Liver Disease in Pregnancy

J. Eileen Hay

Abnormal liver tests occur in 3%-5% of pregnancies, with many potential causes, including
coincidental liver disease (most commonly viral hepatitis or gallstones) and underlying
chronic liver disease. However, most liver dysfunction in pregnancy is pregnancy-related and
caused by 1 of the 5 liver diseases unique to the pregnant state: these fall into 2 main
categories depending on their association with or without preeclampsia. The preeclampsia-
associated liver diseases are preeclampsia itself, the hemolysis (H), elevated liver tests (EL),
and low platelet count (LP) (HELLP) syndrome, and acute fatty liver of pregnancy. Hy-
peremesis gravidarum and intrahepatic cholestasis of pregnancy have no relationship to
preeclampsia. Although still enigmatic, there have been recent interesting advances in un-
derstanding of these unique pregnancy-related liver diseases. Hyperemesis gravidarum is
intractable, dehydrating vomiting in the first trimester of pregnancy; 50% of patients with
this condition have liver dysfunction. Intrahepatic cholestasis of pregnancy is pruritus and
elevated bile acids in the second half of pregnancy, accompanied by high levels of amin-
otransferases and mild jaundice. Maternal management is symptomatic with ursodeoxy-
cholic acid; for the fetus, however, this is a high-risk pregnancy requiring close fetal
monitoring and early delivery. Severe preeclampsia itself is the commonest cause of hepatic
tenderness and liver dysfunction in pregnancy, and 2%-12% of cases are further complicated
by hemolysis (H), elevated liver tests (EL), and low platelet count (LP)—the HELLP syn-
drome. Immediate delivery is the only definitive therapy, but many maternal complications
can occur, including abruptio placentae, renal failure, subcapsular hematomas, and hepatic
rupture. Acute fatty liver of pregnancy is a sudden catastrophic illness occurring almost
exclusively in the third trimester; microvesicular fatty infiltration of hepatocytes causes acute
liver failure with coagulopathy and encephalopathy. Early diagnosis and immediate delivery
are essential for maternal and fetal survival. (HEPATOLOGY 2008;47:1067-1076.)

M
ost pregnant women are young and healthy, and diseases unique to the pregnant state— hyperemesis gravida-
physiological changes in pregnancy must not be rum (HG), intrahepatic cholestasis of pregnancy (ICP), pre-
mistaken for liver dysfunction (Table 1). Abnor- eclampsia, the HELLP syndrome, and acute fatty liver of
mal liver tests occur in 3%-5% of pregnancies, with many pregnancy (AFLP). These conditions are complications of
potential causes (Table 2). Although relatively uncommon, pregnancy itself, and each has a characteristic timing in rela-
any liver disease can occur coincidentally in the pregnant tion to the trimesters of pregnancy: HG in the first trimester,
patient and pregnancy may occur in a patient with underly- ICP in the second half of pregnancy, and the other 3 in the
ing chronic liver disease. However, most liver dysfunction in third trimester.
pregnancy is pregnancy-related1 and due to one of the 5 liver Liver diseases unique to pregnancy fall into 2 main
categories depending on their association with or without
preeclampsia. The preeclampsia-associated liver diseases
Abbreviations: AFLP, acute fatty liver of pregnancy; BA, bile acids; DIC, dis-
seminated intravascular coagulation; FAO, fatty acid oxidation; HELLP, hemolysis
are preeclampsia itself, the HELLP syndrome, and AFLP.
(H), elevated liver tests (EL), and low platelet count (LP); HG, hyperemesis gravi- HG and ICP have no relationship to preeclampsia. Al-
darum; ICP, intrahepatic cholestasis of pregnancy; LCHAD, ␣-subunit, long-chain though still enigmatic, there have been recent interesting
3-hydroxyacyl-CoA dehydrogenase; UDCA, ursodeoxycholic acid.
From the Division of Gastroenterology and Hepatology, The Mayo Clinic, Roch-
advances in understanding of these unique pregnancy-
ester, MN. related liver diseases.
Received July 3, 2007; accepted October 31, 2007.
Address reprint requests to: J. Eileen Hay, Mayo Clinic, 200 First Street SW,
Rochester, MN 55905. E-mail: jhay@mayo.edu; fax: 507-266-2810. Liver Diseases Unique to Pregnancy
Copyright © 2007 by the American Association for the Study of Liver Diseases.
Hyperemesis Gravidarum
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.22130 HG, occurring in 0.3% of pregnancies, is intractable
Potential conflict of interest: Nothing to report. vomiting in the first trimester of pregnancy of such sever-
1067
1068 HAY HEPATOLOGY, March 2008

Table 1. Physiological Changes in Liver Tests During Normal ICP. Impaired sulfation and abnormalities in progester-
Pregnancy one metabolism have been found in ICP.4
Test Normal Range The recognition of familial cases and high incidence in
Bilirubin Unchanged or slightly decreased certain ethnic groups have long suggested a genetic pre-
Aminotransferases Unchanged disposition to ICP. Pedigree analysis of family members
Prothrombin time Unchanged of a child with progressive familial intrahepatic cholestasis
Alkaline phosphatase Increases 2 to 4-fold
Fibrinogen Increases 50% has identified a mutation in the MDR3 (ABCB4) gene
Globulin Increases in ␣ and ␤ globulins associated with ICP. MDR3 is the transporter for phos-
␣-fetoprotein Moderate increase, especially with twins pholipids across the canalicular membrane, and muta-
WBC Increases
Ceruloplasmin Increases
tions may result in loss of function and raised bile acids as
Cholesterol Increases 2-fold a secondary effect.5 At least 10 different MDR3 muta-
Triglycerides Increases tions have been identified in ICP, and MDR3 mutations
Globulin Decreases in gamma-globulin
may account for 15% of cases of ICP.5-8 Exogenous fac-
Hemoglobin Decrease in later pregnancy
tors also may play an etiologic role. ICP recurs in only
45%-70% of pregnancies and with variable intensity, and
there is a clear seasonal variability. It has striking geographical
ity as to necessitate intravenous hydration. Immunologi- variations, and dietary factors such as selenium deficiency
cal, hormonal, and psychological factors associated with have been implicated in some studies from Chile.9
pregnancy may play an etiologic role and risk factors in- Fetal complications in ICP are placental insufficiency,
clude hyperthyroidism, psychiatric illness, molar preg- premature labor, and sudden fetal death, probably due to
nancy, preexisting diabetes, and multiple pregnancies.2,3 elevated fetal levels of bile acids (BA). Fetal BA are nor-
The diagnosis is clinical—intractable, dehydrating mally transported across the placental membrane to the
vomiting, typically between 4 and 10 weeks’ gestation. maternal circulation; high maternal levels of BA correlate
Liver dysfunction occurs in 50% patients with amin- with fetal morbidity and mortality.10 Abnormal placental
otransferases up to 20-fold elevation and with occasional BA transport from fetal to maternal circulation, increased
jaundice.2 Uncomplicated vomiting in pregnancy does maternal BA levels, and immaturity of fetal transport sys-
not cause liver dysfunction. Viral hepatitis must be ex- tems may all contribute to elevated fetal BA levels in ICP.
cluded. Liver biopsy is needed only to exclude more seri- Clinical Features and Diagnosis. Pruritus typically
ous disease; the hepatic histological appearance is starts around 25 to 32 weeks of gestation, but occasionally
generally normal or shows bland cholestasis. Hospitaliza- earlier, even in the first trimester. It affects all parts of the
tion is necessary for rehydration, nutritional support, and body, is worse at night, and in severe cases, the patient
symptomatic measures with antiemetics; occasionally ste- may be suicidal. Occasionally the cholestasis is compli-
roids are used. cated by diarrhea or steatorrhea. Jaundice occurs in 10%-
25% of patients, 2-4 weeks after the pruritus.
Intrahepatic Cholestasis of Pregnancy Aminotransferases levels vary from mild to 10-fold to 20-
ICP is defined as pruritus and elevated bile acid levels fold elevations; bilirubin is usually less than 5 mg/dL.
which appear in the second half of pregnancy and disap- Alkaline phosphatase will be elevated though diagnosti-
pear after delivery, typically to recur in subsequent preg- cally unhelpful in pregnancy; mildly elevated levels of
nancies. It is second only to viral hepatitis as a cause of
jaundice in pregnant women.
Table 2. Diagnostic Categories of Liver Disease in
Etiology. ICP is associated with abnormal biliary
Pregnancy (Trimester of Occurrence)
transport across the canalicular membrane, the etiology of
Coincidental to Underlying Chronic Diseases Unique to
which is probably heterogeneous, with hormonal, genetic Pregnancy Liver Disease (1-3) Pregnancy
and exogenous factors exerting different influences on the
Viral hepatitis (1-3) Chronic hepatitis B or C Hyperemesis gravidarum (1)
hepatocyte or canalicular membrane of different individ- Gallstones (1-3) Autoimmune hepatitis Intrahepatic cholestasis of
uals. It is related in some way to female sex hormones— Drugs (1-3) Primary sclerosing pregnancy (late 2,3)
the temporal relationship to hormone levels in 3rd Sepsis (1-3) cholangitis Preeclampsia (3)
Budd-Chiari* Wilson disease HELLP syndrome (3)
trimester, increase in twin pregnancies, precipitation by Primary biliary cirrhosis Acute fatty liver of
exogenous progesterone in 3rd trimester. Sex hormones (rare) pregnancy (3)
have known cholestatic effects, including inhibition of Cirrhosis (uncommon)
the bile salt export pump, and an abnormal metabolic *Budd-Chiari syndrome, when associated with pregnancy, usually occurs in the
response to increased hormones in pregnancy may cause postpartum period.
HEPATOLOGY, Vol. 47, No. 3, 2008 HAY 1069

Table 3. Distinguishing Features of Intrahepatic Cholestasis of Pregnancy (ICP), the HELLP Syndrome and Acute Fatty Liver
of Pregnancy (AFLP)
ICP HELLP AFLP

% Pregnancies 0.1% (USA) 0.2%–0.6% 0.005%–0.01%

Onset/trimester 25–32 weeks 3 or postpartum 3 or postpartum
Family history Often No Occasionally
Presence of preeclampsia No Yes 50%
Typical clinical features Pruritus Hemolysis Liver failure with coagulopathy, encephalopathy
Mild jaundice Thrombocytopenia(⬍50,000 often) hypoglycemia, DIC
Elevated bile acids
Vitamin K2
Aminotransferases Mild to 10-20-fold elevation Mild to 10-20-fold elevation 300-500 typical but variable ⫹⫹
Bilirubin ⬍5 mg/dL ⬍5 mg/dL unless massive necrosis often ⬍5 mg/dL, higher if severe
Hepatic imaging Normal Hepatic infarcts Fatty infiltration
Hematomas, rupture
Histology Normal–mild cholestasis, no Patchy/extensive necrosis and Microvesicular fat in zone 3
necrosis hemorrhage
Maternal mortality 0% 1%–25% 7%–18%
Fetal/perinatal mortality 0.4%–1.4% 11% 9%–23%
Recurrence in subsequent 45%–70% 4%–19% ␣-subunit, long-chain 3-hydroxyacyl-CoA
pregnancies dehydrogenase (LCHAD) defect—yes
No fatty acid oxidation defect—rare

gamma glutamyltransferase are found in fewer than 30% 2.0 g/day) reduces abnormal maternal and fetal BA levels
cases. The most specific and sensitive marker of ICP is and is completely safe for the fetus.12 UDCA is more
serum BA levels of greater than 10 ␮mol/L and up to effective in reducing pruritus, aminotransferases, and BA
100-fold elevated. levels than cholestyramine, with fewer preterm deliveries
Typical clinical features in the absence of other liver and fewer side effects.10 Dexamethasone (12 mg/day for 7
diseases is strongly suggestive of ICP, especially if the days) has the advantage of promoting fetal lung maturity,
pruritus has been present in other pregnancies and then but this therapy, tested in 130 patients, was less effective
disappeared immediately after delivery. Diagnosis in the than UDCA in reducing pruritus and aminotransferase
first pregnancy is presumptive, made on clinical grounds levels.13 S-adenosyl-L-methionine is also less effective
alone, and can be confirmed only with rapid postpartum than UDCA but may have an additive effect.14
resolution. Elevated BA levels add weight to the diagnosis The main risk in ICP is to the fetus and necessitates
but are not routinely available. Liver biopsy is only needed referral to a high-risk obstetrician. Fetal monitoring for
to exclude more serious liver disease (Table 3). The dif- chronic placental insufficiency is essential but will not
ferential diagnosis of cholestasis in pregnancy is wide and prevent all fetal deaths from acute anoxia, which can be
includes viral hepatitis and gall stones; however, preg- prevented only by delivery as soon as the fetal lungs are
nancy is a cholestatic and pruritogenic state and may mature; 60% of babies are delivered before term. Fetal
therefore unmask underlying chronic liver disease such as distress occurs in 20%-40%, with occasional perinatal
primary sclerosing cholangitis or hepatitis C. death; an early onset in the second trimester and severe
Management. Management of ICP is 2-fold: symp- biochemical abnormalities seem to be risk factors. A re-
tomatic therapy for the mother and close monitoring and cent Swedish population study of more than 45,000 preg-
early delivery for the fetus. Pruritus and liver dysfunction nancies with 693 cases of ICP (1.3%) showed that fetal
resolve immediately after delivery, with no maternal mor- complications correlate with maternal BA levels, with pre-
tality. Withdrawal of exogenous progesterone may cause mature delivery, asphyxial events, and meconium staining
remission of pruritus before delivery. Fat-soluble vitamin occurring only in the 19% of cases with maternal BA
supplementation at the time of delivery may be needed levels greater than 40 ␮mol/L.10 Whether maternal ther-
with severe steatorrhea. apy with UDCA will improve fetal outcome is still un-
Ursodeoxycholic acid (UDCA), generally in doses of known.
10 to 15 mg/kg body weight, is the treatment of choice for Outcome and Counseling. ICP resolves with fetal de-
ICP; UDCA, in several small randomized trials, produced livery to recur in 45%-70% of subsequent pregnancies
relief of pruritus with improvement in liver tests and with and occasionally with oral contraceptives. Some rare fa-
no adverse maternal or fetal effects11; fetal outcome was milial cases of apparent ICP have persisted postpartum,
improved with less prematurity. High-dose UDCA (1.5- with progression to subsequent fibrosis and cirrhosis, but
1070 HAY HEPATOLOGY, March 2008

these cases may represent chronic cholestatic liver disease

from the onset. A recent large Finnish population study15
with more than 10,000 patients showed that patients who
have had ICP subsequently have more gallstones and cho-
lecystitis, more nonalcoholic pancreatitis, more hepatitis
C, and more nonalcoholic cirrhosis. Therefore, in some
patients, ICP may be an indicator of more serious subse-
quent liver disease.

Preeclampsia
Preeclampsia is the triad of hypertension, edema, and
proteinuria in the third trimester of 5%-10% of pregnan-
cies. Liver involvement, although infrequent, always in-
dicates severe preeclampsia with significant perinatal
Fig. 1. Computed tomography of abdomen of 28-year-old woman with
morbidity and mortality; it is the commonest cause of severe HELLP syndrome at 39 weeks’ gestation. A large subcapsular
hepatic tenderness and liver dysfunction in pregnancy. hematoma extends over the left lobe; the right lobe has a heterogeneous,
Aminotransferases are variable from mild to 10-fold to hypodense appearance because of widespread necrosis, with “sparing”
of the areas of the left lobe (compare perfusion with the normal spleen).
20-fold elevations; bilirubin is usually less than 5 mg/dL.
No specific therapy is needed for the hepatic involvement
of preeclampsia, and its only significance is as an indicator
of severe disease with need for immediate delivery to avoid mothers with HELLP do not have a proven increased risk
eclampsia, hepatic rupture, or necrosis. of FAO deficiencies.18,19
Clinical Features and Diagnosis. There are no diag-
HELLP Syndrome nostic clinical features to distinguish HELLP from pre-
Severe preeclampsia is complicated in 2%-12% of eclampsia17,20; most patients present with upper
cases (0.2%-0.6% of all pregnancies) by hemolysis (H), abdominal pain and tenderness, nausea and vomiting,
elevated liver tests (EL), and low platelet count (LP)—the malaise, headache, edema and weight gain, hypertension,
HELLP syndrome.16,17 Though recognized for over 50 and proteinuria; jaundice is uncommon (5%); some pa-
years, diagnosis, management, and pregnancy outcome of tients have no obvious preeclampsia. Most patients
the HELLP syndrome remain controversial. present between 27 and 36 weeks’ gestation, but 25% in
Etiology. The HELLP syndrome is a microangio- postpartum period. HELLP is commoner in white pa-
pathic hemolytic anemia associated with vascular endo- tients, multiparous, and older patients but can occur with
thelial injury, fibrin deposition in blood vessels, and any parity and age.
platelet activation with platelet consumption, resulting in The diagnosis of HELLP must be quickly estab-
small to diffuse areas of hemorrhage and necrosis dissect- lished because of maternal and fetal risk and the neces-
ing from zone 1 to involve the whole lobule, leading to sity for immediate delivery. Diagnosis requires the
large hematomas, capsular tears, and intraperitoneal presence of all 3 laboratory criteria: (1) hemolysis, (2)
bleeding. The precipitating injury is not known.17 There elevated aminotransferases, and (3) thrombocytopenia
is some overlap with AFLP and fatty acid oxidation (Table 4),16,17,20 but, unfortunately, diagnostic criteria
(FAO) defects, but this is much less established than for are used inconsistently.20 Occasionally, disseminated
AFLP. Studies of families with known FAO deficiencies intravascular coagulation (DIC) may be present. Ami-
have shown a high incidence of HELLP, but babies of notransferase elevation is variable, from mild to 10-
fold to 20-fold, and bilirubin is usually less than 5
mg/dL. Computed tomography of the liver may show
Table 4. Diagnostic Criteria for HELLP Syndrome subcapsular hematomas, intraparenchymal hemor-
H ............................................ EL.......................... LP................. rhage, or infarction or hepatic rupture (Fig. 1); these
Hemolysis Elevated liver tests Low platelets
abnormalities correlate with thrombocytopenia of less
Abnormal blood smear AST⬎70U/L ⬍150,000*
than 20,000 but not with liver dysfunction. Occasion-
LDH ⬎600 U/L
Elevated 1 indirect bilirubin ally the HELLP syndrome must be distinguished from
other conditions, especially AFLP, with which it has
*HELLP syndrome may be subdivided, based on platelet count, into severe/
Class 1 (platelets ⬍50,000), moderate/Class 2 (50 –99,000), and mild/Class 3 significant overlap in some cases,17 or from the rare
(100 –150,000). conditions of thrombotic thrombocytopenic purpura,
HEPATOLOGY, Vol. 47, No. 3, 2008 HAY 1071

hemolytic uremic syndrome, or antiphospholipid syn- Complications of the HELLP Syndrome. Serious
drome. maternal complications are common16,17,20—DIC, ab-
Management. The patient with HELLP must be hos- ruptio placentae, acute renal failure, eclampsia, pulmo-
pitalized for antepartum stabilization of hypertension and nary edema, acute respiratory distress syndrome, severe
DIC, for seizure prophylaxis, and fetal monitoring.17 ascites, subcapsular hematoma, hepatic failure, and
Transfer to a tertiary referral center should be effected if wound hematomas. Indications to proceed with liver
possible and a hepatic computed tomography (limited transplantation are very limited—persisting bleeding
views) obtained. from a hematoma or hepatic rupture or liver failure from
Delivery is the only definitive therapy, and for patients extensive necrosis.22 Perinatal mortality is 11%, due to
with severe HELLP there is progressive and often sudden prematurity, dysmaturity due to placental insufficiency,
maternal deterioration.20 At greater than 34 weeks’ gesta- or the consequences of severe maternal complications.
tion or if there is any evidence of multiorgan dysfunction, Hepatic hemorrhage without rupture is managed con-
DIC, renal failure, abruptio placentae, or fetal distress, servatively in a hemodynamically stable patient with close
there is consensus that immediate delivery should be ef- hemodynamic monitoring in an intensive care unit, cor-
fected. Well-established labor should be allowed to pro- rection of coagulopathy, immediate availability of large-
ceed in the absence of obstetric complications or DIC, but volume transfusion of blood products, immediate
many patients (40%-50%) will require caesarean section, intervention for rupture or rapid expansion of hematoma,
especially a primigravida remote from term. Patients may on diagnostic hepatic imaging. Exogenous trauma must
require blood or blood products to correct hypovolemia, be avoided—abdominal palpation, convulsions, emesis,
anemia, and coagulopathy, and prophylactic antibiotics and unnecessary transportation.
are recommended. Liver rupture is a rare, life-threatening complication of
Management remote from term with fetal lung im- HELLP, usually preceded by an intraparenchymal hem-
maturity and a stable maternal condition without DIC orrhage progressing to a contained subcapsular hema-
is controversial, as is the use of corticosteroids.16,17,20,21 toma in the right lobe in patients with severe
In the absence of randomized trials, a National Insti- thrombocytopenia. Survival depends on rapid, aggressive
tutes of Health Consensus Development Panel sug- supportive care and immediate laparotomy. The best sur-
gests that perinatal outcome at less than 34 weeks’ gical management is still controversial; most successful is
gestation is better when corticosteroids (betametha- evacuation of the hematoma with pressure packing and
sone or dexamethasone, which cross the placenta) are drainage, followed by consideration of hepatic artery em-
used for 24 to 48 hours, with delivery thereafter; the bolization or ligation, partial hepatectomy, or oversewing
main benefit of this therapy is fetal lung maturity but it of the laceration. In the rare hemodynamically stable pa-
also improves the maternal platelet count in some tient with contained hepatic rupture or a rapidly enlarg-
cases. There are some advocates for giving dexametha- ing hematoma, angiographic embolization may be
sone to all cases, starting before delivery but completed considered. Maternal mortality from hepatic rupture re-
postpartum with no delay in delivery; they may also aid mains very high at 50%, and perinatal mortality rates are
maternal stability during the transfer time to a tertiary 10%-60%, mostly from placental rupture, intrauterine
referral center. Most cases with longer conservative asphyxia, or prematurity.
therapy will deteriorate in 1 to 10 days after diagnosis, Recurrence of HELLP. Subsequent pregnancies in
with a high risk of fetal loss. patients with HELLP syndrome carry a high risk of com-
Most patients have rapid, early resolution of HELLP plications—pre-eclampsia, recurrent HELLP, prematu-
after delivery with normalization of platelets by 5 days. rity, intrauterine growth retardation, abruptio placentae,
Persistence of thrombocytopenia or hemolysis for more and perinatal mortality.16 However, no long-term effect
than 72 hours, worsening hepatic or renal failure, or life- on renal function has been noted.
threatening complications are taken as an indication for
specific therapy. Many different treatment modalities Acute Fatty Liver of Pregnancy
have been used—plasmapheresis, plasma volume expan- Acute fatty liver of pregnancy (AFLP) is a sudden cat-
sion, antithrombotic agents, steroids, plasma exchange astrophic illness occurring almost exclusively in the third
with fresh-frozen plasma, dialysis— but no clinical trials trimester, where microvesicular fatty infiltration results in
have been done. Heparin therapy has increased bleeding encephalopathy and hepatic failure.23,24 It carries signifi-
complications and is not recommended. In about 25% of cant perinatal and maternal mortality and requires early
cases, HELLP will develop in the postpartum period, and diagnosis and intervention to prevent maternal and fetal
therapy is the same as antepartum. death (Table 3).
1072 HAY HEPATOLOGY, March 2008

Etiology. In some cases the etiology of AFLP involves

abnormalities in intramitochondrial FAO.18 Beta-oxida-
tion of fatty acids in hepatic mitochondria is a complex
process requiring several essential enzymes; mitochon-
drial trifunctional protein and its ␣-subunit, long-chain
3-hydroxyacyl-CoA dehydrogenase (LCHAD), are the 2
enzymes of this metabolic process, whose autosomally in-
herited genetic mutations are most closely associated with
AFLP, especially the G1548C mutation of LCHAD.22 Of
24 babies with defects in FAO, 62% of their mothers had
maternal liver disease, either AFLP or HELLP syn-
drome.18 Further study showed that in 83 pregnancies in
families with known FAO deficiencies, 24 pregnancies
had maternal liver disease, with AFLP in 20 cases, all with
Fig. 2. Histological appearance of the liver of a 32-year-old primi-
the G1528C mutation of LCHAD. A separate study gravida with acute fatty liver of pregnancy. (A) Sudan stain (low power)
showed an 18-fold increase in incidence of maternal liver shows diffuse fatty infiltration (red staining) involving predominantly zone
disease, both HELLP syndrome and AFLP, in the moth- 3, with relative sparing of periportal areas. (B) Hematoxylin-eosin stain
ers of 50 infants with FAO defects.19 (high power) shows hepatocytes stuffed with microvesicular fat (free fatty
acids) and centrally located nuclei.
Babies of mothers with AFLP have been screened for
FAO defects: 5 of 27 pregnancies with AFLP revealed
fetuses with LCHAD deficiencies but no affected babies Other typical abnormalities are normochromic, normo-
in 81 pregnancies with HELLP.18 LCHAD deficiency has cytic anemia, high white blood cell count, normal to low
been identified in about 20% of babies of mothers with platelets, coagulopathy with or without DIC, metabolic
AFLP. Speculation is that maternal heterozygosity for acidosis, renal dysfunction (often progressing to oliguric
LCHAD deficiency reduces the maternal capacity to oxi- renal failure), hypoglycemia, high ammonia, and bio-
dize long-chain fatty acids both in liver and placenta, and chemical pancreatitis.24
this, together with the metabolic stress of pregnancy and The presumptive diagnosis of AFLP is made on com-
fetal homozygosity for LCHAD deficiency, causes accu- patible clinical and laboratory features, the need for expe-
mulation in the maternal circulation of potentially hepa- ditious therapy and presence of coagulopathy precluding
totoxic LCHAD metabolites.18 Perhaps external factors, biopsy. A definitive diagnosis is histological—microve-
such as carnitine deficiency or other dietary factors, exac- sicular fatty infiltration (free fatty acids) predominantly in
erbate this situation.19 There are reports of maternal liver zone 3 with lobular disarray and mild portal inflamma-
disease associated with defects of other enzymes involved tion with cholestasis (Fig. 2). Occasionally the histologi-
in FAO, but the role of these other enzymes in causing cal picture, although usually diagnostic, cannot be
AFLP remains controversial. differentiated from viral hepatitis or preeclampsia. The
Clinical Features and Diagnosis. Unlike HELLP, main differential diagnoses of acute liver failure in the
40%-50% of patients with AFLP are nulliparous, with an third trimester are AFLP, HELLP, and fulminant viral
increased incidence in twin pregnancies.23,24 AFLP occurs hepatitis. In comparison with those with HELLP syn-
almost exclusively in the third trimester from 28 to 40 drome, patients with AFLP are more likely to show liver
weeks, rarely in late second trimester. In a few patients, it failure with coagulopathy, hypoglycemia, encephalopa-
presents as jaundice in the postpartum period. The pre- thy, DIC, and renal failure (Table 3).
sentation can vary from asymptomatic to fulminant liver Management. Early recognition and diagnosis of AFLP
failure. The typical patient has 1 to 2 weeks of anorexia, with immediate termination of pregnancy and intensive sup-
nausea and vomiting, headache, and right upper quadrant portive care is essential for both maternal and fetal survival.
pain, and is ill-looking with jaundice, hypertension, There are no reports of recovery before delivery. Immediate
edema, ascites, a small liver, and hepatic encephalopathy. hospital admission allows maternal stabilization, fetal moni-
Intrauterine death may occur. About 50% of patients toring, and confirmation of diagnosis. Delivery is effected
with AFLP have preeclampsia, and there is some overlap usually by caesarean section, but the type of delivery should
with the HELLP syndrome. be based on obstetric assessment of likelihood of rapid con-
In AFLP, aminotransferases vary from near-normal to trolled vaginal delivery in less than 24 hours. Vaginal delivery
1000, usually about 300 to 500; bilirubin is usually less will reduce the incidence of major intra-abdominal bleeding
than 5 mg/dL but higher in severe or complicated disease. but is best effected with an international normalized ratio of
HEPATOLOGY, Vol. 47, No. 3, 2008 HAY 1073

less than 1.5 and platelet count of greater than 50,000. Pro- and during each of the 3 trimesters of pregnancy. Acute
phylactic antibiotics are recommended to prevent uterine hepatitis A occurs in 1 per 1000, acute hepatitis B in 2 per
infections.24 1000 pregnant women, and hepatitis D is rare. The clin-
By 2 to 3 days after delivery, the aminotransferases and ical and serologic course of acute hepatitis in the Western
encephalopathy will improve, but intensive supportive care world is generally the same as in the nonpregnant patient,
is needed to manage the many complications of liver failure nor does the hepatitis appear to affect the pregnant state
until this recovery occurs. Patients who are critically ill at the adversely, although hepatitis A during the second or third
time of presentation, who develop complications (encepha- trimesters may increase gestational complications. Hepa-
lopathy, hypoglycemia, coagulopathy), or who continue to titis E is extremely rare in the United States but is endemic
deteriorate despite emergency delivery, should ideally be to large areas of Asia, Africa, and Central America, where,
transferred to a liver center. Most patients improve in 1 to 4 in the third trimester of pregnancy, it becomes fulminant
weeks postpartum, although a cholestatic phase with rising with a high mortality (up to 25%), probably influenced
bilirubin and alkaline phosphatase may persist. Recovery can by malnutrition. Herpes simplex hepatitis is rare but must
occur in days or be delayed for months but is complete with be diagnosed because antiviral therapy with acyclovir or
no signs of chronic liver disease. With advances in supportive vidarabine is life-saving; these patients present with a se-
management of these patients, the maternal mortality is now vere or fulminant “anicteric” hepatitis in the third trimes-
7%-18% and fetal mortality 9%-23%. Infectious and bleed- ter. Management of the patient with acute viral hepatitis
ing complications remain the most life threatening. Liver is supportive, and viral hepatitis is not an indication for
transplantation has a very limited role here because of the
termination of pregnancy, caesarean section, or discour-
great potential for recovery with delivery but should be con-
agement for breastfeeding.28 Congenital malformations
sidered in patients whose clinical course continues to deteri-
in the fetus occur only with early cytomegalovirus infec-
orate with advancing fulminant hepatic failure after the first
tion.
1 to 2 days postpartum without signs of hepatic regenera-
All pregnant women are tested for hepatitis B on first
tion.
antenatal visit; for those who are without immune anti-
Recurrence and Screening. Many patients do not be-
come pregnant again after AFLP, either by choice due to the bodies and at high risk for HBV infection during preg-
devastating effect of the illness or by necessity due to hyster- nancy (for example, multiple sex partners, intravenous
ectomy to control postpartum bleeding. Women who are drug use), vaccine can be given in pregnancy with little
carriers of LCHAD mutation have an increased risk of recur- risk to the fetus. Perinatal transmission of hepatitis B is
rence of AFLP in 20%-70% of pregnancies. All babies of highest in those with acute hepatitis, especially with hep-
mothers with AFLP are tested for defects of FAO because atitis B e antigen positivity in the third trimester (50%-
presymptomatic diagnosis and appropriate early manage- 80%), lower in mothers with anti-HBe (25%), and lowest
ment will reduce morbidity and mortality in these babies. in carriers (5%); 80%-90% of these babies have persistent
Expanded newborn screening in many states will include hepatitis B surface antigen positivity. Transmission of
this, but, in its absence, the appropriate clinical and bio- hepatitis B is not transplacentally but at delivery and is
chemical testing must be done for all these babies.26,27 For preventable in more than 95% of cases by passive-active
mothers with previous AFLP, liver tests, glucose, and carni- immunoprophylaxis of the babies at birth with hyperim-
tine levels and plasma acylcarnitine profile may help identify mune B immunoglobulin and hepatitis B virus vaccine (3
the obligate carrier to allow closer fetal and maternal moni- doses: in first 2 days, at 1 month, and at 6 months) Anti-
toring.19 Future options may involve genetic testing for the viral therapy in the third trimester may reduce vertical
carrier state. For mothers without identifiable abnormalities transmission in patients with a high viral load who are
of FAO, AFLP does not tend to recur in subsequent preg- most at risk of vertical transmission to their babies.29 Ver-
nancies, though rare cases have been reported. tical transmission of hepatitis A and D is rare and occurs
only with high viral levels at the time of delivery. Mother-
Liver Diseases Occurring Coincidentally in to-infant transmission of hepatitis C is 1% to 5%, with
a Pregnant Patient maternal risk factors being human immunodeficiency vi-
Viral Hepatitis rus co-infection, history of intravenous drug abuse, and
Viral hepatitis, due to hepatitis A, B, C, D, E, herpes maternal viremia of greater than 106 copies/mL; transmis-
simplex, cytomegalovirus, and Epstein-Barr viruses, ac- sion is unaffected by mode of delivery or breastfeeding.
counts for 40% of jaundice in pregnant women in the Newborns of mothers with hepatitis A in the third trimes-
United States.28 Hepatitis A, B, and C have the same ter should be given passive immunoprophylaxis with im-
frequency in the pregnant and nonpregnant populations mune globulin within 48 hours of birth.
1074 HAY HEPATOLOGY, March 2008

Gallstones and Biliary Disease Table 5. Drug Therapy During Pregnancy for Chronic Liver
Cholesterol secretion increases in the second and third Disease
trimesters compared to bile acids and phospholipids, lead- FDA Pregnancy
Drug Category Uses and Safety
ing to supersaturated bile; in addition, fasting and post-
prandial gallbladder volumes are greater, with reduced Prednisone C Low risk: increased cleft palate,
adrenal insufficiency
rate and volume of emptying. This large residual volume
Azathioprine D Data suggest low risk
of supersaturated bile in the gallbladder of the pregnant Cyclosporine C Most safety data of
patient leads to the retention of cholesterol crystals and immunosuppressants
eventual gallstones. The formation of biliary sludge and Tacrolimus C Probably safe—use as needed
Mycophenylate C Not recommended—limited data
stones is strongly associated with frequency and number mofetil
of pregnancies. Up to 10% of patients develop stones or Sirolimus C Not recommended
sludge over the course of one pregnancy, with obesity and Lamivudine C Low risk
Adefovir C Few data—minimal toxicity
serum leptin being risk factors.30 Despite their prevalence Entecavir C Few data—not recommended
in 5%-12% of pregnant women, symptomatic gallstones Interferon C Not recommended
occur in only 0.1%-0.3% of pregnancies, and symptoms Ribavirin X Contraindicated—severe fetal
toxicity
usually follow multiple pregnancies rather than during
Penicillamine D Embryopathy but need to maintain
gestation. The commonest clinical presentations are bili- therapy for Wilson disease
ary colic (5% jaundice in pregnancy), gallstone pancreati- Trientine C Limited data—potential toxicity
tis, and, least commonly, acute cholecystitis. The clinical Ursodeoxycholic B Low risk; use in ICP
acid
features of biliary disease and pancreatitis are the same as Beta blockers C (1st trimester) Fetal bradycardia; risk of
in the nonpregnant patient, can occur at any time of ges- D (2/3rd trimesters) intrauterine growth retardation
tation, and may recur during the pregnancy and into the Octreotide B Probably safe—limited data
Vasopressin X Contraindicated, uterine ischemia
postpartum period.31
For patients presenting with intractable biliary colic,
severe acute cholecystitis not responding to conservative
measures or acute gallstone pancreatitis, cholecystectomy the postpartum period. The course of autoimmune hep-
is indicated despite the pregnant state. However, with atitis in pregnancy is highly variable, and stable immuno-
uncomplicated acute biliary colic or acute cholecystitis, suppression should be continued throughout pregnancy;
conservative therapy with bed rest, intravenous fluids, and a flare of activity may occur during pregnancy or, more
antibiotics is successful in more than 80%, with no fetal or likely, in the postpartum period.34 A flare is treated by
maternal mortality and is indicated during the first and increased steroids and azathioprine as necessary. Patients
third trimesters. Surgery is avoided in the first trimester with Wilson’s disease must be adequately treated before
because of the abortion risk with anesthesia and in the pregnancy and continue on therapy throughout to pre-
third trimester, due to an increased risk of premature vent the risk of fulminant Wilson disease.35 The safety of
labor. But, because biliary colic will recur in 50% of preg- drugs for chronic liver disease is shown in Table 5.36
nant patients before delivery, symptomatic patients pre- Unfortunately, the optimal management of pregnancy
senting in the first or second trimester, should undergo with cirrhosis and portal hypertension in the modern era
cholecystectomy, ideally laparoscopic, in the second tri- of obstetrics is undefined. Most patients with advanced
mester, with better pregnancy outcome compared with cirrhosis are amenorrheic and infertile due to hypotha-
medical therapy.32,33 An impacted common bile duct lamic-pituitary dysfunction, but successful pregnancy
stone and worsening gallstone pancreatitis are indications may be completed in those with well-compensated disease
to proceed to endoscopic retrograde cholangiopancre- and only mild portal hypertension. However, increased
atography, sphincterotomy, and stone extraction under maternal and fetal problems can be expected in about
antibiotic coverage; minimization of fluoroscopy and ion- 50% cases with increased fetal loss, and all patients with
izing radiation to the fetus is essential. cirrhosis should be followed by a high-risk obstetrician as
well as a hepatologist. The main risk to the mother is from
The Pregnant Patient with Chronic Liver Disease variceal bleeding (20%-25%), especially during the sec-
Women with chronic liver disease (Table 2) may be of ond trimester or during labor. Other maternal risks are
childbearing age, and an uncomplicated pregnancy with hepatic decompensation, jaundice, thrombocytopenia,
no disease flare is expected in those with mild or inactive and rupture of splenic aneurysms. Patients with known
disease. In hepatitis C, aminotransferases may fall and esophageal varices should be considered for endoscopic
viral RNA increase during pregnancy, with the reverse in therapy, shunt surgery, or even liver transplantation be-
HEPATOLOGY, Vol. 47, No. 3, 2008 HAY 1075

fore pregnancy. In addition, all patients, even if no varices 7. Keitel V, Vogt, C, Haussinger D, Kubitz R. Combined mutations of
canalicular transporter proteins cause severe intrahepatic cholestasis of
before pregnancy, should undergo upper endoscopy for pregnancy. Gastroenterology 2006;131:624-629.
assessment of varices in the second trimester and, if large 8. Floreani A, Carderi I, Paternoster D, Soardo G, Azzaroli F, Esposito W, et
varices are present, then beta blocker therapy is intro- al. Intrahepatic cholestasis of pregnancy; three novel MDR3 gene muta-
duced despite occasional fetal effects (Table 5). Whether tions. Aliment Pharmacol Ther 2006;23:1649-1653.
9. Reyes H, Baez ME, Gonzalez MC, Hernandez I, Palma J, Ribalta J, et al.
prophylactic endoscopic therapy for esophageal varices in Selenium, zinc and copper plasma levels in intrahepatic cholestasis of preg-
early pregnancy is beneficial has not been tested. Acute nancy, in normal pregnancies and in healthy individuals, in Chile. J Hepa-
variceal bleeding is managed endoscopically, as in the tol 2000;32:542-549.
nonpregnant, though vasopressin is contraindicated; little 10. Glantz A, Marschall H-U, Mattsson L-A. Intrahepatic cholestasis of preg-
nancy: relationships between bile acid levels and fetal complication rates.
is known about the use of octreotide in pregnancy. Ascites HEPATOLOGY 2004;40:467-474.
and hepatic encephalopathy are treated in the standard 11. Mazzella G, Nicola R, Francesco A, Patrizia S, Luciano B, Anna M, et al.
way. Ursodeoxycholic acid administration in patients with cholestasis of preg-
nancy: effects on primary bile acids in babies and mothers. HEPATOLOGY
Vaginal deliveries with assisted, short second stage are
2001;33:504-508.
preferable, as abdominal surgery is avoided. But in pa- 12. Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and safety of ursodeoxy-
tients with known large varices, avoidance of labor by cholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy.
caesarean section is recommended to avoid increases in Gastroenterology 2005;129:894-901.
13. Glantz A, Marschall H-U, Lammert F, Mattsson L-A. Intrahepatic cho-
portal pressure and risk of variceal bleeding. Postpartum lestasis of pregnancy: a randomized controlled trial comparing dexameth-
hemorrhage and bacterial infections are reduced by cor- asone and ursodeoxycholic acid. HEPATOLOGY 2005;42:1399-1405.
rection of coagulopathy and prophylactic antibiotics. 14. Binder T, Salaj P, Zima T, Vitek L. Randomized prospective comparative
The pregnant liver transplant recipient represents a study of ursodeoxycholic acid and S-adenosyl-L-methionine in the treat-
ment of intrahepatic cholestasis of pregnancy. J Perinat Med 2006;34:383-
unique clinical situation.37 With the success of liver trans- 391.
plantation, more pregnancies are being reported in liver 15. Ropponen A, Sund R, Riikonen S, Ylikorkala O, Aittomaki K. Intrahe-
recipients, and a carefully planned pregnancy in a stable patic cholestasis of pregnancy as an indicator of liver and biliary diseases: a
healthy patient, beyond the first 2 years after orthotopic population-based study. HEPATOLOGY 2006;43:723-728.
16. Baxter JK, Weinstein L. HEELP syndrome: the state of the art. Obstet
liver transplantation, can have excellent outcome for fe- Gynecol Surg 2004;59:838-845.
tus, mother, and graft. However, this is still a high-risk 17. Barton JR, Sibai BM. Diagnosis and management of hemolysis, elevated
pregnancy with increased fetal prematurity and dysmatu- liver enzymes, and low platelets syndrome. Clin Pernatol 2004;31:807-
833.
rity; also, there is some risk to the allograft from acute
18. Sibai BM. Imitators of severe preeclampsia. Obstet Gynecol 2007;109:
cellular rejection or recurrent viral hepatitis; as a result, it 956-966.
is imperative to closely monitor immunosuppression with 19. Ibdah JA. Acute fatty liver of pregnancy: an update on pathogenesis and
adjustment in calcineurin inhibitor doses as needed for clinical implications. World J Gastroenterol 2006;46:7397-7404.
20. Sibai BM. Diagnosis, controversies, and management of the syndrome of
the increased blood volume in the second half of preg-
hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol
nancy. Liver function must be monitored regularly and all 2004;103:981-991.
liver abnormalities investigated and treated as aggressively 21. Van Runnard Heimel PJ, Franx A, Schobben AFAM, Huisjes AJM, Derks
as in the nonpregnant, especially acute cellular rejection. JB, Bruinse HW. Corticosteroids, pregnancy, and HELLP syndrome: a
review. Obstet Gynecol Surg 2004;60:57-70.
22. Shames BD, Fernandez LA, Sollinger HW, Chin LT, D’Alessandro AM,
References Knechtle SJ, et al. Liver transplantation for HELLP syndrome. Liver
Transpl 2005;11:224-228.
1. Ch’ng CL, Morgan M, Hainsworth I, Kingham JG. Prospective study of
23. Reyes H. Acute fatty liver of pregnancy. Clin Liver Dis 1999;3:69-81.
liver dysfunction in pregnancy in Southwest Wales. Gut 2002;51:876-
24. Borwning MF, Levy HL, Wilkins-Haug L, Larson C, Shih VE. Fetal fatty
880.
acid oxidation defects and maternal liver disease in pregnancy. Obstet
2. Kuscu NK, Koyuncu F. Hyperemesis gravidarum: current concepts and
management. Postgrad Med J 2002;78:76-79. Gynecol 2006;107:115-120.
3. Fell DB, Dodds L, Joseph KS, Allen VM, Butler B. Risk factors for hy- 25. Fesenmeier MF, Coppage KH, Lambers DS, Barton JR, Sibai BM. Acute
peremesis gravidarum requiring hospital admission during pregnancy. Ob- fatty liver of pregnancy in 3 tertiary care centers. Am J Obstet Gynecol
stet Gnecol 2006;107:277-284. 2005;192:1416-1419.
4. Dann AT, Kenyon AP, Seed PT, Poston L, Shennan AH, Tribe RM. 26. Goodin B. An overview of expanded newborn screening for inborn errors
Glutathione S-transferase and liver function in intrahepatic cholestasis of of metabolism. Practical Gastroenterol 2006;41:34-51.
pregnancy and pruritus gravidarum. HEPATOLOGY 2004;40:1406-1414. 27. Bellig LL. Maternal acute fatty liver of pregnancy and the associated risk for
5. Dixon PH, Weerasekera N, Linton KJ, Donaldson O, Chambers J, Egg- long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) defi-
inton E, et al. Heterozygous MDR3 missense mutation associated with ciency in infants. Adv Neonatal Care 2004;4:26-32.
intrahepatic cholestasis of pregnancy: evidence for a defect in protein traf- 28. Hay JE. Viral hepatitis in pregnancy. Viral Hepatitis Reviews 2000;6:205-
ficking. Hum Mol Genet 2000;9:1209-1217. 215.
6. Schneider G, Paus TC, Kullak-Ublick GA, Meier PJ, Wienker TF, Lang T, 29. Keefe EB, Dieterich DT, Han S-HB, Jacobson IM, Martin P, Schiff ER, et
et al. Linkage between a new splicing site mutation in the MDR3 alias al. A treatment algorithm for the management of chronic hepatitis B virus
ABCB4 gene and intrahepatic cholestasis of pregnancy. HEPATOLOGY infection in the United States: an update. Clin Gastroenterol Hepatol
2007;45:150-158. 2006;4:936-962.
1076 HAY HEPATOLOGY, March 2008

30. Ko CW, Beresford AA, Schulte SJ, Matsumoto AM, Lee SP. Incidence, 34. Candia L, Marquez J, Espinosa LR. Autoimmune hepatitis and pregnancy:
natural history, and risk factors for biliary sludge and stones during preg- a rheumatologist’s dilemma. Semin Arthritis Rheum 2005;35:49-56.
nancy. HEPATOLOGY 2005;41:359-365. 35. Scheinberg IH, Jaffe ME, Sternlieb I. The use of trientine in preventing the
31. Yates MR III, Baron TH. Biliary tract disease in pregnancy. Clin Liver Dis effects of interrupting penicillamine therapy in Wilson’s disease. N Engl
1999;3:131-146. J Med 1987;317:209-213.
32. Lu EJ, Curet MJ, El-Sayed YY, Kirkwood KS. Medical versus surgical 36. Mahadevan U. American gastroenterological association institute technical
management of biliary tract disease in pregnancy. Am J Surg 2004;188: review on The use of gastrointestinal medications in pregnancy. Gastroen-
755-759. terology 2006;131:283-311.
33. Rollins MD, Chan KJ, Price RR. Laparoscopy for appendicitis and chole- 37. Armenti VT. Pregnancy after liver transplantation. Liver Transpl 2006;12:
lithiasis during pregnancy. Surg Endosc 2004;18:237-241. 1037-1039.