1. Intrahepatic Cholestasis of Pregnancy
Rare

2. 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)

3. Cholestasis

4. 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

5. 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

6. 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)

7. 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, Cleveland Clinic.

8. 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

9. 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

10. 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

11. 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

12. Case Study

13. What is the Problem

14. 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

15. 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

16. Questions?

17. Inherited and Pediatric Liver Disease
A Brief Overview

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

19. 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

20. 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

21. 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

22. 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

23. 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

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

25. 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

26. 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

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

28. 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

29. 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

30. 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

31. Case Study