Liver disease in pregnancy.pdf

Online Submissions: wjg.wjgnet.com World J Gastroenterol 2009 February 28; 15(8): 897-906

wjg@wjgnet.com World Journal of Gastroenterology ISSN 1007-9327

EDITORIAL

Liver disease in pregnancy

Noel M Lee, Carla W Brady

Noel M Lee, Department of Medicine, Duke University

Medical Center, Durham, NC 27710, United States

Carla W Brady, Division of Gastroenterology, Duke University

Medical Center, Durham, NC 27710, United States

Author contributions: Lee NM and Brady CW contributed to

this paper.

Correspondence to: Carla W Brady, MD, MHS, Division of

Gastroenterology, Duke University Medical Center, Box 3913,

Durham, NC 27710, United States. brady017@mc.duke.edu

Telephone: +1-919-6843262 Fax: +1-919-6848264

Received: December 25, 2008 Revised: February 1, 2009

Accepted: February 8, 2009

Published online: February 28, 2009

Lee NM, Brady CW. Liver disease in pregnancy. World J

Gastroenterol 2009; 15(8): 897-906 Available from: URL:

http://www.wjgnet.com/1007-9327/15/897.asp DOI: http://

dx.doi.org/10.3748/wjg.15.897

INTRODUCTION

Liver diseases in pregnancy are usually categorized into

liver disorders that occur only in pregnancy and liver

diseases that occur coincidentally in pregnancy. There

are five liver disorders that are pregnancy-specific:

hyperemesis gravidar um, preeclampsia/eclampsia,

syndrome of hemolysis, elevated liver tests, and low

platelets (HELLP), acute fatty liver of pregnancy, and

intrahepatic cholestasis of pregnancy. These disorders

typically occur at specific times during the course of

pregnancy (Table 1), and they may lead to significant

maternal and fetal morbidity and mortality. There is

a role for certain medications in these disorders, but

the risks and benefits of the use of such therapies

must be considered (Table 2). Delivery of the fetus

usually terminates the progression of these disorders.

Chronic liver diseases that occur coincidentally in

pregnancy include cholestatic liver disease, autoimmune

hepatitis, Wilson disease, and viral hepatitis. Some of

the pharmacological agents used to treat chronic liver

disease may be used in pregnancy, but there are other

agents whose teratogenicity precludes use in pregnancy.

Although uncommon, women with cir rhosis may

become pregnant and may have a relatively benign

course of pregnancy. However, the presence of portal

hypertension may contribute to maternal complications.

Given the complexity of these disorders and the

potential risks to both the mother and the fetus, it is

important that obstetricians and gastroenterologists/

hepatologists collaborate in providing management of

liver disease in pregnancy.

Abstract

Liver diseases in pregnancy may be categorized into

liver disorders that occur only in the setting of preg-

nancy and liver diseases that occur coincidentally with

pregnancy. Hyperemesis gravidarum, preeclampsia/ec-

lampsia, syndrome of hemolysis, elevated liver tests

and low platelets (HELLP), acute fatty liver of preg-

nancy, and intrahepatic cholestasis of pregnancy are

pregnancy-speciic disorders that may cause elevations

in liver tests and hepatic dysfunction. Chronic liver dis-

eases, including cholestatic liver disease, autoimmune

hepatitis, Wilson disease, and viral hepatitis may also

be seen in pregnancy. Management of liver disease

in pregnancy requires collaboration between obstetri-

cians and gastroenterologists/hepatologists. Treatment

of pregnancy-specific liver disorders usually involves

delivery of the fetus and supportive care, whereas

management of chronic liver disease in pregnancy is

directed toward optimizing control of the liver disorder.

Cirrhosis in the setting of pregnancy is less commonly

observed but offers unique challenges for patients and

practitioners. This article reviews the epidemiology,

pathophysiology, diagnosis, and management of liver

diseases seen in pregnancy.

HYPEREMESIS GRAVIDARUM

Hyperemesis gravidarum (HG) is deined as intractable

nausea and vomiting during pregnancy that often leads

to fluid and electrolyte imbalance, weight loss of 5%

or greater, and nutritional deiciency requiring hospital

admission [1] . The incidence of HG varies from 0.3%-2%

of all live births [2] . HG often occurs between the 4th and

10th wk of gestation and usually resolves by the 20th wk.

Key words: Liver disease; Pregnancy; Maternal out-

come; Fetal outcome; Cesarean section; Cholestasis;

Viral hepatitis.

Peer reviewer: Mauro Bernardi, Professor, Internal Medicine,

Cardioangiology, Hepatology, University of Bologna, Semeiotica

Medica-Policlinico S. Orsola-Malpighi-Via Massarenti, 9,

Bologna 40138, Italy

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Table 1 Features of pregnancy-associated liver diseases

Disease

Timing of occurrence Clinical features

Histology

Hyperemesis gravidarum

First trimester

Nausea, vomiting, weight loss, nutritional

deiciency

No distinct histopathology, may see

normal tissue or hepatocyte necrosis, bile

plugs, steatosis

Preeclampsia/eclampsia

Second/third trimester Hypertension, edema, proteinuria,

neurological deicits (headaches, seizures,

coma)

Periportal hemorrhage, necrosis, ibrin

deposits, may see microvesicular fat

Syndrome of hemolysis, elevated liver

tests, and low platelets (HELLP)

Third trimester

Abdominal pain, nausea, vomiting, edema,

hypertension, proteinuria

Necrosis, periportal hemorrhage, ibrin

deposits

Acute fatty liver of pregnancy (AFLP) Third trimester

Nausea, vomiting, abdominal pain, fatigue,

jaundice

Microvesicular fat

Intrahepatic cholestasis of pregnancy

(ICP)

Second/third trimester Pruritus, jaundice, fatigue, abdominal pain,

steatorrhea

Centrilobular cholestasis, no

inlammation

Table 2 Safety of drugs used in pregnancy-associated liver diseases

Drug

FDA pregnancy category Comments

Antiemetics

Promethazine

Possible respiratory depression if drug is administered near time of delivery

Metoclopramide

Available evidence suggests safe use during pregnancy

Ondansetron

Additional studies are needed to determine safety to the fetus, particularly during the irst

trimester

Prochlorperazine C

There are isolated reports of congenital anomalies; however, some included exposures to other

drugs. Jaundice, extrapyramidal signs, hyper-/hyporelexes have been noted in newborns

Antihypertensives

ACE inhibitors

C/D

First trimester exposure to ACE inhibitors may cause major congenital malformations

Second and third trimester use of an ACE inhibitor is associated with oligohydramnios and

anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate

Beta blockers

C/D

Fetal bradycardia, hypotension, risk of intrauterine growth retardation

Calcium channel blockers C

Teratogenic and embryotoxic effects have been demonstrated in small animals. There are no

adequate and well-controlled studies in pregnant women

Anticoagulation

Aspirin

C (1st/2nd trimesters)

D (3rd trimester)

Adverse effects in the fetus include intrauterine growth retardation, salicylate intoxication,

bleeding abnormalities, and neonatal acidosis. Use of aspirin close to delivery may cause

premature closure of the ductus arteriosus. Data have shown low-dose aspirin (60-150 mg/

day) may be safe in pregnancy

Enoxaparin

No adequate and well-controlled studies using enoxaparin. Postmarketing reports include

congenital abnormalities and also fetal death

Heparin

Does not cross the placenta

Intrahepatic cholestasis

Ursodeoxycholic acid

Relatively low risk

S-adenosyl-L-methionine Not evaluated by FDA

Relatively low risk

Cholestyramine

Cholestyramine is not absorbed systemically, but may interfere with vitamin absorption

United States Food and Drug Administration (FDA) pregnancy categories: Category A: Well-controlled studies failed to show a risk to the fetus in the irst

trimester of pregnancy (and there is no evidence of risk in the second or third trimesters). Category B: Animal reproduction studies failed to show a risk

to the fetus, and there are no adequate studies in pregnant women. Category C: Animal reproduction studies have shown an adverse effect on the fetus.

There are no adequate studies in humans, but potential beneits may warrant use of the drug in pregnant women despite potential risks. Category D: There

is evidence of human fetal risk based on data from investigational or marketing experience or studies in humans. However, the potential beneits may

warrant use of the drug in pregnant women despite potential risks. Category X: Data have demonstrated fetal abnormalities in animals and humans, and/

or there is positive evidence of human fetal risk based on data from investigational or marketing experience. The risks of the use of the drug in pregnant

women outweigh potential beneits.

However, in approximately 10% of HG patients,

symptoms continue through pregnancy and resolve only

with delivery of the fetus [3] .

HG remains a poorly understood condition and most

likely involves a combination of hormonal, immunologic,

and genetic factors. Data have shown increased levels

of human chorionic gonadotropin (HCG) in HG, and

proposed mechanisms for the effect of HCG on HG

include stimulation of secretory processes of the upper

gastrointestinal tract and stimulation of the thyroid

gland [4-7] . Other proposed factors contributing to HG

include elevations of estrogen, decreases in prolactin

levels, and overactivity of the hypothalamic-pituitary-

adrenal axis [6] . It has been speculated that immune and

inflammatory mechanisms also contribute to HG. In

particular, increased levels of tumor necrosis factor-

alpha have been observed in HG patients [8] . Higher

levels of immunoglobulin G (IgG), immunoglobulin M

(IgM), C3, and C4 levels, as well as increased lymphocyte

counts and natural killer and extra-thymic T cell levels

have been observed in HG patients [9,10] .

Liver involvement is seen in about 50%-60% of

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Lee NM et al. Liver disease in pregnancy

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patients with HG [11] . Most commonly seen are mild

ser um aminotransferases elevations, but there are

reported cases of severe transaminase elevations (alanine

aminotransferase (ALT) levels 400 to over 1000 U/L) [12] .

Mild hyperbilirubinemia with mild jaundice can be seen

as well. Other complications include disturbances in

electrolytes and in water and acid-base balance that can

usually be treated adequately with hydration.

While mater nal morbidity is well documented,

the effects of HG on the fetus are less clear. Some

data sug gest no differences between fetuses bor n

to mothers with HG and non-HG mothers [13] , but

other data show increased rates of fetal abnormalities

including undescended testicles, hip dysplasia, and

Down Syndrome [2] . In one large cohort study, infants

of HG mothers were found to have lower birth weights

and higher rates of being small for gestational age [14] .

However, no signiicant effect on perinatal survival has

been shown.

Treatment of HG is primarily supportive. Patients

should avoid triggers that aggravate nausea, and eat

small, frequent, low-fat meals. Intravenous fluids,

thiamine and folate supplementation, and antiemetic

therapy may be administered. Promethazine is a irst-line

agent, but other medications such as metoclopramide,

ondansetron, and steroids have also been used. Enteral

feeding is effective, and in severe cases, total parenteral

nutrition may be used cautiously.

hemorrhage, liver cell necrosis, and in severe cases,

infarction; these changes are likely due to vasoconstriction

of hepatic vasculature [17] . Microvesicular fatty iniltration

has also been observed in some cases of preeclampsia,

suggesting a possible overlap with acute fatty liver of

pregnancy [18] .

Maternal mortality from preeclampsia/eclampsia is

rare in developed countries, but may approach 15%-20%

in developed countries [15] . Likewise, the fetal mortality

rate is rare, occurring in 1%-2% of births. Maternal and

neonatal morbidity may include placental abruption,

preterm delivery, fetal growth restriction or maternal

renal failure, pulmonary edema, or cerebrovascular

accident.

The only effective treatment for preeclampsia is

delivery of the fetus and placenta. However, if mild

preeclampsia is evident before fetal lung maturity at

3 6 w k g e s t a t i o n , o n e m a y c o n s i d e r e x p e c t a n t

management with intensive monitoring. Pharmacological

agents used in preeclampsia include antihypertensives

such as calcium channel blockers and low-dose aspirin.

Magnesium sulfate may be administered if eclampsia

develops.

HEMOLYSIS, ELEVATED LIVER TESTS

AND LOW PLATELETS

HELLP syndrome is a multisystemic disorder of

pregnancy involving hemolysis, elevated liver tests, and

low platelets. About 70% of cases occur antenatally,

and most cases occur during the last trimester of

pregnancy [19] . The pathogenesis of HELLP is thought

to involve alterations in platelet activation, increases in

proinflammatory cytokines, and segmental vasospasm

with vascular endothelial damage. An association

with a defect in long-chain 3-hydroxyacyl-coenzyme

A dehydrogenase (LCHAD) has also been described,

suggesting a possible overlap of HELLP syndrome and

acute fatty liver of pregnancy.

Most patients present with right upper quadrant

abdominal pain, nausea, vomiting, malaise, and edema

with signiicant weight gain. Less commonly associated

conditions include renal failure (with increased uric acid),

diabetes insipidus, and antiphospholipid syndrome.

Other late findings of HELLP include disseminated

i n t r a v a s c u l a r c o a g u l o p a t h y ( D I C ) , p u l m o n a r y

edema, placental abruption, and retinal detachment.

Hypertension and proteinuria may be seen, but in

20% of patients, hypertension is absent [19] . Laboratory

indings include hemolysis with increased bilirubin levels

(usually less than 5 mg/dL) and lactate dehydrogenase

(LDH) levels greater than 600 IU/L, moderately elevated

aspartate aminotransferase (AST) and ALT levels (200

IU/L to 700 IU/L), and thrombocytopenia (less than

100 000/mL). In early stages, prothrombin time and

activated partial thromboplastin time are normal, but

in later phases, DIC may be present with increased

levels of ibrin degradation products and D-dimer, and

thrombin-antithrombin complexes. The pathogenesis

PREECLAMPSIA/ECLAMPSIA

Preeclampsia is a disorder defined by the triad of

hypertension, edema, and proteinuria. It affects about

5%-10% of all pregnant women and usually occurs

late in the second trimester or in the third trimester. In

preeclampsia, hypertension is deined as having a systolic

pressure greater than 140 mmHg and a diastolic pressure

greater than 90 mmHg on at least two occasions that

are at least 4 to 6 h apart in a previously normotensive

patient, and proteinuria is deined as equal to or greater

than 300 mg of protein in a 24 h urine collection or

1+ protein or greater on urine dipstick testing of two

random urine samples collected at least 4 to 6 h apart [15] .

Eclampsia involves all features of preeclampsia and

includes neurologic symptoms such as headaches,

visual disturbances, and seizures or coma. Risk factors

for preeclampsia and eclampsia include nulliparity,

extremes of maternal age, insulin resistance, obesity, and

infection [15,16] . The pathophysiology of preeclampsia/

eclampsia is thought to involve procoagulant and

p r o i n f l a m m a t o r y s t a t e s t h a t c r e a t e g l o m e r u l a r

endotheliosis, increased vascular permeability, and a

systemic inflammatory response that results in end-

organ damage and hypoperfusion.

Abnormal laboratory values include a 10- to 20-fold

elevation in aminotransferases, elevations in alkaline

phosphatase levels that exceed those normally observed

in pregnancy, and bilir ubin elevations of less than

5 mg/dL. Liver histolog y generally shows hepatic

sinusoidal deposition of fibrin along with periportal

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of hepatic damage in HELLP syndrome involves

intravascular ibrin deposition and sinusoidal obstruction

that can lead to hepatic hemorrhage and infarction.

Histologically, one may see focal hepatocyte necrosis,

periportal hemorrhage, and ibrin deposits.

The reported maternal mortality from HELLP

is 1%, and the perinatal mortality rate ranges from

7%-22% and may be due to premature detachment

of placenta, intrauterine asphyxia, and prematurity [11] .

Other complications of HELLP syndrome include

acute renal failure, adult respiratory distress syndrome,

pulmonary edema, stroke, liver failure, and hepatic

infarction. The only definitive treatment for HELLP

s y n d r o m e i s d e l ive r y. I f t h e p r e g n a n t wo m a n i s

greater than 34 wk gestation, immediate induction is

recommended. If gestational age is between 24 wk and

34 wk, corticosteroids are administered to accelerate

fetal lung maturity in preparation for delivery 48 h

later. After delivery, close monitoring of the mother

sh o uld co n tinue, a s da ta h ave sh own wo r sen in g

thrombocytopenia and increasing LDH levels up to

48 h postpartum [20] . However, most laboratory values

(transaminases, bilirubin, LDH) normalize in 48 h, and

the presence of persistent or worsening laboratory

abnor malities by the four th postpar tum day may

signal postpartum complications [21] . For patients with

ongoing or newly developing postpartum symptoms

of HELLP, modalities such as antithrombotic agents,

plasmapheresis, and dialysis may be employed.

moderate to severe hypoglycemia, hepatic encephalopathy,

a n d co a g u l o p a thy. A p p r ox i m a tel y 5 0 % o f th es e

patients will also have signs of preeclampsia, although

hypertension is generally not severe [24] . Laboratory indings

include elevations in aminotransferase levels, which

may range from being mildly elevated to approaching

1000 IU/L. Many cases involve neutrophilic leukocytosis,

and as the disease progresses, thrombocytopenia (with or

without DIC) and hypoalbuminemia may occur. Rising

uric acid levels and impaired renal function may also be

seen.

Since AFLP can lead to signiicant maternal and fetal

morbidity and mortality, prompt diagnosis must be made.

The most deinitive test is liver biopsy. Histopathologic

indings reveal swollen, pale hepatocytes in the central

zones with microvesicular fatty iniltration that can be

identified on frozen section with oil red O staining.

Electron microscopy may also show megamitochondria

and paracrystalline mitochondrial inclusions. Although

liver biopsy may be helpful, it is often not done due to

the presence of coagulopathy. Imaging studies, including

ultrasound and computed tomog raphy (CT), are

inconsistent in detecting fatty iniltration [25,26] . Therefore,

the diagnosis of AFLP is usually made on clinical and

laboratory indings.

As with most pregnancy-associated liver diseases,

the treatment of AFLP involves deliver y of the

fetus. However, many laboratory abnormalities may

persist after delivery and may initially worsen during

the first postpartum week. In rare cases, patients will

progress to fulminant hepatic failure with need for

liver transplantation [27] . In addition to monitoring the

mother closely, careful attention should also be paid to

the infant given the increased risk of cardiomyopathy,

neuropathy, myopathy, nonketotic hypoglycemia, hepatic

failure, and death associated with fatty acid oxidation

defects in newborns. Finally, affected patients should be

screened for defects in fatty acid oxidation as recurrence

in subsequent children is 25%, and recurrence of AFLP

in mothers is also possible [11,23] .

ACUTE FATTY LIVER OF PREGNANCY

Acute fatty liver of pregnancy (AFLP) is a rare but seri-

ous maternal illness that occurs in the third trimester

of pregnancy. With an incidence of 1 in 10 000 to 1 in

15 000 pregnancies, it has a maternal mortality rate of

18% and a fetal mortality rate of 23% [17,22] . AFLP is

more commonly seen in nulliparous women and with

multiple gestation.

The pathophysiology of AFLP involves defects in

mitochondrial fatty acid beta-oxidation. Under normal

circumstances, an individual that is heterozygous for

enzymatic mutations in fatty acid oxidation will not

have abnor mal fatty oxidation. However, when a

heterozygous woman has a fetus that is homozygous

for such mutations, fetal fatty acids accumulate and

return to the mother’s circulation. The extra load of

long-chain fatty acids and subsequent triglyceride

accumulation lead to hepatic fat deposition and impaired

hepatic function in the mother. A deficiency in long-

chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) is

thought to be associated with the development of AFLP.

LCHAD is a component of an enzyme complex known

as the mitochondrial trifunctional protein (MTP), and it

is believed that the G1528C and E474Q mutations of

the MTP are responsible for causing LCHAD deiciency

that subsequently leads to AFLP [23] .

Patients with AFLP typically present with a 1 to 2 wk

history of nausea, vomiting, abdominal pain, and fatigue.

Jaundice occurs frequently, and some women experience

I N T R A H E P A T I C C H O L E S T A S I S O F

PREGNANCY

Intrahepatic cholestasis of pregnancy (ICP), also

known as obstetric cholestasis, is a rare pregnancy-

speciic liver condition that occurs in the late second or

third trimester and has a prevalence of about 1/1000

to 1/10 000. It is signiicantly more common in South

Asia, South America (especially Chile), and Scandinavian

countries. ICP is also more common in women of

advanced maternal age, multiparous women, and in

women with a personal history of cholestasis with oral

contraceptive use [28] . The prognosis for women with

ICP is usually good, but it is associated with increased

fetal morbidity and mortality, particularly from chronic

placental insuficiency, preterm labor, fetal distress, and

intrauterine death [29] .

The etiolog y of ICP is likely multifactorial and

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Lee NM et al. Liver disease in pregnancy

901

may include genetic, hor monal and environmental

variations. Mutations in the phospholipid translocator

known as the ATP-cassette transporter B4 (ABCB4)

or multidrug resistant protein-3 (MDR3) are associated

with the development of ICP [30] . Changes induced by

these genetic mutations lead to increased sensitivity to

estrogen, which impairs the sulfation and transportation

of bile acids. The pregnancy-associated increase in

estrogen may also contribute to ICP. This is supported

by the fact that women with multiple gestations and

proportional increases in estrogens have an increased

r i s k o f I C P [ 3 1 ] . E s t r o g e n s a r e t h o u g h t t o a c t o n

hepatocytes by decreasing membrane per meability

and bile acid uptake by the liver. The maternal-to-

fetal transfer of bile acids across the placenta becomes

impaired, leading to potentially toxic bile acid levels

in the fetus [32] . The elevation in bile acid levels is also

thought possibly to affect myometrial contractility and

to cause vasoconstriction of chorionic veins in the

placenta, which may contribute to preterm deliveries and

fetal distress seen in ICP [33,34] .

Maternal complications are much less severe. The

classic symptom is pruritus that usually begins in the

second or third trimester. It usually occurs in the palms

and soles and may progress to the rest of the body, and

the pruritus is often worse at night. Pruritus may be

severe but is usually relieved within 48 h after delivery of

the fetus. Jaundice occurs in approximately 10%-25% of

patients and may appear within the irst four weeks of

the onset of pruritus [35] . Cholelithiasis and cholecystitis

have been observed to occur with greater frequency in

women with ICP [36] . Other symptoms include fatigue,

anorexia, epigastric pain, and steatorrhea due to fat

malabsorption. Malabsorption may also lead to vitamin

K deficiency leading to prolonged prothrombin times

and postpartum hemorrhage.

Abnormal laboratory findings include elevated total

bile acid levels up to 10- to 25-fold, with an increase

in cholic acid and a decrease in chenodeoxycholic

acid leading to a marked elevation in the cholic/

chenodeoxycholic acid ratio. The glycine/taurine

ratio is also reduced. Other findings include mild

aminotransferase elevations, which are seen in about 60%

of ICP patients. AST and ALT levels rarely exceed two

times the upper limits of normal, but may approach 10-

to 20-fold elevations in rare cases. Bilirubin levels may be

elevated, but are usually less than 6 mg/dL. Serum alkaline

phosphatase levels may also be elevated, but this is usually

less helpful to follow given typical alkaline phosphatase

elevations seen in pregnancy. Histopathologic indings on

liver biopsy include nondiagnostic centrilobular cholestasis

without inlammation and bile plugs in hepatocytes and

canaliculi [17] . Liver biopsy is usually not required to make

the diagnosis of ICP.

The treatment of choice for ICP is ursodeoxycholic

acid (UDCA), which helps to relieve pr uritus and

improve liver test abnor malities. It is unclear how

UDCA works, but it is felt that UDCA conjugates help

target and insert key transporter proteins, such as MRP2

(ABCC2) or bile salt export pumps (ABCB11) into

the canalicular membranes [37] . Data have also shown

that UDCA increases expression of placental bile acid

transporters, which may allow for improved bile acid

transfer [38] . Other medications, such as cholestyramine

and S-adenosyl-L-methionine, have been associated

with improving pruritus and normalizing biochemical

proiles, but studies have found UCDA to be superior

over cholestyramine and S-adenosyl-L-methionine [39,40] .

Dexamethasone has also been used, but has shown to be

much less effective in reducing bile acids and bilirubin

and ineffective in relieving pruritus [41] . Antihistamines are

frequently used to alleviate pruritus, and vitamin K and

other fat-soluble vitamin supplementation should also be

administered if fat malabsorption is suspected.

GALLSTONES

The for mation of biliar y sludge and g allstones is

associated with parity. The prevalence of gallstones in

pregnancy is 18.4%-19.3% in multiparous women and

6.9%-8.4% in nulliparous women [42] . The etiology for

an increased prevalence of biliary sludge and gallstones

in pregnancy is multifactorial. Increased estrogen levels,

especially in the second and third trimesters, lead to

increased cholesterol secretion and supersaturation

of bile, and increased progesterone levels cause a

decrease in small intestinal motility [43] . Also, fasting

and postprandial gallbladder volumes are larger, and

emptying time is reduced [44] . The large residual volume

of supersaturated bile in the pregnant woman leads

to biliary sludge and the formation of gallstones. Pre-

pregnancy factors observed to be associated with the

development of gallstones in pregnancy include a

high body mass index, high serum leptin levels, low

high-density lipoprotein (HDL) levels, and insulin

resistance [45,46] .

Pregnant women with gallstones may present with

right upper quadrant pain that may radiate to the lank,

scapula, or shoulder. They may also report nausea,

vomiting, anorexia, fatty food intolerance, and low-

g rade fever. Conser vative medical management is

recommended initially, especially during the first and

third trimesters, in which surgical intervention may

confer risk of abortion or premature labor, respectively.

Medical management involves intravenous f luids,

correction of electrolytes, bowel rest, pain management,

and broad spectrum antibiotics. However, relapse rates

(40%-90%) are high during pregnancy; thus, surgical

inter vention may be war ranted [47,48] . Laparascopic

cholecystectomy in the second trimester is preferred [49] .

Endoscopic retrog rade cholangiopancreatog raphy

(ERCP) may also be required if there are concerns about

choledocholithiasis, and this can be performed safely

in pregnancy by shielding the fetus and minimizing

luoroscopy time [50] .

PRIMARY BILIARY CIRRHOSIS

Primary biliary cirrhosis (PBC) is a chronic cholestatic

disease that affects persons in their 30s to 60s [51] . It is

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