LIVER IN PREGNANCY

By
Amr Abd Elmoty
 THE LIVER IN PREGNANCY
INTRODUCTION
The liver is influenced by the physiologic state of pregnancy and
thus abnormalities that may usually signify hepatic dysfunction may not
represent actual liver damage and should be interpreted with caution.

In addition, the anatomic location of the liver is changed because it is

shifted superiorly as pregnancy progresses secondary to the enlarging
gravid uterus.

Therefore liver that is palpable below the right subcostal margin

during pregnancy usually indicates an ongoing pathologic hepatic
process.
 Liver diseases unique to pregnancy can be classified:

1. Hyperemesis gravidarum (HG)—Usually occurs in the first trimester

of pregnancy and is not associated with preeclampsia.

2. The syndrome of hemolysis, elevated liver enzymes, and low

platelets (HELLP)—Usually occurs in the third trimester and is
associated with preeclampsia.

3. Intrahepatic cholestasis of pregnancy (ICP)—Can occur at any time

during pregnancy and is not associated with preeclampsia.

4. Acute fatty liver disease of pregnancy (AFLP)—Usually occurs in the

third trimester and is associated with preeclampsia.
 Associated with Not associated with
preeclampsia/eclampsia preeclampsia/eclampsia

Help syndrome Hyperemesis gravidarum

Acute fatty liver disease

Intrahepatic cholestasis of pregnancy
of pregnancy

First trimester Second trimester Third trimester

Hyperemesis
Help syndrome
gravidarum
Acute fatty liver of
pregnancy
Intrahepatic cholestasis of pregnancy
 Changes in liver anatomy and function during normal
pregnancy Liver anatomy and histology

Anatomically, the gross appearance of the liver does not change.

Histologically, subtle changes that include:

1. Increased variability in hepatocyte size and shape.

2. Enhanced granularity of hepatocyte cytoplasm.
3. Increased numbers of cytoplasmic fat vacuoles in centrilobular
hepatocytes.
4. Hypertrophied Kupffer cells.
5. Hepatocytes exhibit proliferation of the smooth and rough
endoplasmic reticula; and giant mitochondria .
 Hemodynamic and hepatic blood flow
• Pregnancy is characterized by an increase in extracellular and plasma
volume of 50% to 70%.
• Red blood cell mass also increases, but the increase is moderate
(20% to 30%) and delayed.
• As a consequence hemodilution occurs.
• This phenomenon of hemodilution should be considered during
interpretation of all serum concentrations during pregnancy.
• Cardiac output increases to a similar degree as the blood volume until
the second trimester, and then decreases and normalizes near term.
• Absolute hepatic blood flow remains unchanged, but the percentage
of cardiac output to the liver decreases.
 CHANGES IN LIVER FUNCTION
Drug Metabolism
Various hemodynamic changes during pregnancy, such as the increase
in blood volume, cardiac output, and glomerular filtration rate, may
contribute to altered drug metabolism, disposition, and clearance.
Gastrointestinal absorption or bioavailability of drugs may vary
because of changes in gastric secretion and motility.
Drug properties such as lipid solubility, protein-binding
characteristics, and ionization constant influence the placental passage
of drugs.
Pregnancy alters the ability of a drug to be distributed within the body,
due to reduced concentrations of both albumin and α1-acid
glycoprotein.
 CHANGES IN LIVER FUNCTION
Drug Metabolism
Moreover, the increase in body weight in late pregnancy results in a
decrease in dose per kilogram.
Caffeine metabolism is reduced during pregnancy because of
decreased activity of CYP1A2.
The activity of P-450 2A6 is increased and drugs such as nicotine
exhibit substantially lower serum concentrations.
The activity of CYP3A4 is increased and drugs such as nifedipine,
catbamazepine, midazolam, indinavir, lopinavir, and ritonavir,
metoprolol, fluoxetine, citalopram, and nortriptyline may exhibit
increased clearance.
 CHANGES IN LIVER FUNCTION
Drug Metabolism
The dose of selective serotonin re-uptake inhibitors (SSRIs) must be
increased to maintain efficacy in pregnancy.
Furthermore, glomerular filtration rate is increased in pregnancy
because of an increase in cardiac output; therefore drugs that are
eliminated by renal mechanisms have increased clearance rates, such as
ampicillin, cefuroxime, ceftazidime, cephradine, cefazolin, piperacillin,
atenolol, sotalol, digoxin and lithium.
Both estrogen intake and pregnancy impair hepatic activity of
glucuronosyltransferase (UGT).
 Category by class in pregnancy for
common drug therapy in liver disease
FDA category B FDA Category C FDA Category D FDA category X
(no risk to foetus) (adverse effect of (foetal risk/but benifical to (leads to foetal
foetus) mother) abnormalities)
Ursodeoxycholic Interferon alfa Azathioprine Ribavirin
acid
Octreotide Prednisone D- Penicillamine Vasopressin
Acyclovir Lamivudine Warfarin
Adefovir
Entecavir
Telbivudine
Tenofovir
Mycophenolate
mofetil
Tacrolimus
Sirolimus
Trientine
Zinc sulfate
Cyclosporine
Propranolol (in first Proparanolol (in second/ third
trimester) trimester)
Nadolol (in first Nadolol (in second/ third
trimester) trimester)
Heparin
 SERUM PROTEINS AND LIPIDS
A. Normally, up to 10 g of albumin is produced and secreted by the liver
daily. Serum albumin concentrations decrease during the second
trimester reaching concentrations approximately 70% to 80% of normal
values at the time of delivery, secondary to hemodilution. By contrast,
there is an increase in serum concentration of some proteins such as α2-
macroglobulin, α1-antritrypsin, and ceruloplasmin.

B. Levels of fibronogen and most coagulation factors (II, VIII, IX and XII)
increase, protein S levels decrease, and fibrinolysis is inhibited. These
physiologic changes in hemostasis limit bleeding during delivery but
are associated with an increased risk of thromboembolism during
pregnancy and the postpartum period.
 SERUM PROTEINS AND LIPIDS
C. Prothrombin time (PT) is generally not affected by pregnancy and
any change in the prothrombin time during pregnancy should be
considered pathologic and warrants further investigation.

D. Serum cholesterol, triglyceride, and phospholipid concentrations

increase in late pregnancy by 25% to 50%, whereas concentrations of
serum triglycerides increase twice to four times.
 Changes in laboratory profile
during normal pregnancy
Test Change
WBCs Increased
Hemoglobin Decreased
Platelets -
Albumin Dcreased
Aminotransferase -
Alkaline phosphatase Increased
GGT -
Bilirubin -/ Decreased
Prothrombin time -
Fibrinogen Increased
Globulins Increased in α- and β-globulins; decreased in γ-globulin
Glucose -
Creatinine -
Uric acid -
Bile acid -
Cholesterol Increased
Triglycerides Increased
α-Fetoprotein Increased
Ceruloplasmin Increased
Ferritin Increased
CGT, γ-glutamyltransferase, WBC, white blood cell
 In pregnant women the total and free bilirubin concentrations are
significantly lower during all three trimesters, due to hemodilution.
HELLP syndrome has been associated with postpartum indirect
hyperbilirubinemia and should be differentiated from Gilbert syndrome.

Patients with Crigler-Najjar type I (CN1) disorder the fetus is at high

risk of being adversely affected by the bilirubin, because unconjugated
bilirubin can cross the placenta and may cause kernicterus , a potentially
neurotoxic condition. Successful pregnancy in patients with Crigler-
Najjar syndrome has been reported with the use of phenobarbital and
phototherapy.

Dubin-Johnson syndrome (DJS), Pregnancy and use of oral contraceptives

in women with Dubin-Johnson syndrome cause a reversible increase in
serum conjugated bilirubin level. but pruritus and signs of generalized
cholestasis are absent.
 BILE ACIDS
Pregnancy could be associated with subclinical cholestasis. Organic
anion transport, including bilirubin and sulfobromophthalein (BSP), is
impaired during pregnancy. This is due to that estrogen/pregnancy-
induce decreases in the canalicular organic aniontransporting pump
multidrug resistance-associated protein-2 (MRP2: ABC C2).

Concentrations of bile salts in blood are within the normal range in

most pregnant women, but levels of glycocholate, taurocholate, and
chenodeoxycholate may rise progressively until term and exceed levels
measured early in pregnancy by two- to three-fold.
 Pregnancy- or estrogen-induced decreases
bile-salt transport due to
Pregnancy could be associated with subclinical cholestasis. Organic
anion transport, including bilirubin and sulfobromophthalein (BSP), is
impaired during pregnancy. This is due to that estrogen/pregnancy-
induce decreases in the canalicular organic aniontransporting pump
multidrug resistance-associated protein-2 (MRP2: ABC C2).

Concentrations of bile salts in blood are within the normal range in

most pregnant women, but levels of glycocholate, taurocholate, and
chenodeoxycholate may rise progressively until term and exceed levels
measured early in pregnancy by two- to three-fold.
 Pregnancy- or estrogen-induced decreases
bile-salt transport due to
A. Reductions in both sinusoidal (Na+/ taurocholate co-transporting
polypeptide [NTCP].
B. Reduction in canalicular (bile-salt export pump [BSEP].
C. Reduction in ATP-binding cassette [ABC].
In clinical practice, pruritus during pregnancy, measurement of
serum bile acid concentration may be useful for the diagnosis of
cholestasis, especially when routine liver function tests are still within
normal limits.
 CHANGES IN LIVER FUNCTION TEST VALUES

A. Serum ALT and AST: activity levels remain within the normal limits
established in nonpregnant women. Thus it should be emphasized that
serum ALT and AST activity values above the upper limit of normal
values before labor should be considered pathologic and should lead to
further investigations.
B. Serum alkaline phosphates activity levels increase in late pregnancy,
mainly during the third trimester. This increase during pregnancy is
not due to an increase in the hepatic isoenzyme but rather

Largely attributable to the production of the placental and bone

isoezymes. Thus measurement of serum alkaline phosphates activity is
not a suitable test for the diagnosis of cholestasis during late pregnancy.
 LIVER-RELATED SYMPTOMS AND
PHYSICAL EXAMINATION IN PREGNANCY
Nausea and vomiting are common symptoms of early pregnancy and
occur in more than half of all pregnant women.

Hypermesis gravidarum defined by severe vomiting beginning in

early pregnancy and often requiring hospitalization, is much less
frequent.

Nausea or vomiting occurring during the second or third trimester

should be considered pathologic and prompt investigation, including
measurement of serum aminotrasferases activity.

Vascular spiders and plamar erythema are commonly associated with

chronic liver disease and pregnancy.
 VIRAL HEPATITIS

Viral hepatitis_ caused by hepatitides A,B,C,D, E ,herpes

simplex,cytomegalovirus, and Epstein – Barr virus.

The clinical and serologic course of acute hepatitis in the western world
is generally the same as that observed in the nonpregnant patient.
Hepatitis E, which in the third trimester of pregnancy may lead to
fulminant liver failure and may carry a high mortality (up to 31.1%).

Herpes simplex hepatitis is rare .The death rate is about 40%. Patients
with herpes hepatitis present with severe or fulminant ”anicateric”
hepatitis in the third trimester.
 A B

Herpes simplex hepatitis during pregnancy. (A) large area

of confluent hepatocellular necrosis (double-headed arrow).
(B) Infected hepatocytes with intranclear eosinophilic Cowdry
types A inclusions (arrows). (hematoxlin and eosin stain)
 Summary of Mode of Transmission, Effect
on Pregnancy, and Management of Viral
Hepatitdes A, B, C And E in Pregnancy
Mode of
Type of virus Effect on pregnancy Mangement
transmission
Perinatal transmission
rare Supportive care safety of
Acute infection vaccination not determined
Hepatitis A Fecal – oral
associated with preterm Postexposure immunoglobulin safe
labor and maternal breastfeeding not contraindicated
complication
Supportive care
Active and passive immunization
Parental, Acute infection can recommended
Hepatitis B sexual, and cause fetal and neonatal Limivudine, given during second
parenteral hepatitis and third trimesters, decreases risk
of transmission
Breastfedding not contraindcated
Parental,
No effects on pregnancy Supportive care
Hepatitis C sexual, and
and fetal outcome Breast feeding appears to be safe
parenteral
Preterm labor and
Supportive care
Similar to increased maternal
Hepatitis E Breast feeding appears to be safe
hepatitis A mortality in third
No therapy to prevent transmission
trimester
 HEPATITIS A
The overall case/fatality ratio among reported cases is less than 1% and
does not lead to chronic infection, although 10% to 15% of symptomatic
individuals can have a prolonged or relapsing disease lasting up to months.

If a pregnant woman becomes infected with hepatitis A, generally

the baby is not affected. Intrauterine transmission of hepatitis A virus is
very rare; however, prenatal transmission could occur.

The management of acute HAV in pregnancy does not differ from

that used in nonprenant patients.

The safety of hepatitis A vaccination during pregnancy has not been

determined. Mothers infected with hepatitis A virus are encouraged to
breastfeed and HAV infection is not a contraindication for breastfeeding.
 HEPATITIS B
Hepatitis B virus has a high rate of vertical transmission causing fetal
and neonatal hepatitis. Because it is highly pathogenic and infectious,
perinatal transmission of HBV infection represents the single largest
cause of chronically infected individuals worldwide.

However, if the mother is seropositive for both HBsAg and hepatitis

B e-antigen (HBeAg), the frequency of vertical transmission increases to
approximately 90% without neonatal prophylaxis.

Therefore, the American Congress of obstetricians and gynecologists

and the centers for disease control and prevention recommend universal
screening for HBsAg in all pregnant women during the third trimester.
 HEPATITIS B
Pregnant women who are directly exposed to hepatitis B virus
should receive a hepatitis B immunoglobulin (HBIG) injection ideally
within 72 hours of exposure and then a hepatitis B vaccine within 7 days
of exposure. HBV vaccines contain noninfectious HBs Ag and should
cause no potential risk to the fetus.

Hepatitis B vaccines administration to pregnant women is relatively

safe and its benefits outweigh its risks.

Hepatitis B vaccination can be delayed more than 24 hours after the

baby's birth but should be given within the first week of delivery.
 HEPATITIS B
The combination of passive and active immunization is very
effective the reducing the frequency of perinatal transmission of
hepatitis B virus (85% to 95% efficacy).

Interferon and oral nucleoside analogue that are classified as an

FDA Category C drug in terms of safety, is given to mothers with high
HBV DNA during the second and third trimesters to reduce the risk of
transmission at the time of delivery.
 HEPATITIS C
All pregnant women should be screened for hepatitis C so that risk
stratification can be performed and measures taken to both reduce perinatal
transmission.
Individuals who are HCV positive should have a PCR test fot HCV
RNA as the risk of perinatal transmission is dependant on the presence of
HCV RNA .liver function should be performed at the time of checking HCV
RNA status as HIV co-infection increases the risk of transmission
Risk of vertical transmission is increased with high viral load
prolonged rupture of membranes and invasive procedures where possible
fetal scalp electrodes and fetal scalp sampling should be avoided in women
with HCV.
Caesarean section is not recommended as a means of reducing perinatal
transmission of hepatitis C.
 HEPATITIS C
As for blood borne infections it is recommended to bath the baby to
remove any maternal body secretions and blood prior to IM injections.

HCV infection is not a contraindication to breastfeeding except in the

presence of craked or bleeding nipples.In this instance expression and
discarding of the milk is adviced whilist waiting for healing of the
cracked nipples.

All infants of HCV positive mothers should be screened following

delivery to determine they have been infected care should be taken to
ensure the appropriate interval passed for the neoborn to become pcr +\-
antibody positive.
 HEPATITIS C
Given that antiviral curative treatment for hepatitis c is now readily
avilable consideration should be given to screeining all women prior to
pregnancy so that they are able to make an informed choice regarding
treatment prior to embarking on pregnancy ,exiting treatments for hcv are
not recommended during pregnancy of breastfeeding in particular
ribavrin is teratogenic.

For all women and male parterns recieving ribavrin reliable

contraceptoion must be used during treatment and for 6 months after
completion of treatment.
 HEPATITIS E
HEV infection is known to cause severe hepatitis, fulminant liver
failure, preterm labor, and increased mortality in pregnant women,
especially in their third trimester with reported maternal death rates as
high as 20% to 31.1%.

The mechanisms of fulminant hepatitis E in pregnancy is not clear

but is thought to be attributable to induction of type 2(TH2) cytokines.

At the present time, it appears safe to continue breastfeeding during

epidemics of HEV in underdeveloped and endemic areas to prevent a
greater risk of infant mortality from other infectious diseases.
 AUTOIMMUNE HEPATITIS
Pregnant women with AIH have a reduced fertility rate secondary to
amenorrhea and anovulation, which might be related to hypothalamic-
pituitary dysfunction. However, AIH has been reported to occur de novo
during pregnancy or the postpartum period. Because of improved
management of AIH patients and reduced hepatocellular injury from use
of immunosuppression therapy, menstruation may ensue and more
women with AIH are able to conceive.

In a retrospective study the rate of serious maternal complications

was 9% and a high rate (52%) of postpartum exacerbation was noted. The
rate of adverse pregnancy outcome was 26%, which was highly associated
with the presence of antibodies to SLA/LP and Ro/ SSA.
 AUTOIMMUNE HEPATITIS
These data and other illustrate that pregnancy can ameliorate
autoimmune hepatitis, whereas delivery can exacerbate it.

Immunosuppressive therapy with azathioprine (AZA) and corticosteroid

therapy induces clinical, laboratory, and histologic improvements in 80% of
patients with autoimmune hepatitis, but most women with AIH require
maintenance immunosuppression therapy. At this time successful completion
of pregnancy is a realistic expectation for patients with well-controlled AIH.

Corticosteroids and azathioprine are generally safe during pregnancy

but birth defects have been described. Pregnant women with AIH need
careful monitoring during pregnancy and for several months postpartum.
 WILSON DISEASE
Wilson disease is a rare autosomal recessive disorder of hepatic
copper transport leading to inhibition of biliary copper excretion.

This causes an increase in copper deposition in vital organs such as

liver, kidney, brain, and eyes. Two copper transporting ATPases, Menkes
(AT7A; MNK) and Wilson (ATP7B; WND), are expressed in the placenta
and both are involved in placental copper transport.

Pregnancy does not seem to have an adverse effect on the clinical

course of Wilson disease although recurrent abortions are common in
untreated patients, which can be seen in 26% of cases.
 WILSON DISEASE
Indeed, untreated symptomatic women with Wilson disease tend to
suffer amenorrhea, oligomenorrhea, irregular menses, and multiple
miscarriages, However, pregnancy in women with Wilson disease is safe
and successful when treatment with a chelating durg is continued
uninterrupted.

With the current available copper chelators such as D-penicillamine,

trientine, and Zinc, fertile women are able to conceive. Pencillamine and
trientine have teratogenic effects in animals, and penicillamine has
known teratogenic effects in humans as well. D-Penicillamine probably
inhibits thyroperoxidase activity in utero.
 WILSON DISEASE
Infants born to mothers with Wilson disease may develop transient
goitrous hypothyroidism.

Zinc intake at a dose of 25 to 50 mg three times daily in pregnancy

appears to be safe with very minimal teratogenicity.

It is important that treatment of Wilson disease with anticopper

agent continues during pregnancy without interruption. Both mother and
baby should be monitored while on chelation therapy.
 PORTAL VEIN THROMBOSIS
Portal vein thrombosis (PVT) is a rare occurrence during pregnancy.
PVT is caused by a combination of local and systemic risk factors.

Causes: Malignant tumors, cirrhosis, intrabdominal inflammation (e.g.,

pancreatitis, appendicitis, cholecystitis, duodenal ulcer, inflammatory
bowel disease) Additionally, systemic prothrombotic risk factors such as
myeloproliferative disorders; antiphosholipid syndrome; protein C, protein
S, and antihrombin deficiency; and factor V Leiden, factor II, and
methylenetrahydrofolate reductase gene mutations are other potential risk
factor for PVT and are responsible for 60% to 70% of cases.
 CLINICAL MANIFESTATIONS
Acute PVT usually presents with abdominal or lumbar pain that
either is sudden in onset or progresses over a few days.

Partial thrombosis of the portal vien is associated with fewer

symptoms.

Rapid and complete obstruction of the portal or mesenteric venous

arches, induces intestinal congestion that is manifested by severe and
continuous colicky abdominal pain with occasional nonbloody diarrhea.

Acute septic PVT referred to as acute pyleophlebitis is characterized by

infected thrombus. The presentation is spiking fever and chills, a tender
liver, and occasionally shock, persistence of severe pain beyond 5 to 7
days, bloody diarrhea, and ascites along with features of acidosis and
renal or respiratory dysfunction are suggestive of intestinal infarction.
 LABORATORY AND IMAGING FEATURES
Liver function is persevered in both acute and chronic PVT because
increased hepatic arterial blood flow compensates for the decreased
portal inflow.

Abdominal US with Doppler studies of the portal veins reveals

absent or sluggish flow.

Persistent pain, presence of ascites, or development of multiorgan

failure indicates that intestinal infarction is likely and surgical
exploration should be considered.

A tumor-like cavernoma, a rare form of chronic PVT, is characterized

by tiny collateral channels forming a mass that encases the main bile
duct and can be confused with carcinoma of the main bile duct
 TREATMENT
ACUTE (PVT)
1. In the presence of pyelophlebitis, antibiotics should be administered.
2. Anticoagulation medication should be administered for at least 3
month and permanent anticoagulation therapy should be considered
for patients with prothormbotic conditions.

3. Surgical thrombectomy, systemic or in situ thrombolysis, and

transjugular intrahepatic portosystemic shunt (TIPS) are extremely
limited. Chronic (PVT)
 TREATMENT
ACUTE (PVT)
Pregnant patients with chronic PVT should be offered screening for
gastroesophageal varices.

Anticoagulation therapy should not be initiated until after adequate

prophylaxis for varical bleeding.

Additionally, long-term anticoagulation therapy should be

considered only in patients with chronic PVT, without cirrhosis, and
with a permanent risk factor for venous thrombosis.
 BUDD-CHIARI SYNDROME
Clinical and Laboratory features
Presentation can range from complete absence of symptoms to
fulminant hepatic failure.

This syndrome usually present in the last trimester or the puerperium.

The characteristic clinical triad of acute BCS is right upper quadrant
pain, hepatomegaly, and ascites.
 BUDD-CHIARI SYNDROME
Clinical and Laboratory features
Chronic thrombosis typically evolves slowly with dull abdominal
pain, lower extremity edema, gastrointestinal bleeding, and hepatic
encephalopathy. Jaundice is relatively uncommon.
Marked dilation of dilation of subcutaneous veins on the trunk has a
high specificity but a low sensitivity for IVC obstruction.
Levels of serum aminotransferases and alkaline phosphatase can be
normal or increased. Levels of serum albumin, serum bilirubin, and
prothombin can be normal or abnormal, and in some patients are
markedly abnormal. The protein level in ascetic fluid varies from patient
to patient. Ascites protein content is greater than 3.0 gl/dl, and serum
ascites albumin gradient (SAAG) greater than 1.1 is generally suggestive
of portal hypertension.
 IMAGING FEATURES
Diagnostic modalities including right upper quadrant abdominal US
with Doppler studies of the hepatic veins have the advantage of being
noninvasive or minimally invasive.
 TREATMENT
1. Women with history of BCS who wishes to become pregnant should
be screened for portal hypertension by upper endoscopy and, when
indicated, prophylaxis of varices.
2. Non pregnant should recieve long-term warfarin therapy.
3. Pregnant patients should recieve low-molecular-weight heparin
(LMWH) as soon as possible, preferably before conception.It should
be given to twice-daily dosing of LMWH. Delivery should be
scheduled 24 hours after the last therapeutic dose and restarted 12
hours after vaginal delivery or 24 hours after cesarean section either
with LMWH or with warfarin.
4. BCS diagnosed during pregnancy, Doppler US should be used as the
first modality.
 TREATMENT
Warfarin (FDA category X) is contraindicated. LMWH at a curative
dose should be started as soon as the diagnosis is established.

Pharmacologic and endoscopic therapy for portal hypertension can be

applied.

Angioplasty and TIPS insertion have been reported for refractory

varicel bleeding.
 HEREDIATRY HEMORRHAGIC
TELANGIECTASIA
Characaterized by widespread cutaneous, mucosal, and visceral
arteriovenous malformations that can involve the lund, brain, and/or liver.
Liver vascular malformations include both microscopic and macroscopic
malformation of variable size, ranging from tiny telangicetasis to discrete
arteriovenous malformation. The majority of cases are asymptomatic.
 The three most common initial clinical presentations

1. High-output heart failure. (shortness of breath, dyspnea on exertion,

ascites, and/or edema)

2. Portal hypertension.
3. Biliary ischemia.

The diagnosis of HHT by Doppler US

Treatment In patients with symptomatic HHT, treatment is directed
toward the clinical manifestation of heart failure and portal hypertension.
 CIRRHOSIS AND PORTAL HYPERTENSION

During pregnancy a hypervolemic state develops, leading to an increase

in portal flow and elevation of portal pressure transmitted to the collateral
veins with increased risk of variceal bleeding.
PHT occurs during the last stages of the second trimester of pregnancy
and is associated with increased risk of varical bleeding in the later stages of
pregnancy.
Esophageal variceal bleeding has been reported in 18% to 32% of
pregnant women with cirrhosis and in up to 50% of those with known
portal hypertension. Of those with preexisting varices, 78% will have
gastrointestinal bleeding during pregnancy, with a mortality of 18% to 50%.
 CIRRHOSIS AND PORTAL HYPERTENSION

Pregnant patients with cirrhosis face unique risks that include spontaneous
abortion, prematurity, pulmonary hypertension, splenic artery aneurysm
rupture, and postpartum hemorrhage, and a potential for life-threatening
variceal hemorrhage and heptic decompensation.
Endoscopic surveillance and banding of esophageal varices is
recommended during pregnancy.
On the basis of the endoscopic finding, primary prophylaxis with
nonselective β-blockers such as propranolol and/or nadolol (designated by
FDA as Pregnancy Category C) is recommended. The risks of nonselective
β-blockers include fetal bradycardia, hypotension, hypoglycemia, and
intrauterine growth retardation.
 CIRRHOSIS AND PORTAL HYPERTENSION

Endoscopic banding ligation seems to be a safe procedure in

pregnancy. When bleeding is not arrested endoscopically, an emergency
TIPS procedure should be considered.
Ascites rarely occurs in pregnant women with cirrhosis and the
mainstay of treatment is sodium restriction and the use of diuretics.
Hepatic encephalopathy In the setting of cirrhosis, secondary to
medications, Sepsis, hypoxia, gastrointestinal bleeding, and hypotension.
Postpartum uterine hemorrhage occurs in 7% to 10% of pregnancies in
patients with cirrhosis and represents a potential source of maternal
morbidity and mortality.
 CIRRHOSIS AND PORTAL HYPERTENSION

Vaginal delivery is usually safe and early assistance with forceps

delivery or vacuum extraction should be considered to prevent further rise
in portal pressure secondary to prolonged straining during labor.

Termination of pregnancy is warranted in the presence of progressive

hepatic decompensation.
 GALLSTONES AND BILIARY TRACT DISEASE
There are several changes that occur during the course of pregnancy
that lead to the formation of biliary sludge and gallstone.

1. Decline in the contractility of the gallbladder. This is most likely

caused by hormonal change during pregnancy, with progesterone
having the greatest effect.
2. Alteration in the content of bile. Compared with bile acids and
phospholipids, cholesterol secretion increase in the second and third
trimesters, leading to lithogenic.

Despite their prevalence in 5% to 12% of pregnant women,

symptomatic gallstones occur in only 0.1% to 0.3% of pregnancies.
 TREATMENT
1. Cholecystectomy during pregnancy is not associated with a high rate
of fetal demise. Laparoscopic cholecystectomy is probably a safe
option. during the second trimester of pregnancy.

2. Endoscopic management of biliary tract disease using endoscopic

retrograde cholangiopancreatography (ERCP) is also a viable option.
 LIVER DISEASE UNIQUE TO PREGNANCY
Four unique disorders of liver dysfunction have been recognized
during pregnancy. These include

1. Hepatic involvement in HG.

2. ICP.

3. HELLP syndrome.

4. AFLP.
 HEPATIC INVOLVEMENT IN
HEPEREMESIS GRAVIDARUM

HG is a severe and persistent form of NVP that predominantly

affects pregnant women in their first trimester and is characterized by
intractable vomiting that leads to loss of 5% or more of pre-pregnant
body weight and dehydration.

HG can be associated with dehydration, imbalanced electrolyte

levels, ketonuria, abnormal levels of liver enzymes, low birth weight,
avitaminosis, and Wernicke's encephalopathy; rarely, it can be fatal.
 Etiology and pathophysiology: The underlying mechanism of maternal
liver disease associated with hyperemesis gravidarum is not clear.
Risk Factors: Women with previous history of hyperemesis gravidarum,
previous molar pregnancy, preexisting diabetes, gastrointestinal disorders,
asthma, singleton female pregnancies, pregnancies with multiple male
fetuses, multiple gestations, hyperthyroid disorders, psychiatric illness, and
low prepregnancy body weight are at increased risk.
The relationship between infection with Helicobacter pylori and HG
is not clear.
Pathogenesis of liver injury in HG is not clear. Intense vomiting
leads to dehydration, ketonuria, starvation, and malnutrition, may result
in depletion of glycogen stores and an increase in mitochondrial injury
caused by oxidative stress
 DIAGNOSIS
1. Intense nausea and vomiting in the first trimester associated with a
5% or greater weight loss, dehydration, ketonuria, electrolyte
imbalance, and metabolic alkalosis is highly suggestive of
hyperemesis gravidarum.

2. Clinically; fever, abdominal pain, headache, elevation in white blood

cell count, anemia, thrombocytopenia, and coagulopathy should
elude to nausea and vomiting of other causes.

3. Mild elevation of levels of liver transaminases (usually <300 U/L),

total bilirubin level is generally less than 4 mg/dl.
 MANAGEMENT
Nutritional support, hydration, and control of emesis are the mainstay
of therapy.

Ginger has been shown to be effective in reducing nausea and

vomiting.

Metoclopramide and vitamin B6 appear to be safe and effective.

Thiamine supplementation for women with prolonged vomiting is
recommended to prevent Wernicke-Korsakoff syndrome.

Nerve stimulation therapy is effective in reducing nausea and

vomiting and in promoting weight gain in symptomatic women in the
first trimester of pregnancy.

Low –dose prednisolone has been shown to have a similar effect as

promethazine in reducing nausea and vomiting with fewer side effects.
 INTRAHEPATIC CHOLESTASIS OF PREGNANCY
Characterized by; Pruritus, elevated levels of serum bile acids.
Although most affected pregnant women have a mild form of the disease,
the disease can be associated with meconium staining in 45%,
spontaneous preterm labor in 44%, and intrapartum fetal distress in 22%
of pregnancies, as well as low birth weight.

Etiology
• The etiology of ICP is still unknown.
 Possible mechanisms
A. Genetic:

• Occurrence within familial clustering and endemic ethnic groups.

• Heterozygous nonsense mutation of the multidrug resistance-

associated protein-3 (MDR3) gene.

B. Hormonal: High levels of maternal sex hormones in a susceptible

patient may lead to ICP. Hypersensitivity to estrogen and estrogen-
sulfated metabolities is considered to be the main precipitant.
 Pathophysiology
The exact gene defect in bile acid secretion has not been defined.
Low serum selenium concentration and lower levels of serum placental
protein 10 (PP10) have also been noted in ICP patients.

Diagnosis
A)Clinically: Generalized intractable pruritus in the second or third
trimester of pregnancy with elevated levels of maternal serum bile acids
in the absence of radiologic evidence of biliary obstruction.

Pruitus is severe and tends to follow an ascending pattern of

distribution. Initially it involves the palms of the hands and the soles of
the feet and subsequently the arms, legs, and trunk are involved. Pruritus
tends to abate after resolution of gestation but to occure in subsequent
pregnancies.
 B) Lab: Elevated levels of maternal serum bile acids are the hallmark
of cholestasis and are usually 10µmol/L or greater. A cutoff level of serum
bile acids of 40µmol/L or greater is associated with impaired fetal
outcome.

Serum aminotransferase levels are usually elevated but less than

1000 U/L.

Levels of cholestatic enzymes, such as alkaline phosphatase, are also

elevated; however, use of alkaline phosphatase level as a single indicator
of the disease is not recommended because it is produced by both
placenta and bone.

Serum γ-glutamyltranspeptidase (GGT) level is normal or slightly

elevated.
 Intrahepatic cholestasis of pregnancy showing canaliuclar bile
plugs (arrows) with well preserved hepatocytes containing yellow
(hematoxyli and eosin (H& E) stain)
 MANAGEMENT
Strict felal monitoring must be carried out, especially during the last
few weeks of pregnancy when rates of fetal morbidity and mortality
are increased.

Ursodeoxycholic acid (UDCA).

The recommended dose is 15 mg/kg/day.

 SYNDROME OF HEMOLYSIS, ELEVATED LIVER
ENZMES, AND LOW PLATELET COUNT
Precclampsia is defined as the presence of edema, proteinuria, and
hypertension with a blood pressure greater than 140/90 mm Hg in a
previously normotensive patient. The exact cause remains unknown and
the definitive treatment is still delivery.

The liver involvement in preeclampsia may manifest as HELLP

syndrome. The incidence of HELLP syndrome is 3.1 % to 12% of patients
with preeclampasia. HELLP syndrome can be life-threatening to both the
mother and fetus. The associated liver disease may progress to the point
that liver transplantation may become necessary. HELLP syndrome
occurs in the antepartum period in 70% to 92 % of cases and during the
postpartum period in 8% to 30% of patients.
 PATHOGENESIS

A. One theory emphasizes structural and functional changes in the

systemic vasculature as a major role in the development of HELLP
syndrome.

B. Another theory is that placenta-derived proteins mediate apoptosis

of liver cells. In animal models interaction of placenta-derived CD95
(APO-1, Fas) with its ligand, CD95L (FasL), induce apoptosis in
hepatic cells, A new therapeutic agent (LY 498919) that blocks CD95-
induced apoptosis is under investigation.
 CLINICAL FINDINGS
A. Patients are typically seen in the early third trimester with
nonspecific symptoms including right upper quadrant pain, malaise,
nausea, and vomiting.

B. Concomitant signs and symptoms of preeclampsia (hypertension,

proteinuria, and edema) may or may not be present.

C. Jaundice, bleeding attributable to thrombocytopenia are a very

uncommon mode of presentation.

D. Severe right upper quadrant abdominal pain that is radiated to the

neck or shoulder may herald impending hepatic rupture or the
presence of hepatic hematoma.
 DIAGNOSIS
Two major diagnostic classification systems are currently used for
the classification of HELLP syndrome.
 MAIN DIAGNOSTIC CRITERIA
OF HELLP SYNDROME
Tennessee classification Mississippi classification
Complete syndrome: Class 1: Platelets ≤ 50 × 109/L
Platelets ≤ 100 × 109/L AST or ALT ≥ 70 units/L
AST ≥ 70 units/L LDH ≥ 600 units/L
LDH ≥ 600 units/L
Class 2: Platelets ≤ 100 × 109/L
≥ 50 × 109/
AST or ALT ≥ 70 units/L
Incomplete syndrome any one LDH ≥ 600 units/L
or two of above Class 3: Platelets ≤ 150 × 109/L
≥ 100 × 109/
AST or ALT ≥ 40 units/L
LDH ≥ 600 units/L
 A B

Liver in Hellp Syndrome. (A) periportal patchy hemorrhage

and necrosis (arrow). (B) sinusoidal deposition of fibrin
(arrow). (H & E stain)
 ASSESSMENT OF THE SEVERITY
OF THE PATHOLOGIC PROCESS
Class 1 HELLP syndrome having a worse prognosis and longer hospital
stay than either class 2 or class 3.
Both HELLP syndrome and acute fatty liver of pregnancy occur in the
third trimester and have similar presentations, but liver dysfunction is
usually more pronounced in the latter and is more frequently associated
with Coagulopathy, hypoglycemia, and renal failure.
The coagulopathy of AFLP is due to liver failure, whereas in HELLP
syndrome coagulopathy develops as a part of disseminated intravascular
coagulation (DIC) syndrome.
 MANAGEMENT
Because of significant morbidity and mortality, HELLP syndrome is
considered an indication for immediate delivery.
A)Prompt Delivery:
• Gestation is greater than 34 weeks.

• Fetal testing results are nonreassuring.

• Any of the following conditions are present:

• Maternal multiorgan dysfunction, DIC, liver infarction or

hematoma, renal failure, or abruption placentae.
 MANAGEMENT

B) Seizure prophylaxis with magnesium sulfate and blood

pressure control is also required

C)Corticosteroids

D)Platelet transfusion is recommended in the case of bleeding

or severe thrombocytopenia (platelet count <20 × 109/L)

Prognosis: After delivery, initial worsening of laboratory values with

subsequent spontaneous recovery is observed.
 COMPLICATION OF HELLP SYNDROME
A. Serious maternal complications are common, including DIX, abrupt
placentae, acute renal failure, eclampsia, pulmonary edema, acute
respiratory distress syndrome, ascites, subcapsular hematoma,
hepatic failure, and wound hematomas.

B. Indications to proceed with liver transplantation include persistent

bleeding form a hematoma or hepatic rupture or liver failure form
extensive necrosis.

C. Liver rupture is a rare, life-threatening complication of HELLP

syndrome that carries a very high maternal mortality. It is usually
preceded by an intraparenchymal hemorrhage progressing to a
contained subcapsular hematoma in the right hepatic lobe in patients
with severe thrombocytopenia.
 COMPLICATION OF HELLP SYNDROME
Abdominal CT scan may be the most sensitive and specific way to
detect hepatic hemorrhage and/or rupture.

MANAGEMENT OF LIVER RUPTURE

Immediate laparotomy and evacuation of the hematoma with
pressure packing and drainage, followed by consideration of hepatic
artery embolization or ligation, partial hepatectomy, or oversewing of the
laceration. In the rare hemodynamicaly stable patient, angiographic
embolization may be considered.
 RECURRENCE OF HELLP SYNDROME
HELLP syndrome can recur in subsequent pregnancies. Subsequent
pregnancies in patients with HELLP syndrome carry a high risk of
complications such as preeclampsia, recurrent HELLP, prematurity,
intrauterine growth retardation, abruption placentae, and perinatal mortality
Abdominal computed tomography scan showing
a sub-capsular hematoma (arrow) in the right lobe
in a woman with HELLP syndrome
 ACUTE FATTY LIVER OF PREGNANCY
Acute fatty liver of pregnancy is a clinical entity unique to pregnancy that
occurs during the occurs during the third trimester. Although it is a rare
condition, it carries significant perinatal and maternal mortality.
AFLP is more common in primiparous women and generally occurs
between 30 and 38 weeks of gestation.
Multiple gestations and gestations with male fetuses results in generally
higher prevalence of AFLP when compared with the average population. The
disease tends to recur in future pregnancies.
 PATHOGENESIS
Unknown, Recent molecular advances suggest that AFLP may result
from mitochondrial dysfunction.
Several reports have documented a strong association between AFLP and
a deficiency of the enzyme long-chain 3-hydroxyacyl-CoA dehydrogenase
(LCHAD) in the fetus, a disorder of mitochondrial fatty acid β-oxidation.
 CLINICAL FINDINGS
Acute fatty liver of pregnancy usually occurs most commonly in the
third trimester with a few case reports in the second trimester.

Nonspecific with malaise, nausea, vomiting, and headache and can be

easily misdiagnosed.

Right upper quadrant pain and epigastric abdominal pain .

Fever, headache, diarrhea, back pain suggestive of acute pancreatitis.

Rarely patients may present with frank liver failure and bleeding
attributable to liver failure-induced coagulopathy, Preeclampsia co-
exists in >50% of patients with AFLP.
 CLINICAL FINDINGS
Occasionally, the patient may present with signs and symptoms of
eclampsia (agitation, increased thirst, premature labor, seizures).

Hypertension is mild or may absent because of a decrease in

peripheral vascular resistance associated with hepatic failure.

Rarely AFLP may present as asymptomatic elevation of transaminase

levels. Jaundice is seen in initial presentation in severe cases.
 PHYSICAL FINDINGS
Right upper quadrant tenderness may be the only abnormality found.
The liver is usually non-palpable.

As the disease progresses, jaundice, altered mental status, ascites, and

edema arise
 COMPLICATIONS
Acute renal failure.

Acute pancreatitis.

Hypoglycemia, and infection.

Hepatic encephalopathy.

Any combination of these complications may lead to significant

maternal and fetal mortality.
Delivery is often complicated with severe postpartum bleeding. Diabetes
insipidus may also complicate AFLP.
 DIAGNOSIS OF AFLP
A moderate elevation in the levels of transaminases is usually seen,
ranging from just slightly above normal to a value more than 1000 U/L
above normal.

Normocytic anemia, leukocytosis and thrombocytopenia is common

when DIC is present.

Elevation of blood urea nitrogen (BUN) and creatinine.

As liver function progressively worsens, encephalopathy, hypoglycemia,

and elevated ammonia concentration .
 Liver Biopsy show cytoplasmic vacuolization predominantly in the
perivenular and midzonal regions with microvesicular fatty infiltration. In
severe cases lobular disarray is seen with cell dropout and fatty change may
be diffuse and involve all zones. Portal inflammatory changes can be seen as
well, suggestive of cholangitis.
Imaging studies are of little value in the diagnosis of AFLP. They are
mainly useful for excluding other pathologic processes in the liver (e.g.,
hepatic ischemia, hepatic infarct, Budd-Chiari syndrome, or hepatic
hematoma/rupture). Liver US and CT were inconsistent in detecting fatty
infiltration of the liver in patients with AFLP; the role of MRI and
spectroscopy in particular requires further investigation.
 DIFFERENTIAL DIAGNOSIS
1)AFLP AND HELLP SYNDROME
Both conditions present late in pregnancy and both can be associated
or complicated with preeclampsia.Hypoglycemia and/or prolongation of
prothrombin time is suggestive of AFLP.

Histopathology shows extensive hepatocellular necrosis, in HELLP

syndrome, which is absent in AFLP, and microvesicular fatty infiltration,
the predominant feature of AFLP, is generally absent in HELLP syndrome
 DIFFERENTIAL DIAGNOSIS
2)AFLP AND ACUTE HEPATITIS
A history of exposure and viral serologic testing are the key in
making the diagnosis.

The degree of elevation of liver transaminase levels is much higher

in patients with acute viral hepatitis than in AFLP
 MANAGEMENT
Patients are usually very ill and require hospitalization in the
intensive care unit. Timely delivery after initial patient stabilization will
cure the patient
A B C

Acute fatty liver of pregnancy. (A) Fat accumulation is greater in pericentral

hepatocytes (arrow) compared with periportal hepatocytes (arrowhead). (H &
E stain.) (B) The small (microvesicular fat droplets surround but do not
displace hepatocyte nuc;ei (arrows). (H & E stain.) (C) Fat is readily
appreciated with oil-red O stain on frozen liver tissue
 Distinguishing features of liver
disease unique to pregnancy
DISEASE/Features HG ICP HELLP AFLP
Incidence in pregnancy 0.3%-2% 0.1%-0.01%(US) 0.2%-0.6% 0.005%-0.01%
Third trimester,
Third trimester or Third trimester or
Onset during pregnancy First trimester but can occur in
postpartum postpartum
second trimester
Presence of preeclampsia No No Yes >50%
Intense nausea
Generalized Liver failure with
and vomiting,
pruritus, elevated Hemolysis, coagulopathy,
Clinical features dehydration,
maternal serum thrombocytopenia hypoglycemia, and
electrolyte
bile acids DIC
abnormality
Usually 300 Mild to 20-fold Typically 500 Typically 300-500
Aminotransferases
units/L increase units/L units/L
Bilirubin Usually 4 mg/dl 5 mg/dl 5 mg/dl 5 mg/dl
May show hepatic
May show fatty
Imaging Normal Normal rupture or
infiltrate
infraction
Normal or Patch/extensive
Microvesicular
Histology bland Cholestasis necrosis and
steatosis in zone 3
cholestasis hemorrhage
Preterm and low
Preterm and low birth weight, Perinatal morality, Fetal mortality 9%-
Perinatal/fetal outcomes
birth weight meconium prematurity 23%
staining
AFLP, acute fatty liver disease of pregnancy, HELP, hemolysis, elevated liver enzymes,
and low platelet count; HG, hyperemesis gravidarum; ICP, intrahepatic