Liver Disease in Pregnancy Preethi Reddy, MD

Assistant Professor of Medicine University of Texas Health Science Center at Houston

Memorial Hermann- Texas Medical Center

Liver in Pregnancy

• Normal physiology of pregnancy

• Liver Diseases:

– Pregnancy-associated

– Coincidental to pregnancy

– Chronic liver disease in pregnancy

Normal Physiology of Pregnancy

• Hyperdynamic, pro-coagulant • Physical Exam:

– Spider angioma – Palmar erythema

• Normal ALT, AST, GGT, bilirubin, INR/protime • alkaline phosphatase

• placenta, fetal bone • AFP

• fetal liver • fibrinogen, factors II, V, VII, X, XII • Hemoglobin, albumin, urea

Biochemical Changes in Normal Pregnancy

Test Change Trimester

ALT --

AST --

Alkaline phosphatase third

GGT --

Total bilirubin --

Albumin second

Urea second

Hemoglobin second

Fibrinogen, factors II, V, VII, X, XII second

Olans et al. Liver Disease in Pregnancy 2003.

Abnormal in Pregnancy • Jaundice • Hepatomegaly • Splenomegaly • Abdominal pain • Murphy’s sign • Diffuse excoriations • Hypertension • Orthostatic hypotension • Peripheral edema • Neurologic findings (asterixis, hyperreflexia) • Ecchymosis, petechiae

Diagnostic Tests • History and physical exam are key

• Routine blood chemistry and blood count

• Serum bile acid level- ICP

• Uric acid- AFLP, pre-eclampsia

• DIC panel- AFLP

• Amylase, lipase- abdominal pain

• Viral hepatitis serologies

• Avoid sedative medications and radiation

• Ultrasound is safe and helpful

• MRI is safe

– Gadolinium should not be used

• Liver biopsy is RARELY needed

Differentials for Elevated LFTs

1st Trimester 2nd Trimester 3rd Trimester

Hyperemesis gravidarum Cholelithiasis Viral hepatitis Drug-induced hepatitis Uncommon: ICP

ICP Cholelithiasis Viral hepatitis Drug-induced hepatitis Uncommon: Pre-eclampsia/eclampsia HELLP syndrome

ICP Pre-eclampsia/eclampsia HELLP syndrome AFLP Hepatic rupture Cholelithiasis Viral Hepatitis Drug-induced hepatitis

Olans et al. Liver Disease in Pregnancy 2003.

Pregnancy-associated Liver Diseases

• Hyperemesis Gravidarum

• Intrahepatic Cholestasis of Pregnancy (ICP)

• Overlap Syndromes:

– Pre-eclampsia/eclampsia

– HELLP (hemolysis, elevated liver tests, low platelets)

– Acute Fatty Liver of Pregnancy (AFLP)

Hyperemesis Gravidarum

• Most common in the 1st trimester • Intractable nausea and vomiting

– Dehydration, electrolyte abnormalities, weight loss of ≥ 5%, nutritional deficiencies

• Risk factors: history of HG, hyperthyroidism, DM, overweight, multiple gestations, primiparity, age <25

• Abnormal liver function tests 50% of cases – ↑ALT 1-3X upper limit of normal (ULN)

• Up to 20X ULN – Rarely increased bilirubin

• Treatment: hydration, vitamin supplementation (thiamine), anti-emetics, nutrition

• Good maternal and fetal outcome

ICP • Reversible intrahepatic cholestasis

– Late 2nd/ 3rd trimester

– Resolves 4-6 weeks post-delivery

• Intense pruritus (palms/soles → whole body), jaundice (10-25%)

• Risk factors: personal or family history of ICP, prior cholestatic hepatitis (OCPs/estrogen), progesterone use in pregnancy, advanced maternal age, multiple gestations, underlying HCV

• Etiology: genetic, hormonal, environmental

– Gene variants of hepatocanalicular transport proteins • Increased sex hormone production in pregnancy

• Impaired hepatic clearance of bile acids from portal blood

– Sensitivity to estrogens

– Selenium deficiency? Friedman et al. Handbook of Liver Disease 2011. Glantz et al. Hepatol 2004. Ambros-Rudolph et al. JAMA 2007.

ICP • Elevated aminotransferases

– Up to 4X ULN

• ↑ serum bile acid levels ( > 11 μmol/L)

– 10-100X ULN

• Vitamin K deficiency (malabsorption)

• US to rule out cholelithiasis

• Liver biopsy: cholestasis, mild hepatocellular necrosis

• Treatment:

– Ursodeoxycholic acid (UDCA) 10-15 mg/kg body weight, cool environment, emollients

– Early delivery

• Typically good maternal outcome

• Fetus: Increased risk of preterm delivery, meconium staining of amniotic fluid, fetal distress/loss

– Better outcome with lower bile acid levels (<40 μmol/L) Ambros-Rudolph et al. JAMA 2007.

Pre-eclampsia/Eclampsia

• Late 2nd/ 3rd trimester (>20 weeks)

• Previously normotensive

• Hypertension (SBP >140, DBP >90), proteinuria (>300 mg/24h), edema

• Seizures, coma (eclampsia)

• Hepatic, renal, CNS, hematologic and fetal placental involvement

• Risk factors: history of pre-eclampsia/eclampsia, young and advanced maternal age, multiple gestations, obesity, insulin resistance, infection, inadequate prenatal care

• Unknown etiology

Pre-eclampsia/Eclampsia

• Elevated aminotransferases (5-100X ULN)

– Eclampsia (90%)

– Severe pre-eclampsia (50%)

– Pre-eclampsia (24%)

• Mild increase in total bilirubin (≤ 5 mg/dL)

• Thrombocytopenia, MAHA

• Treatment:

– Anti-hypertensives, bed-rest, magnesium sulfate

– Delivery if eclampsia (or late pre-eclampsia)

• Maternal and fetal outcome depends on severity

– Death commonly from cerebral involvement

– ↑ risk of hepatic rupture and HELLP

– Resolution of abnormal LFTs post-delivery

Friedman et al. Handbook of Liver Disease 2011.

HELLP Syndrome

• Hemolysis, elevated liver tests, low platelets • 3rd trimester • Postpartum (15-25%, usually within 2 days) • Risk factors: personal history, advanced maternal age, Caucasian,

multiparity • Epigastric pain, nausea, vomiting, H/A, hypertension, visual

changes, weight gain, edema, jaundice • MAHA, ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin, schistocytes • ↑ aminotransferases (mild- 100 x ULN) • Thrombocytopenia ( <10K) • Proteinuria

Fang et al. Br J Haematol 2008.

HELLP Syndrome

• Treatment:

– Anti-hypertensives, seizure prophylaxis

– Fetal monitoring

– Early delivery

• Maternal/fetal distress

• Severe thrombocytopenia

– Corticosteroids to improve fetal lung maturity (<34 weeks)

• Maternal mortality (1%)

• High infant mortality (up to 20%)

– Prematurity, IUGR, coagulopathy

AFLP • Rare • Microvesicular steatosis of the liver→ liver failure • 3rd trimester • May occur immediately post-partum • Etiology:

– Nutritional factors – Changes in lipoprotein synthesis – Mitochondrial urea cycle enzyme deficiencies – Defects in maternal mitochondrial fatty acid beta-oxidation

• Fetal LCHAD deficiency (long–chain 3-hydroxyacyl –coenzyme A dehydrogenase)

• Fetal homozygosity/maternal heterozygosity • LCHAD:

– component of MTP (mitochondrial trifunctional protein) – catalyzes β-oxidation of long-chain fatty acids (LCFA)

Friedman et al. Handbook of Liver Disease 2011.

AFLP: LCHAD Deficiency

↑↑↑ fetal LCFA

{Maternal circulation}

Heterozygosity of mother/reduced ability to oxidize

LCFA

Fatty infiltration

Progressive liver failure

Jaundice

Coagulopathy

Hepatic encephalopathy

Renal failure

• Hepatic carnitine palmitoyl transferase I deficiency

AFLP • ↑ aminotransferases (< 500 U/L) • Mild to moderate ↑ AP and bilirubin • Hyperuricemia • Fatty infiltration on imaging • Liver biopsy with Oil-Red-O stain • Swansea Criteria (6 or more):

– Abdominal pain – Vomiting – Polyuria/polydipsia – Hepatic encephalopathy – Hyperbilirubinemia – Leukocytosis – Ascites/ fatty infiltration of the liver on US – Transaminemia – Coagulopathy – Elevated ammonia – Renal dysfunction – Microvesicular steatosis

Kingham et al. Gut 2010.

AFLP

• Treatment:

– Emergent delivery

– Liver transplant if acute liver failure

– Plasma exchange

– Improving outcomes with supportive care

• Mostly good maternal outcome

• Screen for fatty acid oxidation defect for those affected

Pre-eclampsia/eclampsia

HELLP

AFLP

(severe thrombocytopenia)

Hepatic

intraparenchymal hemorrhage

Subcapsular hematoma

HEPATIC RUPTURE

• 3rd trimester • Sudden onset

abdominal pain, N/V, distension

• Hypovolemic shock • US, CT, MRI • Prompt delivery • Surgical or IR

intervention • High maternal and

fetal mortality

Coincidental to Pregnancy

• Autoimmune Hepatitis (AIH)

• Drug-Induced Hepatitis

• Viral Hepatitis A-E, Herpes Simplex Virus

• Cholelithiasis/Cholecystitis

• Budd-Chiari Syndrome

Viral Hepatitis A-E

• Only hepatitis E course is affected by pregnancy – Jaundice is more common – Acute liver failure – Increased maternal and fetal mortality – Vertical transmission in ≈ 30% – Check HEV IgM – Supportive care

• Vertical transmission in uncommon with hepatitis A and D – HAV immunoglobulin – Control hepatitis B to prevent transmission of hepatitis D

• HCV: – Higher rate of vertical transmission if significant or HIV co-infection (≈35%) – Breastfeeding is safe

Friedman et al. Handbook of Liver Disease 2011. Aggarwal et al. J Gastoenterol Hepatol 2009.

Hepatitis B • Perinatal transmission is most likely to occur at delivery

– C-section not indicated

• Who to treat?

• HBsAg + mothers with HBV DNA PCR >200,000 IU/Ml

– No data on when to stop therapy

– Monitor for flares if therapy is discontinued

– Pregnancy Class B: telbivudine, tenofovir (preferred)

• Infants of all HBsAg+ mothers: HBIG and initiation of HBV vaccination series within 12 hours of birth

– Reduced rate of vertical transmission (> 90% to <10%)

• Breastfeeding is safe Terrault et al. Heptol 2015. Zou et al. J Viral Hepatol 2012. Atkins et al. BMJ 2004. Lok et al. Hepatol 2009. WHO Guidelines 2015. Ott et al. Vaccine 2012.

Herpes Simplex Hepatitis (HSV)

• Disseminated HSV

– Rare

– Late 2nd/ 3rd trimester

– Presentation: fever, nausea, vomiting, cutaneous lesions, abdominal pain, thrombocytopenia, coagulopathy, ↑↑↑aminotransferases

– Check HSV PCR

– Complications: acute liver failure, hepatic necrosis, DIC, death

– Treatment: prompt acyclovir

Vascular and Biliary Disease in Pregnancy • Budd-Chiari Syndrome: Hepatic vein occlusion

– Usually associated with thrombotic diathesis

• Pregnancy and OCP (20%)

– Acute onset abdominal pain, hepatomegaly and ascites

– Ultrasound, MRI

– Avoid venography or angiography

– High maternal mortality (70%)

• Cholelithiasis/Cholecystitis: ↑ estrogen ↑ bile lithogenicity (2nd and 3rd trimester) biliary sludge, gallstones ↑ progesterone ↑ gallbladder volume/ ↓ emptying time Fluids, replete electrolytes, bowel rest, antibiotics Laparascopic cholecystectomy is safest in 2nd trimester

Chronic Liver Disease in Pregnancy

• Viral Hepatitis

• Autoimmune Hepatitis (AIH)

• Primary Biliary Cholangitis (PBC)

• Wilson’s Disease

• Cirrhosis and Portal Hypertension

AIH • Variable course in pregnancy

– Can improve

• Discontinue immunosuppression where possible

– Pregnancy Class D: Azathioprine

• Monitor for flares during pregnancy and early postpartum

– ↑ frequency of flares postpartum (↓ estrogen)

– Resume standard therapy 2 weeks prior to delivery

– Monitor liver enzymes q3weeks for 3 months postpartum

• Favorable outcomes with well-controlled AIH

• 3% maternal mortality

• Rate of fetal loss is comparable to other chronic diseases

– Related to prematurity

• 19% mortality with deliveries at <20 weeks

• Pre-conceptional counseling in AIH patients of childbearing age Manns et al. Hepatol 2010. Candia et al. Semin Arthritis Rheum 2005. Heneghan et al. J Hepatol 2006. Schramm et al. Am J Gastroenterol 2006.

PBC

• Biochemical improvement in pregnancy

– ALT, AP, bilirubin, IgG, IgM, AMA titers

• ↑ estrogen→ cholestasis→ ↑pruritus

• Risk of flare postpartum

• Treatment: Continue UDCA

Wilson’s Disease

• May decrease fertility • Increased rate of spontaneous of abortion • Maintain anticopper therapy throughout pregnancy

– Penicillamine, trientene, zinc • Limited safety data in pregnancy • Benefits of therapy outweigh risks • Reduce dose of chelating agents (25%-50% of prepregancy dose) • Standard zinc dosing

• No breastfeeding with D-penicillamine – ?safety with trientene and zinc

• Cessation of therapy may lead to acute liver failure

Roberts et al. Hepatol 2008.

Cirrhosis and Portal Hypertension

• Increased risk of variceal hemorrhage

– Screening EGD before pregnancy or in the 2nd trimester (↑↑maternal blood volume)

– Beta blockers are safe

– Shorter labor is favorable

• ↑ risk of VH with Valsalva maneuver

Key Points • Normal pregnancy physiology may affect the normal range of liver

function tests.

• Elevated aminotransferases, coagulopathy, proteinuria, hyperuricemia and elevated serum bile acid levels are abnormal.

• History and physical exam are key.

• Ultrasound may be helpful.

• Liver biopsy is RARELY needed.

• Risk of recurrence with pregnancy-associated diseases.

• Pre-eclampsia/eclampsia, HELLP and AFLP are overlap syndromes.

• Prompt diagnosis is crucial for a favorable outcome.

• Severe pre-eclampsia, eclampsia, AFLP and HELLP syndrome are indications for prompt delivery.

Thank You