Jacquelyn F.

Fleckenstein, MD

Pregnancy and the Liver

No relationships to disclose. Content of the presentation does not include discussion of offlabel/investigative use of medicine(s), medical devices, or procedure(s).

Pregnancy and Liver Disease

Jackie Fleckenstein, M.D. Associate Professor of Medicine UT Health Science Center

Key Concepts
Lab tests for assessing the liver are normal during pregnancy
Elevations in aminotransferases and bilirubin indicate liver disease Cholestasis of pregnancy is a true cholestatic syndrome (elevated bile acids) GGTP, alkaline phosphatase generally normal

Key Concepts
Certain disorders are unique to

pregnancy

HELLP syndrome, AFLP, cholestasis of pregnancy, hyperemesis gravidarum Gestational age aids in differential diagnosis 1st trimester hyperemesis gravidarum 2nd trimester cholestasis 3rd trimester HELLP, AFLP

Key Concepts
Certain diseases are not unique
to pregnancy but more severe
Hepatitis E Herpes simplex hepatitis

Some disorders precipitated by

pregnancy
Cholelithiasis Budd-Chiari syndrome

Key Concepts
Pregnancy in chronic liver disease - rare Pregnancy post transplant associated
with prematurity and low birth weight

A 28 y/o healthy, asymptomatic woman in her 2nd trimester is referred due to finding of spider angiomas and palmar erythema. PE reveals only the above skin findings. Laboratory studies are normal including liver chemistries, GGT. Which of the following management plans is most appropriate?

Best Management:
1. Begin extensive evaluation for
presumed cirrhosis 2. Proceed directly with liver biopsy 3. Immediate referral to transplant program 4. Reassure patient and referring physician; reassess after delivery

Normal pregnancy
Not uncommon to have spider angiomas and palmar
erythema Alkaline phosphatase can increase late
Increased placental and bone isoenzymes

AST and ALT generally remain normal GGT decreases slightly in late pregnancy Total bilirubin, prothrombin time, fasting serum total bile
acid levels - normal Dilutional decrease in albumin Fibrinogen may increase in late pregancy

Hyperemesis gravidarum (HG)

Severe nausea/vomiting with dehydration/ ketosis; 4th to
20th weeks 1-1.5% of pregnancies no differences in fetal outcome Liver involvement mild 50% of cases Increased transaminases: ALT > AST
Low 100s Severity correlates with vomiting Resolve with rehydration/gut rest

Rare increased bilirubin Liver biopsy little or no abnormalities

Question
You are asked to evaluate a 28 y/o woman, 28 weeks into her first pregnancy, with abnormal liver chemistries. Aside from pruritus, she has no complaints. PE reveals scratch marks but is otherwise normal. Labs are significant for: ALT of 95 U/L, alk phos 180 U/L, total bilirubin of 1.8 mg/dl, INR of 1.6 and total bile acid level 4X normal. Ultrasound is normal. You recommend which of the following plans?

Question: Best management plan

1. ERCP for likely choledocholithiasis 2. Recommend immediate delivery as

findings suggest AFLP 3. No therapy except reassurance that the cholestasis is benign and will resolve 4. Begin therapy with ursodeoxcholic acid and Vit K. Early delivery if fetal distress.

Intrahepatic cholestasis of pregnancy (ICP)

Occurs during 2nd and 3rd trimester- resolves after birth 2/1000 in US; higher in Europe, Chile Pruritus severe at night, palms and soles Elevated fasting serum total bile acids (10-100x) 15% develop jaundice (< 6 mg/dl); alk phos (1-4x), aminotransferases(2-10x); GGT-nl or mild increase Vit K deficiency Liver biopsy cholestasis without inflammation May recur pregnancy, OCP use

ICP Etiologic factors

Etiologic factors Genetic predisposition
Hyperestrogenemia (3rd trimester peaks) Abnormal progesterone metabolism Strong regional clustering Higher prevalence in family members Defects in multidrug resistance type -3 gene (MDR-3) Encodes for the canalicular phospholipid pump protein

ICP treatment/outcome
Maternal outcome good, may recur 66% Fetal outcome can be poor Treatment
Meconium ileus, prematurity, stillbirth Ursodeoxycholic acid, replete Vit K Delivery soon after fetal maturity (32 weeks if fetal distress or 38 weeks if no distress)

A 35 y/o woman who is 36 weeks pregnant is evaluated for headaches, nausea, vomiting and mild leg edema. On PE, the pt is anxious and pale. BP is 160/100 mmHg. Abdominal exam reveals mild RUQ tenderness but her liver and spleen are not enlarged. She does have mild edema to her knees. A diagnosis of pre-eclampsia is made and the fetus is delivered without complication. You are asked to see the pt 36 hours after delivery for worsening lab abnormalities.

Significant lab values Lab values Hgb (g/dL) INR Total bilirubin Direct bilirubin ALT U/L AST U/L Alk phos U/L U/A Baseline 9.4 1.0 2.2 1.8 130 155 240 3+ protein 36hr postpartum 8.2 80,000 1.0 4.2 2.0 360 390 220 1+ protein

Plt count/cc mm 100,000

Which of the following is the most likely diagnosis?

1. Acute fatty liver of pregnancy 2. Sepsis with DIC 3. HELLP syndrome 4. Herpes simplex hepatitis 5. Acute Hepatitis E

Herpes Simplex Hepatitis

3rd trimester - History! Prodrome of fever, malaise, URI for 4-14 days PE: RUQ pain, occasional cutaneous lesions Labs: moderately increased bilirubin but very high aminotransferases, often > 1000 U/L CT scan multiple low density, nonenhancing areas likely hemorrhagic necrosis Maternal mortality 43%. Start acyclovir early! Transmission to infants 33-50%

HELLP syndrome: hemolysis, elevated liver chemistries and low platelets

Endotheial/microvascular injury from activation of

complement, increased vascular tone, plt aggregation Low haptoglobin, + schistocytes Normal PT/PTT, LDH > 600 IU/L Aminotransferases mean 150 U/L (2-20X); Total bilirubin > 1.2 mg/dl Platelets < 50,000-100,000/mm3 Complication of severe pre-eclampsia 0.1-0.6% all pregnancies; ~12% in severe eclampsia 2/3 occur in 3rd trimester, 1/3 after delivery

HELLP SYNDROME
Symptoms/signs
Epigastric/abdominal pain Liver normal or increased in size Jaundice 5% Generalized edema 90%; HTN

Maternal lab abnormalities peak in first 2 days

post partum Maternal mortality: 1-2%; 1% - hematoma
Mortality 30% with rupture

Fetal mortality: 10-35%(depends upon gest.age)

Acute fatty liver of pregnancy (AFLP)

Overlap with HELLP Nulliparous Nausea/vomiting, epigastric pain, jaundice Symptoms/signs of liver failure Liver frequently small Elevated PT/PTT, creatinine, NH3

Acute fatty liver of pregnancy

LCHAD abnormalities
LCHAD deficiency caused by genetic defect of
mitochondrial trifunctional protein (MTP) Mothers obligate heterozygotes with reduced capacity to oxidize LC fatty acids Fetus homozygote; unable to oxidize LC fatty acids Fatty acids spill into maternal circulation via placenta Accumulation of hepatoxic long chain fatty acid metabolites in mothers - ? 3-hydroxy-fatty acids

LCHAD deficiency in infants

ALFP and possibly severe HELLP may indicate
fatty oxidation disorder in fetus Fetus homozygous LCHAD deficiency often present with hypoketotic hypoglycemia Acylcarnitine profile and molecular screening should be done Early detection and treatment of LCHAD deficiency improves prognosis of newborn

A 30 y/o woman in her 37th week of pregnancy comes to the ER with complaints of nausea, vomiting, abdominal pain and bleeding gums for 3 days. On PE, the pt is mild distress. BP is 110/70 mm Hg. She has tenderness in the epigastric area and slight edema of the lower extremities.

Laboratory abnormalities Leukocyte count Platelet count Prothrombin time INR Serum creatinine Total bilirubin ALT AST Urinalysis 15,000/cu mm 150,000/ cu mm 17 seconds 1.8 1.8 mg/dl 2.5 mg/dl 300 U/L 250 U/L 1+ protein

Which of the following is most likely diagnosis

1. 2. 3. 4. 5.

Benign cholestasis of pregnancy Acute fatty liver of pregnancy Acute cholecystitis Acute viral hepatitis HELLP syndrome

Treatment of AFLP
Delivery and supportive care Disease systemic acute pancreatitis,

renal failure/oliguria, GI bleeding, DIC Case reports of successful liver transplantation

Viral Hepatitis
Most common cause of jaundice in pregnancy in US Increased risk of transmission of hepatitis A and B

during delivery if mother viremic Less risk for transmission of hepaitis C unless coinfected with HIV. No effective passive immunoprophylaxis Hepatitis E - Enteric transmission to mother
travel to Asia, Africa, Middle East and Mexico. Vertical transmission reported. History!

A 22 y/o woman presents for obstetric care at 30 weeks of pregnancy. She denies medical problems and her pregnancy has been uneventful. Her physical examination is notable only for her gravid state. Routine screening lab studies reveal HBsAg+ with normal liver chemistries. Her HBV DNA is found to be >100,000,000 copies/ ml. Her mother and brother both are known to have hepatitis B. You are asked to recommend measures to prevent vertical transmission of hepatitis B.

Prevention of vertical transmission of hepatitis B your recommendation is:

1. Administer hepatitis B vaccination at birth 2. Recommend c-section and vaccination 3. Begin hepatitis B vaccination before delivery
and give HBIG after delivery 4. Give HBIG and 1st hep B vaccination within 12 hours of delivery; consider antiviral therapy after 34 weeks of gestation

Hepatitis B prevention in neonates

Placenta excellent barrier Transmission generally during delivery (no role for c-section) Maternal viremia important:

70-90% transmission rate if HBeAg+ 10-30% if HBeAg Lamuvudine* consider therapy at 34 weeks in HBeAg+ mothers with prelabor HBV DNA > 108 copies/ml

Infants of HBsAg-positive mothers should receive

HBIG (0.5 ml) within 12 hours and 1st dose of hep B vaccine

Chronic hep B treatment in pregnancy

Lamivudine, adefovir, entecovir, interferon and
peginterferon alpha - Category C Telbivudine Category B Consider treating with lamivudine during pregnancy and switch to another agent post partum if continued therapy needed* Controlled trials needed Report treated pregnant patients to pregnancy registry www.APRegistry.com Breastfeeding not recommended during treatment with lamivudine, adefovir, entecavir and telbivudine

Hepatitis B - infant
Check for antiHBs between 9-18 months Passively acquired anti-HBc detected up to
24 months ? Vertical transmission father to fetus American Academy of Pediatrics breastfeeding not contraindicated for infants born to mothers who are HbSAg+ ( after vaccination/HBIG)

Vertical transmission of Hepatitis C

Risk of vertical transmission from
chronically infected mother ~ 5% Risk factors:
High levels of hepatitis C RNA HIV coinfection Long duration between membrane rupture and delivery

Hepatitis C and infants

Higher rate of spontaneous clearance Test infants with HCV RNA on 2 occasions
between the ages of 2 and 6 months and/or test for HCV antibody after 15 mo ? C-section beneficial Avoid fetal scalp monitoring Breast feeding - acceptable unless clear nipple trauma or abrasions

Portal Hypertension during Pregnancy

Portal pressure increases due to increased plasma
volume and cardiac output; increased vascular resistance from external compression of IVC Risk of variceal hemorrhage greatest in 2nd trimester and during labor ( 75% if pre-existing varices) Prognosis better for noncirrhotic portal HTN Treatment of variceal hemorrhage banding Safety of octreotide unknown, avoid vasopressin Possible use nonselective betablockers Minimize second part of labor, avoid excessive fluids

Splenic artery aneurysm

Splenic artery rupture occurs in up to 2.5
% of cirrhotics during pregnancy Pregnant patients with cirrhosis should undergo Doppler ultrasound to screen Consider surgical or IR therapy if > 2 cm Clinical findings: abdominal pain, pulsatile left upper quadrant mass, abdominal bruit

Cholelithiasis and cholecystitis

Pregnancy promotes bile lithogenicity and sludge ~ 10% of pregnant women have cholelithiasis Pregnancy does not increase frequency or severity of
complications; ERCP - consider tertiary center Cholecystectomy-best performed in 2nd trimester
1st trimester increased fetal death 3rd trimester premature labor Estogen increases cholesterol synthesis Progesterone impairs gallbladder motility

Laparoscopic cholecystectomy - safe

Hepatic adenomas
Accelerated growth from high estrogen levels Complications:
Hemorrhage and intraperitoneal rupture Adenomas > 5 cm or symptomatic or intralesional bleeding should be considered for surgical resection before contraception

Contraception and pregnancy post liver transplantation

Delay pregnancy 1-2 years Increased risk of HTN and pre-eclampsia Most immunosuppressant regimens with

acceptable risk profiles Liver enzyme abnormalities evaluate at transplant center Most pregnancies
Live births Intrauterine growth retardation

Pregnancy post liver transplantation

All should be considered high risk - requiring
multidisciplinary team All immunosuppressants cross maternalplacental-fetal barrier Graft rejection 4-17%, fetal malformations - 3% Data on outcomes available from the Pregnancy Transplant Registry American Academy of Pediatrics - endorses breast feeding for mothers taking corticosteroids but not cyclosporine No recommendations for azathioprine or tacrolimus