Liver Disease in Pregnancy

1. Liver Disease in Pregnancy Britt B. Drake, M.D. Resident�s Conference

2. Normal Changes During Pregnancy Size and appearance of liver unchanged Blood flow to liver unchanged despite increased maternal blood flow Labs: Alkaline phosphatase increases 1.5-4x normal Mild increases in bilirubin AST/ALT unchanged Decreased serum albumin Bilirubin � decreased hepatic clearance and impaired bili transport Albumin � slightly decreased hepatic synthesis, hemodilution Bilirubin � decreased hepatic clearance and impaired bili transport Albumin � slightly decreased hepatic synthesis, hemodilution

3. Normal Changes During Pregnancy Altered protein synthesis PT unchanged Decreased antithrombin III + increased fibrinogen = prothrombotic state Decreased ceruloplasmin Decreased transferrin Increased cholesterol production (HDL, VLDL, LDL, total cholesterol, triglycerides) Drug metabolism is unpredictable

4. Physical Examination Spider angiomata 60-70% Palmar erythema (63% white, 39% black women) Liver not palpable Jaundice is NOT normal Spiders, palmar erythema � hyperestrogenemia in pregnancy, gone by 7 wks pp Spiders, palmar erythema � hyperestrogenemia in pregnancy, gone by 7 wks pp

5. Pregnancy-Related LiverDysfunction Hyperemesis gravidarum Intrahepatic cholestasis of pregnancy (ICHP) Acute Fatty Liver of Pregnancy (AFLP) Hemolysis, Elevated LFTs, Low Platelets (HELLP)

6. Hyperemesis Gravidarum Severe, persistent nausea and vomiting First trimester Complicates 0.35% - 0.8% of pregnancies 50% have increased LFTs (2-3x normal) seen 1-3 weeks after onset Mild jaundice, pruritis LFTs don�t go over 1,000s More severe the vomiting, higher the LFT elevations Jaundice, pruritis correlate with bili elevation LFTs don�t go over 1,000s More severe the vomiting, higher the LFT elevations Jaundice, pruritis correlate with bili elevation

7. Hyperemesis Gravidarum Present with hypovolemia, dehydration Electrolyte imbalances can develop Resolves rapidly with cessation of emesis Negligible mortality See K, Cl and metabolic alkalosisSee K, Cl and metabolic alkalosis

8. Intrahepatic Cholestasisof Pregnancy Pruritis, increased LFTs and jaundice Late 2nd trimester to 3rd trimester Complicates 1-2% pregnancies in US/Europe Etiology unclear (genetic, hormal factors) Recurs in 2/3 subsequent pregnancies 5x more frequent with multiple gestations Seasonal variations reported Complicates 14% - S. America, Scandinavia 24% Aracanian Indians of Chile 50% who develop IHCP will become jaundiced on BCPs � genetic defect in estrogen processing?Complicates 14% - S. America, Scandinavia 24% Aracanian Indians of Chile 50% who develop IHCP will become jaundiced on BCPs � genetic defect in estrogen processing?

9. IHCP Pathogenesis Multifactorial ? Increased sensitivity of liver to cholestatic effects of estrogen Markedly increased serum bile acids Genetic defects found in sulfotransferase activity Genetic defects found in a biliary phospholipid translocator Exogenous prednisone can be a trigger for IHCP Incr bile acids � decr. Hepatic capacity to process/transport them? Sulfation detoxifies estrogens and bile acidsIncr bile acids � decr. Hepatic capacity to process/transport them? Sulfation detoxifies estrogens and bile acids

10. IHCP Presentation Intense pruritus in palms and soles Pruritus worse at night No skin lesions seen Onset between 28-30 weeks gestation Serum bile acids do NOT correlate with severity Jaundice starts 1-4 weeks after pruritus Jaundice + pruritus = pruritus gravidarum Jaundice seen in 20-60% of patientsJaundice seen in 20-60% of patients

11. IHCP Presentation Nausea and vomiting 5-75% Abdominal pain 9-24% Labs with cholestatic picture Bilirubin rarely > 5-6mg/dL AST/ALT elevated 2-10x normal in 20-60% PT can be elevated PT elevation due to vitamin K deficiency PT elevation due to vitamin K deficiency

12. IHCP Management Diagnosis of exclusion Vitamin K before delivery Cholestyramine (8-16g per day) Ursodeoxycholic acid under investigation Symptoms resolve with delivery Complications: Premature labor Meconium-stained amniotic fluid 27% Fetal distress 18% Stillbirth 3% Caution: cholestyramine can decrease vit K absorption Urso can cross placenta can potentially cause fetal toxicity Premature labor up to 5 fold increase Caution: cholestyramine can decrease vit K absorption Urso can cross placenta can potentially cause fetal toxicity Premature labor up to 5 fold increase

13. Acute Fatty Liverof Pregnancy 3rd trimester More common with primiparas, male & twin gestations ? Decreased mitochondrial oxidation of fatty acids with elevated estrogen levels LCHAD deficiency identified in 20% Decreased oxidation of fatty acids = poor processing of triglycerides and ffa�s which deposit in hepatocytes LCHAD � autosomal recessiveDecreased oxidation of fatty acids = poor processing of triglycerides and ffa�s which deposit in hepatocytes LCHAD � autosomal recessive

14. Acute Fatty Liverof Pregnancy Present with: headache, nausea, vomiting, fatigue, polydipsia Jaundice eventually develops 1-2 weeks after jaundice, rapid deterioration Preeclampsia (HTN, proteinuria) seen in > 50% AST / ALT elevated Leukocytosis with neutrophilic left shift Thrombocytopenia in 90% AST/ALT elevations < 1,000 Don�t reflect disease severity AST/ALT elevations < 1,000 Don�t reflect disease severity

15. Acute Fatty Liver of Pregnancy Complications Upper GI bleed 30-40% Renal dysfunction 70% DIC 56% Pancreatitis 30% Severe hypoglycemia 25-50%

16. Acute Fatty Liverof Pregnancy Medical and obstetric emergency DDX: acute viral hepatitis, drug-induced hepatitis, preeclampsia related liver disease, tetracycline-induced fatty liver, biliary dz Liver biopsy � centrilobular hepatocytes are swollen with microvesicular fat globules Treatment � deliver baby ASAP! Mortality of mother 15%, baby 36%

17. HELLP Syndrome Severe, life-threatening complication of preeclampsia Third trimester Incidence of 0.17-0.85% Occurs in 20-25% of women with preeclampsia 20% with HELLP have no HTN or proteinuria ? Imbalance between vasoconstrictive and vasodilative forces causing endothelial dysfunction and platelet aggregation

18. HELLP Syndrome Presentation: Mean age � 25 years RUQ pain 70-90% Nausea, vomiting common Headache 25% Visual changes 15-30% Generalized edema 50-67% Ascites 8-10%

19. HELLP Syndrome Lab Abnormalities Low haptoglobin level in 95% Bilirubin elevation 47-62% Low platelets 50% AST/ALT elevation (3x above normal) Low haptoglobin � most sensitive measure for hemolysis. Seen before plt count drops. Low haptoglobin � most sensitive measure for hemolysis. Seen before plt count drops.

20. HELLP Syndrome Maternal complications DIC 4-38% Placental abruption 10-16% Acute renal failure 1-8% Severe ascites 5-8% Pulmonary edema 2-10% ARDS 1% Hepatic infarction / rupture 1% Maternal complication seen in 12-65% of casesMaternal complication seen in 12-65% of cases

21. HELLP Syndrome Management Complete bed rest Onset of DIC = immediate delivery Corticosteroids beneficial Maternal mortality 8% Fetal mortality 8-37% 50% mortality due to hepatic hematoma with rupture50% mortality due to hepatic hematoma with rupture