Diseases of the Liver, Biliary System, and Pancreas

Acknowledgment

This chapter is based on a similar chapter by Richard H. Lee, MD, Raymond T. Chung, MD, and Patricia Pringle, MD in the eighth edition.

Liver Function in Normal Pregnancy

Normal pregnancy often elevates the liver superiorly, particularly as gestation progresses in the second through third trimesters as a result of the expanding uterus. Physiologically, proportional hepatic blood flow remains relatively constant in pregnancy (approximately 25% to 33% of cardiac output), and significant histological remodeling does not appear to occur.

Substantial compositional changes do occur in the serum concentration of plasma proteins during gestation, however, which may persist throughout the typical postpartum period. Increasing plasma volume leads to total serum protein concentration decrease, driven by a 20% to 40% reduction in serum albumin concentration. A reciprocal relationship between rising levels of alpha fetoprotein and the decline in serum albumin concentration accompanies the progressing gestation as well.

Fibrinogen biosynthesis and manufacture of other coagulation factors, such as factors VII, VIII, IX, and X, increase during pregnancy. Estrogens increase hepatic rough endoplasmic reticulum, which accelerates protein synthesis. Progesterone leads to proliferation of smooth endoplasmic reticulum and an increase in cytochrome P-450 isoenzyme levels. The serum levels of other proteins, such as ceruloplasmin and transferrin, also increase with gestation. The concentrations of specific binding proteins, such as thyroxine-binding globulin and corticosteroid-binding globulin, increase in normal pregnancy, which affects the concentration of the bound portion of these hormones.

A prospective, cross-sectional study of 430 women at a single center was carried out to determine the reference ranges for liver function tests in uncomplicated pregnancies. The study found a decrease in the upper limit of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transpeptidase in normal pregnancy ( Table 64.1 ). The investigators also demonstrated a decrease in bilirubin concentration, but this finding has not been consistently demonstrated in other studies.

TABLE 64.1

Liver Function Test Results in Normal Pregnancy

Modified from Girling JC, Dow E, Smith JH. Liver function tests in pre-eclampsia: importance of comparison with a reference range derived for normal pregnancy. BJOG . 1997;104:246–250.

Test	Not Pregnant	1st Trimester	2nd Trimester	3rd Trimester
AST (IU/L)	7–40	10–28	11–29	11–30
ALT (IU/L)	0–40	6–32	6–32	6–32
Bili (μmol/L)	0–17	4–16	3–13	3–14
GGT (IU/L)	11–50	5–37	5–43	5–41
Alk phos (IU/L)	30–130	32–100	43–135	130–418

Alk phos, Alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Bili, bilirubin; GGT, γ-glutamyl transpeptidase.

Total serum alkaline phosphatase (ALP) activity increases dramatically during pregnancy due to placental production. This peaks at two to four times its baseline level by the third trimester, returning to normal levels within a few weeks after delivery. Occasionally, the ALP concentration may increase to more than 1000 U/L, and although this is almost invariably of placental origin, isoenzyme testing may be requested to exclude elevated ALP from hepatic or bone etiologies. Most studies of plasma lipids in pregnancy agree that total cholesterol and triglyceride levels are increased during pregnancy.

Liver function test results change significantly in the puerperium ( Table 64.2 ) and are affected by common obstetric events, including delivery itself. This can be a confounding factor in clinical interpretation of women with laboratory abnormalities after delivery, particularly in those delivered via cesarean section or utilizing opioids for pain control.

TABLE 64.2

Liver Function Test Results After Delivery in Normal Pregnancy

Modified from David AL, Kotecha M, Girling JC. Factors influencing postnatal liver function tests. BJOG . 2000;107:1421–1426.

Test	Postnatal Peak (day)	Mean Increase (%)	Range of Increase (%)
AST	2–5	88	0–500
ALT	5	147	0–1140
GGT	5–10	62	0–450

ALT, Alanine aminotransferase; AST, aspartate aminotransferase; GGT, γ-glutamyl transpeptidase.

Clinical Diagnosis of Liver Disease

Frank hepatomegaly is not a normal finding during pregnancy. It may signify an inflammatory condition such as acute fatty liver of pregnancy (AFLP), an infectious process (e.g., viral hepatitis), vascular congestion in the context of right-sided heart failure, venous occlusion in Budd-Chiari syndrome, or a malignant process (e.g., metastases, lymphoma, primary or secondary malignancies, etc.).

Skin findings typically associated with chronic liver disease, such as palmar erythema and spider nevi, are often found in normal pregnancy. However, other common indicators of hepatic dysfunction, such as jaundice and scleral icterus, are abnormal findings that always warrant further evaluation.

Ultrasound remains the primary imaging tool because of its ease, substantial utility, and safety record in pregnancy; it is particularly useful in assessing for cholelithiasis and general hepatic composition as well as vascular flow. Computed tomography (CT) may be used during pregnancy; however, precautions should be taken to shield the fetus from radiation or to provide dosimetry estimates if significant exposure is likely; a threshold of less than 5 rads or 50–100 milligray (mGy) has not been associated with adverse gestational, neonatal, nor childhood outcomes. Magnetic resonance imaging (MRI) has the advantage of no radiation exposure, and it has an established safety profile in pregnancy. Cholangiopancreatography is feasible in pregnancy, either via MRI-assisted or the endoscopic technique; the endoscopic approach does utilize ionizing radiation, however.

If a liver biopsy for histologic assessment is indicated for further evaluation during gestation, it should be performed by experienced clinicians, ideally with normal coagulation parameters; pregnancy itself is not an absolute contraindication to this assessment.

Liver Disorders Unique to Pregnancy

Intrahepatic Cholestasis of Pregnancy

Epidemiology

Intrahepatic cholestasis of pregnancy (ICP) affects 0.7% of White pregnant women, approximately twice as many South Asian women, and up to 5% of Chilean women. The geographic variation in prevalence of the condition can be explained by genetic and environmental influences, particularly because ICP is seen less frequently in Chile and Scandinavia than it was in the past. ^, ICP occurs more frequently in winter months. ^, The reasons for these epidemiologic fluctuations is not clear, but they indicate that environmental factors likely play a role in the cause of ICP. ICP has occurred more commonly in women with multiple gestations and in women older than 35 years. The recurrence rate of ICP varies from 60% to 90% in different populations.

Pathogenesis

The cause of ICP is complex, with genetic, endocrine, and environmental factors playing roles. Evidence for a genetic origin includes the demonstration that parous sisters of affected women have a 20-fold increased risk of developing ICP. This idea is further supported by pedigree studies ^, and the demonstration of genetic variation in biliary bile acid receptors and transporters. A few women with ICP have relatively highly penetrant heterozygous mutations in biliary transporters that result in abnormal biliary transport and accumulation of bile acids, which produces a clinical picture of cholestasis.

Mutations have been reported in the ABCB4 and ATP8B1 genes that encode phospholipid transporters, the ABCB11 gene that encodes the principal bile salt transporter, and the main bile acid receptor. Heterozygosity for the common ABCB11 mutations accounts for 1% of European ICP cases, and these two mutants are probably responsible for the reduction in the folding efficiency of the bile salt export pump protein. Women who carry these mutations do not usually have symptoms when they are not pregnant, but they develop cholestasis in pregnancy.

Evidence that elevated levels of reproductive hormones cause susceptible women to develop cholestasis includes the increased prevalence of ICP in multiple pregnancy and the recurrence of cholestasis symptoms when women who previously had ICP are given exogenous estrogens or oral contraceptive (OC) pills. ^, Progestogens may also play a role; 34 (68%) of 50 women in a French prospective series of OC-related ICP cases had been treated with oral micronized natural progesterone for risk of premature delivery. Hormonal alterations may also cause ICP by impairing the farnesoid X receptor, which has a central role in bile acid transport gene expression.

Other environmental factors may influence susceptibility to ICP. Women with hepatitis C infection develop cholestasis more commonly than other pregnant women. Plasma selenium levels were significantly reduced in pregnant women on OCs compared with controls in Finnish and Chilean studies, and it has been proposed that selenium deficiency in women on OCs may contribute to estrogen-induced oxidation damage to hepatocytes. The Chilean study demonstrated that plasma selenium levels have increased in nonpregnant individuals since the 1980s, and the investigators suggested that this may partly explain the reduction in the prevalence of ICP among women on OCs in Chile since then.

The pathogenesis of the symptom of pruritus in ICP is not fully understood. Treatments that have some efficacy in treating cholestasis-related pruritus in nonpregnant patients include anion exchange resins, rifampicin, opiate antagonists, ondansetron, and phototherapy.

Fetal complications that occur more commonly in ICP pregnancies include preterm labor, fetal asphyxial events, meconium staining of amniotic fluid, and intrauterine death. Three studies have demonstrated that ICP patients with higher maternal serum bile acid levels (>40 μmol/L in two studies) more commonly have pregnancies complicated by meconium-stained amniotic fluid and fetal asphyxial events, and the largest study demonstrated that patients with higher levels of bile acids had higher rates of spontaneous preterm labor.

The likely pathogenesis of the fetal complications of ICP may be related to increased levels of fetal serum bile acids, but the precise mechanisms are not understood. Most stillborn infants are of appropriate weight and have no evidence of uteroplacental insufficiency. ^, The evidence suggests that the intrauterine death is a sudden event. Studies have shown an abnormal fetal heart rate ^, or arrhythmia in pregnancies complicated by ICP, and in vitro studies of neonatal heart cells indicate that they are susceptible to bile acid–induced arrhythmia. The increased frequency of preterm labor may be a consequence of bile acid–induced release of prostaglandins, which may initiate labor. The increased rates of meconium-stained amniotic fluid ^, ^, ^, may be related to the toxic effects of bile acids or may be a consequence of bile acids stimulating gut motility.

Diagnosis

ICP should be evaluated for in pregnant women with intractable pruritus. The pruritus is commonly generalized or affects the palms and soles, but it can occur on any part of the body. Intense pruritus may lead to excoriations or prurigo nodules, which can be mistaken as a rash; however a rash is otherwise not typical with ICP. Serum bile acids are most commonly utilized to assign the diagnosis, with a level >10 μmol/L being diagnostic per most authorities, and >40 μmol/L signaling severe disease. Measuring total liver functions (i.e., AST, ALT, bilirubin levels) in conjunction with serum levels of bile acids can be helpful to evaluate for other hepatobiliary causes. This is an additionally useful screening test because some patients have elevated transaminase levels several weeks before the bile acids are increased. If the patient continues to complain of pruritus and initial biochemical tests are normal, we recommend repeating laboratory tests because pruritus may precede biochemical abnormalities by several weeks.

Cholestasis may occur in conjunction with other liver diseases. Consideration of performing a liver ultrasound examination to exclude biliary obstruction may be indicated. Affected women may also have gallstones, which may be due to a genetic predisposition, as some of the genes implicated in ICP are also mutated in pedigrees with familial gallstones. However, the gallstones are unlikely to be the cause of the cholestasis unless the woman has symptoms of biliary obstruction. Other conditions that can be associated with ICP are hepatitis C virus infection, autoimmune hepatitis (AIH), and primary biliary cirrhosis. These conditions have important implications for the subsequent health of the mother, and it is therefore advisable to screen for them.

Management

Maternal Disease

Ursodeoxycholic acid (UDCA) is the only drug that has consistently been shown to improve the maternal symptoms and biochemical features of ICP. There have been several reports about the efficacy of UDCA in ICP. ^, One of the larger trials showed that UDCA reduced levels of pruritus, AST, ALT, and bilirubin compared with dexamethasone or placebo and that it was particularly effective in women with serum levels of bile acids higher than 40 μmol/L. UDCA is dosed at 10–15 mg/kg/day, usually initiated at a dose of 500 mg twice daily, and may be increased to a maximum of 2000 mg daily as needed. In a randomized trial of 111 women, UDCA reduced itching, albeit not to the extent specified a priori as clinically meaningful.

Other drugs have been proposed as treatments for ICP, including dexamethasone, S -adenosylmethionine, cholestyramine, and guar gum, but there is less evidence for their efficacy than there is for UDCA. Topical aqueous cream with menthol may improve the symptoms of ICP, although it does not affect the disease process.

Fetal Concerns and Timing of Delivery

No treatments have been shown to reduce fetal risks associated with ICP. However, it is likely that treatments that reduce levels of maternal bile acids also reduce fetal risk, based on the data that implicate bile acids in pregnancies complicated by spontaneous preterm delivery, fetal asphyxial events, and meconium-stained amniotic fluid. None of the UDCA trials have been powered to investigate whether the drug protects the fetus, but it is known that UDCA treatment improves the serum bile acid levels measured in cord blood and amniotic fluid at the time of delivery. In vitro studies have shown that maternal cholestasis causes impairment of placental bile acid transfer and that this is restored to normal in the placentas of women treated with UDCA. Studies of neonatal rat cardiomyocytes have also shown that incubation of cells in culture medium containing UDCA or dexamethasone protects networks of contracting cells from the arrhythmogenic effect of bile acids.

The only forms of fetal surveillance that have predicted which fetuses may be at risk are amniocentesis and amnioscopy for meconium. However, these approaches have associated risks and may be unacceptable to the patient. Although there is not evidence that frequent antenatal testing (e.g., nonstress tests, biophysical profile assessments) can prevent fetal complications, it is not unreasonable that abnormal electronic fetal monitoring findings which prompt immediate delivery may be identified.

Compared to patients without ICP, those affected by ICP have a higher stillbirth rate; it appears that early delivery is currently the only way to reduce this risk as pregnancy progresses. In a prospective cohort study evaluating patients affected by ICP with total bile acid concentrations of 40 μmol/L or greater, Geenes and colleagues, after adjusting for confounders, found a higher incidence of stillbirth in the population with ICP compared to the unaffected controls (1.5% [10 of 664] versus 0.5% [11 of 2205]; adjusted odds ratio [OR] = 2.58; 95% confidence interval [CI], 1.03 to 6.49). This risk remained significant when compared to their national data (1.5% [10 of 664] versus 0.4% [2626 of 668,195]; OR = 3.05; 95% CI, 1.65 to 5.63). Stillbirths in ICP pregnancies seem to cluster toward the end of the third trimester. Early delivery is the only known intervention that reduces the risk of stillbirth, as was recommended more than 40 years ago by Reid and coworkers, who reported five stillbirths in 56 pregnancies affected by ICP. Subsequently, they adopted a practice of inducing labor at term that led to a decrease in their hospital’s ICP-related perinatal mortality rate from 107 per 1000 down to 35 per 1000. This decrease was primarily attributed to a lower incidence of intrauterine deaths and not to advances in neonatal care. Several other studies demonstrated reduced perinatal mortality with early delivery. Lee and associates evaluated 122 patients with ICP with a common practice of delivery at 37 weeks’ gestation. The average gestational age at delivery for their cohort was 36.7 ± 2.1 weeks. Elective delivery occurred in 86.9% (106 of 122) of patients (n = 86, labor induction; n = 20, elective cesarean delivery [e.g., repeat, malpresentation]), and spontaneous labor occurred in 13.1% (16 of 122). There was one stillbirth that occurred at 30 weeks’ gestation. Recently, further research has reported an increased incidence of stillbirth above the baseline population rate only in pregnancies complicated by bile acids >100 μmol/L, though it is unclear whether this signals the absence of excess risk below this level or confounding due to the common practice of late preterm/early term delivery. ^,

Prevention

The rate of ICP recurrence varies from 40% to 90% and patients should be apprised of this for subsequent pregnancies. It is not possible to prevent the condition in predisposed women, although it is possible to screen for biochemical abnormalities before symptoms occur. If a woman with a history of ICP requires antibiotics, it is advisable to avoid drugs that more commonly cause cholestasis in susceptible individuals, such as erythromycin, flucloxacillin, and amoxicillin–clavulanic acid. Women with a history of ICP should be advised to use hormonal contraception with care, because there is a 10% chance of developing pruritus or hepatic impairment, or both.

Overlap Syndromes With Liver Dysfunction

Preeclampsia, HELLP syndrome ( h emolysis, e levated l iver enzymes, and l ow p latelets), AFLP, and liver rupture are separate conditions that may present with some similar findings, and each commonly occurs during the latter portions of pregnancy. They are often characterized by hypertension, elevated levels of liver enzymes, and thrombocytopenia, and resolution usually follows delivery (see Chapter 45 ). In rare cases, there may be progressive disease with multisystem organ failure and possibly maternal death. HELLP syndrome is a severe variant of preeclampsia, with accompanying involvement of the hepatic and hematologic systems along with the more typical hypertension and proteinuria as features. Preeclampsia occurs in approximately 50% of patients with AFLP as well. ^,

It is essential for the clinician to differentiate the overlap syndromes from unrelated conditions, which do not improve after delivery. A multidisciplinary team approach consisting of maternal-fetal medicine and gastroenterology/hepatology is recommended to guide evaluation and management.

Fatty Acid Oxidation Pathways

Disorders of fatty acid β-oxidation play a role in the cause of AFLP, HELLP syndrome, and preeclampsia. Fatty acids are a major metabolic fuel for humans. In the presence of oxygen, fatty acids are catabolized to carbon dioxide and water, and approximately 40% of the free energy produced in this process is conserved as adenosine triphosphate. The remainder of the energy is released as heat, a process that occurs in the mitochondria by β-oxidation. This enzymatic process is particularly important for the provision of energy when glycogen stores are depleted. It consists of many transport processes and four enzymatic reactions that cause two-carbon fragments to be successively removed from the carboxyl end of the fatty acid, which has been described in detail by Ibdah.

An enzyme that plays a central role in this pathway is long-chain 3-hydroxyacyl–coenzyme A dehydrogenase (LCHAD). It is part of an enzyme complex, the mitochondrial trifunctional protein (MTP), which is located on the inner mitochondrial membrane. In LCHAD deficiency, there is accumulation of long-chain hydroxyl-acylcarnitines, free plasma hydroxyl–long-chain fatty acids, and dicarboxylic acids, which results in cell toxicity. MTP defects are autosomal recessive conditions that cause nonketotic hypoglycemia and hepatic encephalopathy in early infancy and that may progress to coma and death if untreated. The defects also can cause cardiomyopathy, peripheral neuropathy, myopathy, and sudden death, although the latter clinical features are not characteristically seen in isolated LCHAD deficiency. It is important to diagnose MTP disorders because the clinical complications can be avoided with dietary manipulation.

Several case series have demonstrated an increased prevalence of AFLP and, to a lesser extent, HELLP syndrome and severe preeclampsia among heterozygous mothers of children who are homozygous for LCHAD deficiency. A study of 27 pregnancies complicated by AFLP demonstrated that 5 had fetuses with MTP mutations and that at least one copy of the common glutamic acid 474–to-glutamine (E474Q) mutation was present in each case. The authors of that study suggested that the neonates of women whose pregnancies are complicated by AFLP may benefit from being screened for MTP disorders or for the E474Q mutation. Several studies of pregnancies complicated by HELLP syndrome have not demonstrated MTP disorders to be common in the fetuses, and screening of these offspring is therefore not recommended at this time.

Maternal liver disease occurs in pregnancies in which the fetus is affected by a spectrum of fatty acid oxidation disorders, including short-chain and medium-chain defects. In a case-control series of 50 infants from pregnancies complicated by severe maternal liver disease, including AFLP and HELLP syndrome, long-chain defects were 50 times more common in cases than controls, and short-chain and medium-chain defects were 12 times more likely to occur.

Acute Fatty Liver of Pregnancy

Epidemiology

AFLP is a rare, potentially life-threatening, pregnancy-related disease that affects 1 in 7000 to 16,000 pregnancies. The condition occurs more commonly in primigravidas, multiple pregnancy, and pregnancies carrying a male fetus. ^, Maternal mortality has been reported from 0% to 12.5% in various case series, potentially related to variance in presentations or availability of advanced multidisciplinary care for this rare condition. ^, ^, Perinatal mortality rates are reported as approximately 10% in recent series, ^, ^, although they have been reported to be as high as 58% in another series, which the investigators proposed was principally a consequence of premature delivery.

Pathogenesis

The pathogenesis of AFLP is not well understood. The previously described studies found that fatty acid oxidation disorders contributed to approximately 20% of cases. In these cases, it is likely that the heterozygous mother has a reduced hepatic capacity to metabolize long-chain fatty acids. Although there is sufficient capacity in the nonpregnant state, when a heterozygous woman becomes pregnant, her liver is required to metabolize fatty acids from the fetoplacental unit in addition to her own. This increased metabolite load likely results in hepatotoxicity, which may be further compounded by the fluctuations in lipid metabolism that occur in normal pregnancy.

Diagnosis

AFLP typically manifests in the third trimester with symptoms of nausea, malaise, and anorexia. Later symptoms include vomiting and abdominal pain; polydipsia and polyuria may also occur. ^, Common manifestations of liver failure due to other conditions (e.g., jaundice, scleral icterus, impaired hepatic synthetic function with hypoglycemia, coagulopathy) may also be concomitant findings, and if present in a pregnant patient, should strongly suggest this diagnosis. Liver function tests should be requested for any pregnant woman reporting these symptoms, because prompt diagnosis of an acute fatty liver allows stabilization of the patient and rapid delivery. Diagnostic criteria for AFLP have been proposed and are listed in Box 64.1 .

Box 64.1

Swansea Diagnostic Criteria for Acute Fatty Liver of Pregnancy

Modified from Ch’ng CL, Morgan M, Hainsworth I et al. Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut . 2002;51:876–880.

ALT, Alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; PT, prothrombin time.

Six or more criteria are required in the absence of another cause:

Vomiting
Abdominal pain
Polydipsia or polyuria
Encephalopathy
Elevated bilirubin level (>14 μmol/L)
Hypoglycemia (<4 mmol/L)
Elevated urea level (>340 μmol/L)
Leukocytosis (>11 × 10 ⁹ /L)
Ascites or bright liver on ultrasound scan
Elevated transaminase levels (AST or ALT >42 IU/L)
Elevated ammonia level (>47 μmol/L)
Renal impairment (creatinine >150 μmol/L)
Coagulopathy (PT >14 s or aPTT >34 s)
Microvesicular steatosis on liver biopsy

It is often difficult to differentiate AFLP from HELLP syndrome. Patients with AFLP more commonly have high levels of bilirubin, creatinine, uric acid, and neutrophils; a prolonged prothrombin time; acidosis; and hypoglycemia. Patients with more severe disease may have coagulopathy, including disseminated intravascular coagulation. Although levels of liver transaminases can be markedly increased, they also may be barely higher than normal; this may be indicative of hepatic failure and lack of further production of transaminases in such patients. Thus the level of ALT or AST should not be taken as a marker of severity of disease, because hepatocytes cannot release these enzymes if they have been destroyed by severe injury. Common laboratory values with AFLP are summarized in Table 64.3 .

TABLE 64.3

Biochemical Features of Acute Fatty Liver of Pregnancy

Modified from Fesenmeier MF, Coppage KH, Lambers DS et al. Acute fatty liver of pregnancy in 3 tertiary care centers. Am J Obstet Gynecol. 2005;192:1416–1419.

Biochemical Feature ^a	Average at Diagnosis	Range at Diagnosis	Peak or Nadir
AST (<32 IU/L)	523	120–2317	692
ALT (<32 IU/L)	423	43–1504	493
BR (3–22 μmol/L)	99.18	15–203	180
LDH (<250 IU/L)	1483	244–3992	1709
Glu (3.9–5.8 mmol/L)	4.5	0.6–8.7	3.1
Creatinine (μmol/L)	212.2	44–389	4950
Platelets (×10 ³ )	88	33–303	88

ALT, Alanine transaminase; AST, aspartate transaminase; BR, bilirubin; Glu, glucose; LDH, lactate dehydrogenase.

a Parenthetic values are average normal values in pregnancy.

Imaging modalities that have been used to diagnose AFLP include liver ultrasound, MRI, and CT. A study that compared the three techniques found that CT was the best modality for demonstrating characteristic fat infiltration of the liver. However, CT was successful in only 50% of cases. Liver biopsy may be used to obtain a definitive diagnosis using an oil red O stain or electron microscopy. However, this is not always practical, particularly if there is a coagulopathy and rapid delivery is required. This diagnosis continues to rely more on clinical and laboratory parameters rather than radiological findings, which may be more useful for ruling out other etiologies.

As delivery is indicated for AFLP, it is important to be mindful that some women who present with apparent AFLP have a different diagnosis altogether. In a series of 32 patients evaluated with suspected AFLP in a tertiary referral unit in London, 6 had other diagnoses. Two patients had malignancy, one had alcohol-induced fatty liver, one had venoocclusive disease with antiphospholipid syndrome, and another had acute viral hepatitis A infection. Poisoning with acetaminophen can cause a clinical presentation that is hard to distinguish from AFLP, as both may present with acute hepatic insufficiency; acetaminophen overdose is much more common than AFLP, however, thus such patients should have the level of this medication assessed with other common laboratory evaluations as well.

Management

Women with more severe degrees of AFLP should be managed by a multidisciplinary team that includes obstetricians, maternal-fetal medicine specialists, hepatologists, anesthesiologists, neonatologists, and intensivists. The mother should be cared for in an intensive care setting. Blood should be taken frequently to ensure that biochemical and hematologic abnormalities are diagnosed and corrected. It is essential to monitor markers of coagulopathy (prothrombin time, partial thromboplastin time, international normalized ratio, fibrinogen), plasma glucose, platelets, creatinine, liver function test results, serum lactate, and arterial blood gases. Fresh-frozen plasma should be given as indicated to correct coagulopathy due to impaired hepatic synthesis. Women may require large amounts of glucose intravenously to correct hypoglycemia. If multisystem failure develops, it may be necessary to employ dialysis and mechanical ventilation.

Women with AFLP should be assessed regularly for encephalopathy. Signs of encephalopathy may manifest with confusion, fetor hepaticus (i.e., unpleasant breath), and/or asterixis (i.e., liver flap). More objective assessments can be performed by asking women to perform a mental status exam (e.g., draw a five-pointed star or a clock face). It is advisable to discuss patients who have AFLP with a gastroenterologist/hepatologist as well as an intensivist at the time of presentation for consultation on the detailed assessment and management of fulminant liver failure, and because assessment of suitability for orthotopic liver transplantation may be necessary. In a study of 56 admissions to a liver failure unit in the United Kingdom, encephalopathy in conjunction with an elevated blood lactate level was highly associated with a poor prognosis and a need for liver transplantation.

The most important management strategy is delivery of the infant. The decision about the mode of delivery is often complex because the mother is likely to have a coagulopathy. As such, correction of coagulopathy with appropriate blood products (e.g., fresh-frozen plasma) should not be delayed; indeed utilization of a massive transfusion protocol may be indicated. Although vaginal delivery reduces the risk of blood loss compared to cesarean birth, induction of labor often takes longer, and this must be weighed against the risks of the ongoing disease process until delivery, which can improve the maternal outcome. Regional anesthesia should be used with caution and in conjunction with close monitoring. Blood tests should be performed frequently to ensure that coagulopathy is rapidly corrected in the days after delivery.

Prevention

AFLP does not commonly recur in subsequent pregnancies, although recurrent cases are reported in the literature. In women who are heterozygous for disorders of fatty acid oxidation, it may be possible to establish whether the fetus is affected, and this can indicate the magnitude of the mother’s risk. If she is carrying a fetus that is homozygous for the disease, she will have a greater chance of recurrence. For heterozygous mothers who do not have affected fetuses and for others who do not have a fatty acid oxidation disorder, the recurrence risk is lower. However, the disease has potentially disastrous consequences, and women who have had one affected pregnancy should be managed in an obstetric clinic specializing in high-risk pregnancies.

Preeclampsia and HELLP Syndrome

Liver involvement often signifies the development of severe preeclampsia. Elevation of liver enzyme levels may also occur as an isolated laboratory abnormality or as a component of HELLP syndrome. Although severe hypertension may be absent in women with HELLP syndrome, in most instances there is some degree of accompanying hypertension that helps to differentiate this disorder from other diseases. Although there may be overlap between HELLP syndrome and AFLP, isolated serum transaminase elevations in severe preeclampsia and HELLP syndrome rarely exceed 500 IU/L. Elevated serum bilirubin levels occur in women with the HELLP syndrome, partly as a consequence of liver damage and partly in response to hemolysis, but bilirubin levels usually are higher in AFLP. Hepatic failure with encephalopathy and coagulopathy are uncommon in preeclampsia and should prompt consideration of a different diagnosis, including AFLP and other causes of hepatic dysfunction.

Hepatic involvement occurs in approximately 10% of women with severe preeclampsia. Most of these women have only liver enzyme elevations and no epigastric pain. The development of right upper quadrant pain usually signifies liver involvement, and liver function tests should be promptly obtained in this setting. The pain likely results from hepatic ischemia, and the increased transaminase levels may occur several hours after the onset of pain in a manner similar to cardiac enzymes after a myocardial infarction. Pain may also be the result of liver rupture or subcapsular hematoma development. Histologic descriptions of hepatic involvement in preeclampsia include periportal hemorrhage, sinusoidal fibrin deposition, and cellular necrosis.

Women with preeclampsia and liver involvement usually should undergo delivery, although administration of steroids first to promote fetal lung maturity can be undertaken in preterm cases when the maternal condition is otherwise stable. Laboratory abnormalities usually improve within 5 days after delivery, although they may become worse before they resolve. Because HELLP syndrome may develop during the postpartum period in 20% of cases, liver function testing and imaging should be undertaken if abdominal pain, thrombocytopenia, or other clinical features suggesting preeclampsia occur after delivery.

Liver Rupture and Infarction

Epidemiology

Rupture of the liver during pregnancy is a rare but often catastrophic event, with substantial risk of fetal and maternal death. ^, More than 95% of cases during pregnancy involve severe preeclampsia and HELLP syndrome. ^, However, liver rupture occurs only in a small proportion of women with preeclampsia. For example, in one series, subcapsular liver hematoma was reported in approximately 1% (4 of 442) of women with HELLP syndrome. Hepatic hematoma and rupture may also occur after uncomplicated pregnancy ^, or in association with biliary disease, infection, aneurysm, and hepatic neoplasm.

Pathogenesis

Although the pathogenesis of hepatic rupture remains unclear, subcapsular hemorrhage is a common finding at autopsy in cases of maternal mortality with preeclampsia. The right lobe of the liver is affected more commonly than the left. Because major hemorrhage might have occurred by the time the patient is seen, there may be minimal or no hypertension at the time of presentation. Subcapsular hemorrhage produces stretching of the liver capsule, and significant right upper quadrant pain can result from the distention. If stretching is expanded, rupture will occur. The resultant hemoperitoneum produces peritoneal signs and may proceed to hemorrhagic hypovolemic shock.

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