Leverafwijkingen tijdens de zwangerschap.

1. Leverafwijkingen tijdens de zwangerschap. H. Reynaert, M.D., Ph.D. Dienst Gastroenterologie-hepatologie, UZ Brussel. Laboratory liver cell biology (LIVR), VUB.

2. Introduction. • 3-5% of pregnant women have abnormal liver tests. • Pre-existing liver disease. • Co-incidental liver disease. • Pregnancy-related. • Significant maternal/fetal morbidity/mortality • Early diagnosis and treatment. Hepatology 2008; 47: 1067-76.

3. Disorders unrelated to pregnancy • Pre-existing disease • Chronic hepatitis B, C • Auto-immune hepatitis • Cirrhosis/ portal hypertension • Transplantation • Co-incidental disease • Acute viral hepatitis (A, B, C, D, E, CMV, EBV, HSV) • Gallstone disease • Vascular disorders (Budd-Chiari) • Toxic (drugs/herbals) Lancet. 2010; 375: 594-605.

4. Disorders “unique” to pregnancy • (Pre)-eclampsia-associated • (Pre)-eclampsia • HELPP syndrome • Acute fatty liver of pregnancy (AFL) • No association with pre-eclampsia • Hyperemesis gravidarum • Intra-hepatic cholestasis of pregnancy (ICP) Lancet. 2010; 375: 594-605.

5. Hemolysis Elevated Liver tests Low Platelets • 0.5% of pregnancies • 85% clear association with pre-eclampsia • 2-10% of pre-eclampsia • Indication of severe disease • Different presentation of same disease? • Usually 3rd trimester or after delivery BMC Pregnancy and Childbirth 2009, 9:8-; Dig Dis Sci 2008, 53:2334–

6. HELLP Am J Obstet Gynecol. 2000; 183: 444-8.

7. Diagnosis HELLP syndrome. • Hemolysis • Microangiopatic hemolitic anemia • Endothelial damage & dysfunction • Abnormal implantation of trophoblast • Angiogenic-antiangiogenic imbalance no low systemic vascular resistance • Destruction of RBC • Blood smear: • Schizocytes, Burr cells, reticulocytes • LDH (>600IU/ml), unconjugated bili, haptoglobin • AST or ALT > 70 IU/ml • Low platelets: • Consumption • <100.000 /μL • INR: Normal BMC Pregnancy and Childbirth 2009, 9:8-; Dig Dis Sci 2008, 53:2334–

8. Management. • ICU: fetal and maternal monitoring • AHT, seizures, Renal failure • DIC, ARDS • Abruptio placentae • Liver hematoma, rupture • Severe pain, fever, shock .. • MRI • Treatment: Angiography, surgery • Delivery • After 34 wks • Before 34 wks • Corticosteroids 24-48h? • Immediate if deterioration • Caesarian 50% BMC Pregnancy and Childbirth 2009, 9:8-; Dig Dis Sci 2008, 53:2334–

9. Acute fatty liver of pregnancy (AFLP) • Rare: 1/7000-1/16.000 • 3rd trimester • ACUTE CATASTROPHY • Hepatic failure • Encephalopathy • Microvesicular fatty infiltration of hepatocytes • “Yellow atrophy of the liver” Lancet. 2010; 375: 594-605. Can J Gastroenterol 2006;20:25-30

10. AFLP Lancet. 2010; 375: 594-605.

11. Mitochondrialβoxidation of fattyacids. Lancet. 2010; 375: 594-605.

12. Clinical features. Can J Gastroenterol 2006;20:25-30

13. Can J Gastroenterol 2006;20:25-30

14. Management. • ICU • Monitoring + stabilization • Hemodynamic • Encephalopathy • Renal function • Metabolic (hypoglycemia) • Coagulation • Pancreatitis • Delivery: emergency! • Never recovery without delivery Can J Gastroenterol 2006;20:25-30

15. Outcome. • Mother: • Mortality: 7-20% • Bleeding, pancreatitis, liver failure, sepsis • Recovery • Immediately or late (1 wk) • Prolonged cholestasis (several wks) • Eventually complete • Recurrence • Theoretically 25% • Child: • Mortality: 10-25% Can J Gastroenterol 2006;20:25-30

16. Hyperemesis gravidarum • 0,3-2% pregnancies • First trimester • Wks 4-18 • Etiology?: unclear. • Motility? Hormonal? Beta-hCG? Leptin? …. • Intractable vomiting, dehydration, weight loss > 5% • Risk factors • Diabetes, obesity, multiple pregnancies, young, … • Lab results: • Hyperthyroidism 60% • Abnormal (50%) ALT > AST up to 20 x ULN • Increased peripheral lipolysis  FFA  liver injury?? • Jaundice is rare Dig Dis Sci 2008, 53:2334–;Lancet. 2010; 375: 594-605.

17. Hyperemesis gravidarum • Treatment • Rehydration IV, short period fasting • Vitamin supplements (Thiamine) • Small, frequent meals • Diet rich in carbohydrates, low fat • Anti-emetics • Phenergan, primperan • Enteral, (parenteral) feeding • Outcome • Mother • Good • Fetus • Slightly increased congenital abnormalities? Lancet. 2010; 375: 594-605; Dig Dis Sci 2008, 53:2334– .

18. Intra-hepatic Cholestasis of Pregnancy • Prevalence <1% in W-Europe • Pathophysiology: incompletely understood • Genetic factors • Bile transporters • Hormonal • Estrogens/progesterone • Environmental • selenium? Orphanet Journal of Rare Diseases 2007, 2: 26-

19. Intra-hepatic Cholestasis of Pregnancy Lancet. 2010; 375: 594-605.

20. Clinical manifestations • Pruritus • Mild  very severe • Palms/soles • > 25-30 wks (as early as 6 wks) • Jaundice • Usually later Orphanet Journal of Rare Diseases 2007, 2: 26-

21. Biochemical abnormalities • bile acids: x10-100 • Fasting serum bile acids > 10μmol/L = diagnostic • ALT: <10x, sometimes > 20x • GGT: normal-slightly elevated • Bilirubin: nl-mildly elevated • Vit K deficiencey Orphanet Journal of Rare Diseases 2007, 2: 26-

22. Treatment: Ursodeoxycholic acid (UDCA). Gastroenterology 2005, 129: 894-901

23. Outcome. • Fetal • Preterm delivery (19-60%), mortality (0,4-4%), … • Associated with increasing fasting serum levels of bile acids (>40 μmol/L) • Good when treated with UDCA • Maternal • Good • Resolves after delivery Orphanet Journal of Rare Diseases 2007, 2: 26 -

24. Conclusions. • Not all abnormal liver tests are caused by pregnancy-related diseases. • Non-pregnancy related liver diseases should be ruled out! • Toxic & drug-induced hepatitis • Viral hepatitis • Biliary disease • Budd-Chiari • Etc.

25. Conclusions. Hepatology 2008; 47: 1067-76.