patients, other causes of abnormal liver tests were excluded, and all patients had either fatty liver on ultrasound or steatosis in liver biopsy. The author proposed that the association between NAFLD and pregnancy may be due to in part to pregnancy-related insulin resistance.95 Further studies are needed to determine the incidence of NAFLD and its association with pregnancy.

Autoimmune hepatitis is a disease that is 3.6 times more prevalent in women than in men.96 It has a bimodal age distribution that frequently affects women of childbearing age. 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.97 The presence of specific maternal antibodies such as antibodies to SLA and Ro/SSA seems to be associated with a more complicated course.98, 99  Pregnancy in women with autoimmune hepatitis has been associated with preterm delivery and an increased risk of fetal loss.98100, 101Also, hepatitis flares are reported in the postpartum period.102 Steroid therapy may be continued safely. Azathioprine, used at the low doses required for autoimmune hepatitis, has a quite low risk of teratogenesis, therefore may be continued.103

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.104 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. Ideally, the disease should be well controlled before pregnancy, however, the disease may first manifest during pregnancy.105 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.106 Every effort should be made to exclude such a treatable disease, preferably with serum-free copper, ceruloplasmin and 24 hour urine copper.104 Patients treated with D-penicillamine, trientene (copper chelators) or zinc salts have carried their pregnancy to term successfully, although some evidence of prematurity with penicillamine has been reported.105, 107 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.104, 108, 109 Therefore, patients with Wilson's disease discovered to be pregnant should continue therapy.

Although little is known about the course of α1-antitrypsin (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.110, 111

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 the lower circulating erythrocyte protoporphyrin burden in pregnancy.112, 113 Little is known of the hepatic aspects of this disease in pregnancy.

 

Cirrhosis/portal hypertension

In the United States, alcohol abuse, hepatitis C, and NASH are the most common etiologies of cirrhosis. With respect to alcohol, women develop alcohol related liver disease at a younger age and at a substantially lower cumulative alcohol dose than men.17 Alcohol itself disrupts reproductive function, as seen in experimental animals, though women who abuse alcohol become pregnant and need to be warned of the risk of fetal alcohol syndrome.114 Since amenorrhea is common in women with advanced liver disease secondary to hypothalamic pituitary dysfunction and the spontaneous abortion rate is higher than that of the general population (reaching 30–40%), it is a minority of such women who become pregnant.115 That being said, a fair number of cirrhotic women are able to become pregnant and good prenatal care is paramount to a successful pregnancy. In pregnant patients with cirrhosis, the risk of prematurity is increased up to 25%.116The frequency and severity of complications during pregnancy are related to the severity of liver function.117 In patients with cirrhosis and significant portal hypertension, 50% will develop maternal/fetal complications.118 Early termination of pregnancy should be considered if severe hepatic decompensation exists.119 However, in those with well-compensated cirrhosis, pregnancy generally is considered to be safe.117

If portal hypertension is suspected clinically, upper endoscopy should be part of the routine prenatal workup to document the presence of esophageal varices. The absence of varices does not preclude development later in pregnancy but makes their occurrence less likely. If no varices are seen early on, patients should be rescreened in the second trimester when increased pressure on the vena cava may exacerbate portal hypertension. Beta-blockers, commonly used to prevent variceal bleeding in nonpregnant patients, have been associated with fetal growth retardation, thus patients with high risk varices can undergo variceal obliteration through band ligation to avert future bleeding.

Variceal hemorrhage is a common complication in pregnant cirrhotic patients. From 20% to 24% of all pregnancies in patients with cirrhosis will be complicated by variceal bleeding,120, 121, 122 with a mortality rate of 18–50%.123, 124The combination of increased blood volume and inferior vena cava compression makes bleeding more likely in the second and third trimesters. Maternal mortality is much higher from variceal bleeding in the cirrhotic patient than in the noncirrhotic patient.125 In addition to hemodynamic stabilization, management of acute variceal hemorrhage in a pregnant woman includes endoscopic intervention. The safety of octreotide, a common adjunct to endoscopic therapy, in pregnancy is not known. No large series have addressed the safety and efficacy of band ligation in pregnancy, though case reports do support the use of band ligation and even transjugular intrahepatic portosystemic shunt (TIPS) in cases of severe or recurrent bleeding during pregnancy.126, 127, 128, 129 Surgical shunting has been reported but should be reserved for refractory life-threatening bleeding after medical, endoscopic, and radiologic therapies have failed.130, 131 In a high volume, experienced centers using coated TIPS, surgical shunting is rarely needed. 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.132 Ideally delivery is vaginal with an assisted short second stage, however, if very large high risk varices are present, a cesarean section can be considered to avoid acute worsening of portal pressures that could occur during vaginal delivery.

The medical regimen used for the complications of cirrhosis should be tailored to each patient individually. However, medications known to have teratogenic potential such as spironolactone, shown to be associated with fetal genital malformations, should be discontinued. Nonselective beta-adrenergic blockers are commonly used as primary prophylaxis for variceal bleeding, however, their use is not generally recommended in pregnancy as they have been associated with fetal growth retardation.133 They may be considered in cases of large or high risk appearing esophageal varices with red wales, findings that increase the likelihood of hemorrhage. An alternative approach to beta-blockers is esophageal band ligation, as previously discussed.

Up to 24% of pregnant patients with cirrhosis will experience hepatic decompensation.122134 A rare but life threatening complication is splenic artery aneurysm rupture which occurs in 2.6% of pregnant patients with cirrhosis, predominantly in the third trimester.135, 136 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. During the postpartum period, 7–10% of the patients may suffer from uterine hemorrhage, for which management is similar to that in patients without cirrhosis.116


Pregnancy and liver transplantation

The patient should be aware that in the absence of liver transplantation, a mother with advanced cirrhosis has a very poor chance of raising the child to adulthood.137 Orthotopic liver transplant is being performed at an increasing number of medical centers, many on women of childbearing age. If transplantation is to be undertaken, pregnancy should ideally be delayed until after transplant. Conception occurring during the first 6–12 months posttransplant carries a higher risk of allograft rejection and opportunistic infection.138 All women of childbearing age undergoing liver transplantation should be counseled on the need for contraception. During the first year after transplant, there is increased risk of prematurity, intrauterine growth retardation, and low birth weight.139 Most recommend that pregnancy should be postponed for at least 1 year after transplant when infection is less of a risk and immunosuppression is optimized.140, 141 Immunosuppression with prednisone, cyclosporine and tacrolimus are the best studied in pregnancy and are associated with an acceptable risk profile. Mycophenolate mofetil (Cellcept) is to be avoided given the risks of fetal malformation that have been reported.142, 143 Although pregnancy after transplant is considered safe, patients need to be followed closely by both a high risk obstetrician and a transplant hepatologist.

Pregnant women after transplantation are at higher risk of having preeclampsia, hypertension, premature rupture of membranes, preterm delivery, fetal mortality, and cesarean delivery than are normal obstetric patients.138 Offspring of such mothers have higher rates of fetal distress and growth restriction, but not congenital anomalies.144Women who enter pregnancy with renal insufficiency appear to be at particular risk.138 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.145

 
Miscellaneous conditions

Hepatic adenomas are observed most often in women taking oral contraceptives.146 The tumors may grow during pregnancy with a risk of rupture of 59% in lesions larger than 6.5 cm, endangering the life of the mother and fetus with a mortality rate of 44% and 38%, respectively.147 The mechanism of growth is related to the effects of sex hormones.148 Similarly, focal nodular hyperplasia and hepatic hemangiomas may grow during pregnancy, a mechanism likely related to the increase in blood volume. In patients with a known history of these tumors, a baseline ultrasound examination early in pregnancy is prudent. It is advisable that adenomas be resected before pregnancy, particularly if they are large, have complicated previous pregnancies or are near the hepatic capsule.149 Pregnancy is considered a risk factor for severe cystic liver disease.150Despite the latter, only two cases of pregnancy complicated by symptomatic adult polycystic liver disease have been reported.151, 152 Multiple transcutaneous cyst aspirations were performed to alleviate pain. Both mothers and fetuses did well, one with labor induced at 35 weeks' and the other at 39 weeks' gestation.

Acute hepatic vein thrombosis (Budd-Chiari syndrome) can be a life-threatening condition and has been reported both during pregnancy and postpartum.153, 154 There are many known causes, but the hypercoagulable state of pregnancy may be a contributing factor. The majority of patients with Budd-Chiari have an underlying hypercoagulable site, thus the evaluation of Budd-Chiari in pregnancy should include a thorough hypercoagulable workup that includes looking for the JAK2 mutation. Budd-Chiari syndrome has been reported with the HELLP syndrome.155 Right upper quadrant pain, hepatomegaly, and ascites are hallmarks of this disease caused by the acute reduction of hepatic outflow. Urgent consultation with a hepatologist is important to assess the degree of hepatic impairment and the role of urgent TIPS. Doppler ultrasonography is the test of choice for the initial evaluation, and once the diagnosis is confirmed, anticoagulation is the first step of treatment.156 In patients with known and treated Budd-Chiari syndrome with well controlled disease, pregnancy is not  contraindicated, since maternal and fetal outcome are good beyond week 20. However, higher rates of fetal loss before week 20 and preterm delivery have been reported in such patients.157, 158

Hepatocellular carcinoma occurs very rarely in pregnancy.159Until now, only 47 cases have been reported worldwide.160 The morbidity and mortality of hepatocellular carcinoma during pregnancy has improved over time since diagnoses have tended to be made earlier and patients have tended to receive surgical and other treatments.160 Abdominal ultrasonography is a good initial diagnostic method if hepatocellular carcinoma is suspected. On the rare occasion in which a hepatocellular carcinoma is diagnosed during pregnancy, management is individualized and varies depending on gestational age and patient preference. There are reports both of termination of pregnancy, followed by appropriate surgical treatment, chemotherapy, or ablative therapy as well as surgical resection without chemotherapy during pregnancy with no untoward effects on pregnancy duration or outcome.161

LIVER DISEASE SPECIFIC TO PREGNANCY

Hyperemesis gravidarum

Hyperemesis gravidarum is a condition of severe nausea and vomiting associated with early pregnancy. It is characterized by persistent vomiting, weight loss of more than 5%, ketonuria, electrolyte abnormalities, and dehydration.162 It complicates 0.3–2% of pregnancies.163 Known risk factors for the development of hyperemesis gravidarum include twin or molar pregnancy, diabetes, hyperthyroidism, and psychiatric disease.164 Approximately 20% of cases will be associated with elevated aminotransferases. Although most commonly such elevations are mild, jaundice can be a feature (bilirubin <4 mg/dL) and ALT and AST can increase to levels upwards of 20 times the upper limit of normal.165, 166 In the latter situation, it would be appropriate to consider other conditions in the differential diagnosis including biliary tract disease, viral hepatitis and pregnancy-related diseases. Liver enzymes should return to normal when hyperemesis gravidarum is successfully treated.165 Rare maternal complications are peripheral neuropathies due to vitamin B6 and B12 deficiency and Wernicke´s encephalopathy due to vitamin B1 deficiency.162 Treatment of hyperemesis gravidarum is supportive with correction of dehydration and electrolyte disturbance, antiemetic therapy and prevention and treatment of complications.167


Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) predominantly affects women in the third trimester, although symptoms also may become manifest as early as the first trimester. It is characterized by cholestasis (pruritus and elevated serum bile acids) late in pregnancy. In general, ICP is a rare disorder, affecting 1 in 1000–10,000 pregnancies worldwide.168 However, there is a much higher incidence in Scandinavia (1–2%) and Chile (14%); in the latter, native Araucanians (24%) are preferentially affected.168, 169 The condition recurs in 60–70% of subsequent pregnancies170 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.171

The etiology of ICP is not well defined though current evidence illustrates several factors, including subclinical bile transporter defects, likely contribute to its pathogenesis. Its occurrence late in pregnancy and correlation with rising hormone levels in addition to a higher prevalence in twin gestations suggest that sex hormones may be an important influential factor. Estrogen and progesterone have known effects on bile transport such as inhibition of the bile salt export pump.172, 173Estrogen can alter biliary excretion in normal subjects, and patients with a history of ICP show an exaggerated response.174 However, ICP only recurs in up to 70% of subsequent pregnancies suggesting that there are likely additional factors that play a role in the development of the disease. Studies of high-prevalence populations have suggested an autosomal-dominant pattern of inheritance.175 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.176 MDR3, a phospholipid transporter on the biliary canalicular membrane, has been associated with ICP and several mutations in this gene (ABCB4) have been uncovered in patients with ICP and such cases may account for up to 15% of cases of ICP.177, 178, 179 Furthermore, genes encoding other canalicular transport proteins or their regulator may also play a role in the pathogenesis of ICP.180, 181 In addition, seasonal variation and dietary factors such as selenium deficiency have been reported.182

The diagnosis of ICP is one 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 and can suggest the possibility of exacerbation of a preexisting biliary process such as primary biliary cirrhosis. Right upper quadrant ultrasound examination should be performed to exclude evidence of biliary tract dilation. Patients with ICP appear to be at increased risk for the development of cholelithiasis.183 If present, further investigation and potentially treatment is warranted. 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.184, 185

Clinical expression varies from pregnancy to pregnancy, but the main complaint is pruritus that often begins in the palms and soles extending to the legs and abdomen. Jaundice occurs in approximately 20% of patients and typically is mild.170 In concert with this, bilirubin elevation typically does not exceed 10 mg/dL.170 Aminotransferases can be mildly elevated or dramatically elevated with levels up to 20-fold the upper limit of normal. The AP levels also may be increased, but the difficulty in evaluating mildly 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.171 Elevation in serum bile acids (>10 μmol/L) is the most sensitive and specific marker for ICP, and levels can exceed 100 times the upper limit of normal.186Abdominal pain is unusual, and most patients appear clinically well; however, nocturnal pruritus and insomnia may cause increasing distress to the expectant mother. Anorexia, nausea, vomiting, and diarrhea also may be reported by some patients. Pruritus should resolve within days of delivery and laboratory abnormalities within 2–4 weeks.170

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.187

Antihistamines have been used to control pruritus, but they are typically only minimally effective and have not been shown to improve the laboratory abnormalities. Cholestyramine, 8–16 g/day in divided doses, is a treatment option for the ICP-related pruritus and has been shown to improve symptoms.188 However, recent studies have shown that cholestyramine does not significantly decrease aminotransferases, gamma-glutamyl transpeptidase or bile acid levels, and that UDCA is more effective in pruritus relief.189, 190 Care must be taken when using cholestyramine, as malabsorption of other medications or fat-soluble vitamins is common. Both ICP (via cholestasis) itself and cholestyramine (binding) can lead to vitamin K malabsorption, deficiency and subsequent coagulopathy in both the mother and the fetus.191 Therefore, vitamin K administration along with cholestyramine therapy seems a reasonable option; though, there are no studies performed to support this practice.189 Cholestyramine also may worsen constipation, a common problem in pregnancy. However, because of the lack of proven efficacy of cholestyramine in this setting as well as common side-effects, its use in ICP remains somewhat controversial.

UDCA is the treatment of choice for ICP. UDCA is a hydrophilic bile acid that induces changes in the bile acid pool, making it more hydrophillic and hence less hepatotoxic. It is generally considered safe in typical doses of 12–15 mg/kg and has shown efficacy in controlling symptoms and reducing bile acid levels in women with ICP.192, 193, 194, 195 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.196, 197 Further investigation is necessary to determine the risk to the human fetus, since initiation of therapy often occurs after organogenesis has been completed. Randomized controlled trials have shown UDCA to be effective in the control of symptoms as well as improvement in fetal outcome.198, 199 Furthermore, UDCA is more effective to decrease pruritus and to improve liver test and serum bile acids, when compared to placebo, cholestyramine and dexamethasone.190, 200, 201 Dexamethasone has been shown to improve both pruritus scores and bile acid levels,202 though it is less effective than UDCA.200 However, there has been a report of dramatic worsening of a patient's condition after beginning therapy.203 More investigation into the safety of dexamethasone is necessary before its acceptance for widespread use.

Management of the patient with ICP not only involves symptomatic treatment but also close monitoring and early delivery of the fetus if necessary. The highest risk in this condition is not to the mother, but to the fetus. Contrary to earlier beliefs, ICP conveys higher rates of fetal distress, spontaneous preterm delivery, thick meconium, and perinatal morbidity and mortality.204, 205, 206 The exact mechanism is not known but likely relates to increased levels of maternal and fetal bile acid levels.207 Regarding to the respiratory fetal distress, it appears to be related to the entering of bile acids into the lung.208

Monitoring for chronic placental insufficiency is very important. Reliable predictors of fetal outcome are lacking in ICP and 60% of children are born preterm from mothers with ICP. Fetal deaths are not predicted by antepartum fetal nonstress testing, suggesting a more acute cause of fetal loss.206, 209, 210, 211Some authors suggest that the cause of the fetal sudden death is a fetal cardiac event; in fact, one recent study found that ICP was associated with an increase in the fetal PR interval.212 A large Swedish study with 693 cases of ICP showed that fetal complications correlated with maternal bile acid levels, particularly when levels exceeded 40 μmol/L.213 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.198, 214, 215, 216 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. However, so far there is no consensus whether delivery should be at 37 or 38 weeks of gestation, or earlier. One retrospective study reported that delivering at 37 weeks was associated with low risk of adverse outcomes.217 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. Interestingly, a study showed that intrahepatic cholestasis might be a predictor for the development of biliary and liver disease in the future, thus follow-up should be considered for these patients.218

Acute fatty liver of pregnancy

Nonalcoholic fatty liver disease, the most common cause of abnormal aminotransferases, is associated with macrovesicular hepatic steatosis. In contrast, AFLP results in microvesicular hepatic steatosis which presents in a more acute fashion. The differential diagnosis of acute hepatic failure in the third trimester of pregnancy includes AFLP, HELLP, and acute viral hepatitis, the latter of which can typically be excluded serologically. Given the potential severity of these diagnoses, a high index of suspicion and understanding of each of these entities is paramount to a successful outcome. AFLP was first described in 1934 as "yellow acute atrophy of the liver" and then recognized as a discrete clinical entity in 1940.219 AFLP is a fascinating and serious disease that likely involves an interplay between genetic defects in the fetus and mother. It typically manifests in the third trimester with liver failure and mental status changes, though its appearance in the late second trimester has been reported. Although it never develops after delivery, the diagnosis can be delayed in some patients who present with jaundice in the postpartum period. Approximately half of patients with AFLP have preeclampsia. 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 must be made.

Although the exact mechanism of liver injury still is unknown, great advances have been made in understanding the pathophysiology of AFLP. Many cases of AFLP are linked to fetal defects in mitochondrial fatty acid oxidation. Defects in two key mitochondrial beta-oxidation enzymes; the mitochondrial trifunctional protein and its alpha subunit, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) result in microvesicular hepatic steatosis.220 Several mutations of these enzymes have been associated with AFLP and HELLP syndrome, however, the G1548C LCHAD mutation, inherited in an autosomal-recessive fashion, has most commonly been implicated.221, 222 LCHAD deficiency has been observed in only 20% of babies born to mothers with AFLP. Conversely, in a study of children with LCHAD deficiency, 67% of their mothers developed either AFLP or HELLP during pregnancy.223 One explanation is that heterozygous mothers pregnant with homozygous fetuses manifest more a profound inability to properly metabolize long-chain fatty acids in the liver and placenta.223 This interaction, in conjunction with the increased metabolic stress of pregnancy, leads to excessive concentrations of toxic fetal metabolites crossing the placental barrier and causing 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.220 Another less well known fetal deficiency, hepatic carnitine palmitoyltransferase I, may be seen in the setting of AFLP.224

The incidence of AFLP has been estimated to range from approximately 1 per 7000 deliveries to 1 per 16,000.225, 226 Two recent studies, one from the United Kingdom and the other from The Netherlands, reported an incidence of AFLP of 5 and 3.2 per 100,000 deliveries, respectively.227, 228 In contrast to HELLP, AFLP occurs in nulliparous women 40–50% of the time and has a higher incidence in twin gestations.229, 230, 227Some have suggested that a low BMI may be related to the occurrence of the disease.227 Although once believed not to recur in subsequent pregnancies, there have been several reports of recurrence of the condition in some women.229, 231, 232, 233 Therefore, women with a history of AFLP should be monitored closely for recurrence in the third trimester of subsequent pregnancies.

Presenting symptoms include nausea or vomiting, epigastric pain, anorexia, or jaundice. Hepatic impairment is variable and ranges from mild to fulminant hepatic failure. 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 preeclampsia, namely hypertension, proteinuria, and peripheral edema.229 Pruritus usually is not a feature of AFLP and may suggest another cholestatic process such as ICP.226, 229

Laboratory test results show mild hyperbilirubinemia without gross evidence of hemolysis. Serum aminotransferases rarely are elevated above 300 IU/mL. A marked prolongation of the prothrombin time, unresponsive to vitamin K, signals hepatic insufficiency and poor outcome. Leukocytosis and thrombocytopenia may be present. Any patient in whom thrombocytopenia develops in the third trimester should be evaluated closely for AFLP and HELLP. 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 and hypoglycemia may also be present and are markers of severe disease.

Radiographically, macrovesicular fatty infiltration of the liver is reflected by increased echogenicity on ultrasound, increased T-1 weighted signal on MRI or decreased attenuation on computed tomography (CT) when compared with the spleen, or prior studies, however, radiographic evidence of microvesicular steatosis as seen in AFLOP can be more elusive.234, 235 One recent study compared both methods for AFLP diagnosis, ultrasound and CT, showing no significant difference between them.236, 237

Although liver biopsy is considered the gold standard for the diagnosis, this is rarely necessary.238 Usually the AFLP diagnosis is made clinically, supported by compatible laboratory results and imaging tests. In 2002 Ch’ng et al. proposed the Swansea criteria for the AFLP diagnosis but, despite its good negative predictive value as a screening tool, it is not yet generally accepted.239, 240Histologically, there is little evidence of widespread necrosis, although scattered areas of necrosis may be present.241 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. Unlike other causes of microvesicular hepatic steatosis such as Reye's syndrome, carnitine deficiency, Jamaican vomiting sickness, and certain drug toxicities, AFLP resolves fairly rapidly with delivery.230, 242

AFLP is an obstetric emergency. It does not resolve spontaneously, and delayed delivery exposes the mother and fetus to an 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.243 Other treatment is mainly supportive, with the level of care being set by the degree of hepatic dysfunction. When any signs of liver failure are present (altered mental status, elevated INR) the patient needs to be monitored in an intensive care unit and evaluated expeditiously at a transplant center in addition to prompt delivery of the fetus. In patients with hepatic failure, special attention must be paid to respiratory status, the prevention of infection and gastrointestinal tract hemorrhage. Qiang Wei and colleagues report that in 353 cases of AFLP, multiple organ failure was the most common cause of death (70.1%).237Furthermore, in the setting of advanced coma, cerebral herniation from elevation in intracranial pressure is the most common cause of death. Patients should be monitored and managed if intracranial hypertension develops, by an experienced center. At times the risk of surges in intracranial pressure continue into the postpartum period, thus patients should be monitored until clinically stable. In extreme cases, liver transplantation may be necessary.244, 245 For the surviving mother, complete hepatic recovery is expected. However, because of the risk of an associated fatty acid oxidation defect in the child, closer monitoring is warranted. Identification of fatty acid β oxidation defects in the child may be obtained from cultured skin fibroblasts.246 In those that manifest a defect in fatty acid oxidation, mortality remains high without appropriate dietary management.247

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 1970,229 has been decreased to less than 10% with prompt intervention and delivery. Similarly, fetal mortality has been reduced significantly from approximately 50% quoted before 1985.229, 248 In the UK study previously mentioned, Knight and colleagues reported one death among 57 pregnant women with AFLP (maternal mortality of 1.8%), and seven fetal deaths among 67 infants (perinatal mortality rate of 104 per 1000 births), demonstrating that maternal and fetal outcomes in AFLP have improved.227


Hemolysis, elevated liver enzymes, and low platelets syndrome

A range of hepatic abnormalities have been reported in preeclampsia/eclampsia and one of its more severe forms, the syndrome of hemolysis (H), elevated liver enzymes (EL), and low platelets (LP) or HELLP.249 Diagnosis requires the presence of all three features. HELLP develops in up to 20% of cases of severe preeclampsia, but can occur in the absence of preeclampsia and in 0.2–0.6% of pregnancies overall.250, 251 It is more common in multiparous, older women. There is a significant degree of overlap in the presentations of HELLP syndrome, hemolytic uremic syndrome, thrombotic thrombocytic purpura, and AFLP. It typically presents between 27 and 36 weeks' gestation though a quarter of patients will be diagnosed in the postpartum period.250

Ninety per cent of patients experience fatigue or malaise prior to seeking medical attention. One-half to two-thirds report epigastric or right upper quadrant pain. Fifty per cent report nausea, vomiting, or headache.252, 253, 254 The degree of elevation of aminotransferases reported has been variable.255, 256, 257 Jaundice usually is mild, and if more severe, should raise the suspicion of another process, though higher values of bilirubin may be observed.255Other laboratory findings are high levels of LDH (due to hemolysis) and low platelet count.258 There are two recognized classification systems for HELLP: the Tennessee system and the Mississippi system, which include levels of AST, LDH and platelets in their criteria.258, 259

HELLP is characterized by a microangiopathic hemolytic anemia associated with vascular endothelial injury that promotes the deposition of fibrin in the vessel lumen. Liver biopsy confirms periportal fibrin deposits.260 Even in asymptomatic cases, perisinusoidal deposits of fibrinogen may be observed. Fatty infiltration occasionally may be seen in the periportal region.261 In more dramatic cases, the periportal fibrin deposits may extend and result in either subcapsular hematomas or overt hepatic rupture, which occurs in 1–2% of HELLP cases and carries a 50% maternal and 10–60% fetal mortality.262, 263 In the latter, abdominal pain and shock quickly ensue, and emergent laparotomy with packing of the affected area is mandatory. Serious maternal complications are common and include disseminated intravascular coagulation, placental abruption, pulmonary edema, retinal detachment, as well as acute liver and renal failure. The maternal mortality rate ranges from 0 to 30%.264 Common fetal complications include fetal growth restriction, oligohydramnios and death; the latter most commonly due to intrauterine asphyxia related to shock or placental rupture or prematurity. Perinatal mortality is approximately 11%.

The only effective management strategy is urgent delivery which results in resolution of symptoms within 5 days of delivery. If severe liver dysfunction occurs, patients should ideally be managed in a tertiary care center with a liver transplant program. Most patients, if not delivered, will deteriorate in 1–10 days and have a high rate of fetal demise or severe maternal complications. Treatment involves management of the hypertension, prevention of eclampsia (with magnesium sulfate) and correction of coagulation abnormalities, if needed. Many treatments have been attempted, but no rigorous clinical trials have supported their efficacy. The use of corticosteroids in the management of HELLP has not shown improvements on substantive clinical outcomes.265 In the exceptional cases of persistent bleeding from hematoma, hepatic rupture or fulminant hepatic failure, liver transplantation has been performed successfully with an 88% survival rate after 5 years.266 The use of corticosteroids (betamethasone or dexamethasone) to accelerate fetal lung maturity earlier than 34 weeks' gestation when delivery is needed has not been proven in good clinical studies, though expert opinion recommends it.

The risk of HELLP recurrence in subsequent pregnancies is not yet clearly established. 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.267 However, in another recent study of 128 women with HELLP syndrome, the risk of HELLP and preeclampsia in subsequent pregnancies were both increased.268

 

SUMMARY

The most important distinction that must be made when initially evaluating a pregnant patient presenting with hepatic abnormalities is whether the clinical picture represents liver disease unrelated to pregnancy, one that occurs with more frequency or severity in pregnancy, or a disease entity specific to pregnancy. Pregnancy can be safe in patients with chronic liver disease and even after liver transplantation though a successful outcome for both mother and fetus depends on the careful attention of both a high risk obstetrician and a hepatologist. Chronic conditions such as portal hypertension can worsen during pregnancy thus necessitating closer follow-up to prevent complications such as a variceal bleeding. Careful monitoring of patients with viral hepatitis helps determine the risk of transmission to the newborn as well as the need for intervention. Liver diseases unique to pregnancy are typically severe, threatening the survival of both mother and fetus if not recognized and managed urgently. Fortunately, most occur later in pregnancy allowing for prompt delivery of the fetus which is often the only effective treatment. 

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