Intrahepatic Cholestasis of Pregnancy Rare

Cholestasis: What Does it Mean? Pathology: Histological demonstration of bile in liver tissue Physiology: Measurable reduction in hepatic secretion of solutes and water Biochemical: Demonstrable accumulation in blood of substances normally excreted in bile (bilirubin, cholesterol, bile acids)

Cholestasis

Liver Diseases in Pregnancy High estrogen state: Intrahepatic cholestasis of pregnancy Gallstones and sludge occur more frequently Altered fatty acid metabolism: Acute fatty liver of pregnancy Vascular diseases affect the liver: Pre-eclampsia HELLP Syndrome Viral hepatitis: Vertical transmission of hepatitis B and C HELLP: Hemolysis, Elevated Liver enzymes, Low Platelets

Pathophysiology Liver is an estrogen sensitive organ Estrogen affects organic anion transport (bilirubin, bile acids) Bilirubin excretion very mildly impaired during normal pregnancy Biliary phospholipids secretion may be impaired (gene mutation, estrogen effect) Pregnancy is associated w/ decreases in GI motility, including gall bladder motility

Physiological Consequences: The Liver in Pregnancy Pregnant women more likely to become jaundiced if cholestatic or hepatocellular injury occur Spider angiomata and palmar erythema develop in up to 2/3 pregnancies due to effects of estrogen and progesterone Cholecystectomy generally safe 3rd Trimester see increased alk phos 2/2 developing placenta (not liver)

Intrahepatic Cholestasis of Pregnancy (IHCP) Incidence 0.1% - 1% of pregnancies Recurrence in subsequent pregnancies Pruritis develops in late 2nd and 3rd trimester High transaminases - 40% > 10 x (Hay) Bilirubin < 5mg/dL Total bile acids increase 100 fold Eileen Hay, Pregnancy related liver disorders: Case studies, Liver Disease in Women Summit. June 15-16, 2007. Cleveland Clinic.

Intrahepatic Cholestasis of Pregnancy (IHCP) Pathogenesis: genetic, hormonal Women who develop clinical cholestasis during pregnancy or with oral contraceptives likely have genetic polymorphisms in the genes responsible for bile formation and flow Familial - 10% occurrence in 1st degree relatives Hormonal – timing in pregnancy, twins

ICHP Clinical Features Pruritis is the defining characteristic About 50% develop jaundice Disappears rapidly after delivery Severity is variable Rarely see a familial, progressive course to cirrhosis

IHCP Therapy Ursodeoxycholic acid 10mg- 10mg/Kg/day Cholestyramine Vitamin K p.r.n. Reassurance and support Consider early delivery in severe cases Unbearable maternal pruritis or risk of fetal distress/death Deliver at 38 weeks if mild, at 36 weeks for severe cases – if jaundice

Summary Normal pregnancy is associated w/ characteristic, benign changes in liver physiology Several unique diseases occur during pregnancy and all resolve following delivery Implications are disorder specific

Case Study

What is the Problem

Case study (Hay) 32 year old Para 1 @ 24 weeks two weeks of severe pruritis Pruritis and abnormal LFTs in last pregnancy Known gallstones – no biliary dilatation on ultrasound No abdominal pain, fever, rash Exam normal apart from pregnancy AST 277 ALT 655 Bili 2.1 Alk Phos 286

Case Study Hepatitis A, B, C serologies non reactive Negative autoimmune markers Urso 300 mg t.i.d. is prescribed 32 weeks - feels well; D/C Urso 33 weeks - pruritis - resume Urso 37 weeks - delivery healthy baby; D/C Urso 2 weeks postpartum - LFTs normal

Questions?

Inherited and Pediatric Liver Disease A Brief Overview

Inherited and Pediatric Liver Diseases Wilson Disease Hereditary hemochromatosis Alpha 1 Antitrypsin Deficiency Inborn errors of metabolism Fibrocystic diseases Pediatric cholestatic diseases Porphyria

Wilson Disease Autosomal recessive pattern of inheritance Defective gene: ATP7B on chromosome 13 Leads to copper overload in liver, other organs World wide distribution Incidence 1:30,000 Carrier state 1:90 Higher in Sardinians and Chinese, infrequent in Africa

Wilson Disease Variable Presentation Liver, brain damage due to oxidative stress Age of onset between 6 to 45 May present as chronic liver disease or acute liver failure, progressive neurological disorder without liver involvement or as a psychiatric illness

Wilson Disease Variable Presentation Neurological sequelae occur 2nd – 3rd decade: Increased or abnormal motor disorder w/ tremor/dystonia Loss of movement w/ rigidity Psychiatric sequelae Depression Phobias Psychosis

Wilson Disease Ocular Features Classic finding: Kayser-Fleisher ring, a golden-brown deposit at the outer rim of the cornea Sunflower cataract, less frequent. Copper deposition in the lens

Wilson Disease Involves Other Organs Hemolytic anemia 2/2 sporadic release of copper into the blood Renal involvement w/ Fanconi syndrome, microscopic hematuria, stones Arthritis 2/2 copper deposit in synovial joints Osteoporosis, Vitamin D resistant rickets 2/2 renal damage

Wilson Disease Involves Other Organs Cardiomyopathy Muscles: Rhabdomyolysis Pancreatitis Endocrine disorders

Wilson Disease Diagnosis and Treatment Lab findings: Decreased ceruloplasmin and serum copper, excess urinary copper 24 hour urine x 3 to confirm diagnosis Histology: Hepatic copper deposition Treatment is chelation: penicillamine, which increases urinary copper excretion ammonium tetrathiomolybdate

Wilson Disease Treatment Zinc interferes w/ copper binding, decreasing absorption Elimination of copper-rich foods from the diet: Organ meats, shellfish, nuts, chocolate, mushrooms Check drinking water supply Liver transplantation if ALF

Wilson Disease Prognosis is good on chelation therapy if diagnosed promptly Affected sibling diagnosed and treated prior to symptom onset has the best prognosis

Pediatric Cholestatic Syndromes Neonatal jaundice is common, transient, usually due to immature glucouronosyl transferase or to breast feeding If jaundice persists after 14 days, investigate Extrahepatic biliary atresia requires urgent surgical repair of abnormal hepatic or common bile ducts

Pediatric Cholestatic Syndromes Neonatal hepatitis 2/2 infection, idiopathic Intrauterine infections i.e., TORCH: toxoplasmosis, rubella, cytomegalovirus, herpes simplex Alagille Syndrome – few bile ducts, congenital heart disease, skeletal abnormalities Autosomal dominant, Incidence: 1:70,000

Pediatric Cholestatic Syndromes Progressive Familial Intrahepatic Cholestasis, another group of autosomal recessive disorders involved w/ errors in bile acid synthesis and bile acid transport Byler Disease now called PFIC1 Byler Syndrome now called PFIC 2

Case Study