liver disease in pregnancy - memorialhermann.org · hyperemesis gravidarum • most common in the...
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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.