Intrahepatic Intrahepatic Cholestasis of Cholestasis of

PregnancyPregnancy

RareRare

Cholestasis:Cholestasis:What Does it Mean?What Does it Mean?

Pathology: Histological demonstration Pathology: Histological demonstration of bile in liver tissueof bile in liver tissue

Physiology: Measurable reduction in Physiology: Measurable reduction in hepatic secretion of solutes and waterhepatic secretion of solutes and water

Biochemical: Demonstrable Biochemical: Demonstrable accumulation in blood of substances accumulation in blood of substances normally excreted in bile (bilirubin, normally excreted in bile (bilirubin, cholesterol, bile acids)cholesterol, bile acids)

Liver Diseases in PregnancyLiver Diseases in Pregnancy High estrogen state:High estrogen state:

– Intrahepatic cholestasis of pregnancyIntrahepatic cholestasis of pregnancy– Gallstones and sludge occur more frequentlyGallstones and sludge occur more frequently

Altered fatty acid metabolism: Altered fatty acid metabolism: – Acute fatty liver of pregnancyAcute fatty liver of pregnancy

Vascular diseases affect the liver:Vascular diseases affect the liver:– Pre-eclampsiaPre-eclampsia– HELLP SyndromeHELLP Syndrome

Viral hepatitis:Viral hepatitis:– Vertical transmission of hepatitis B and CVertical transmission of hepatitis B and C

PathophysiologyPathophysiology Liver is an estrogen sensitive organLiver is an estrogen sensitive organ

– Estrogen affects organic anion transport Estrogen affects organic anion transport (bilirubin, bile acids)(bilirubin, bile acids)

Bilirubin excretion very mildly impaired Bilirubin excretion very mildly impaired during normal pregnancyduring normal pregnancy

Biliary phospholipids secretion may be Biliary phospholipids secretion may be impaired (gene mutation, estrogen impaired (gene mutation, estrogen effect)effect)

Pregnancy is associated w/ decreases in Pregnancy is associated w/ decreases in GI motility, including gall bladder GI motility, including gall bladder motilitymotility

Physiological Consequences:Physiological Consequences:The Liver in PregnancyThe Liver in Pregnancy

Pregnant women more likely to become Pregnant women more likely to become jaundiced if cholestatic or jaundiced if cholestatic or hepatocellular injury occurhepatocellular injury occur

Spider angiomata and palmar erythema Spider angiomata and palmar erythema develop in up to 2/3 pregnancies due to develop in up to 2/3 pregnancies due to effects of estrogen and progesteroneeffects of estrogen and progesterone

Cholecystectomy generally safeCholecystectomy generally safe 33rdrd Trimester see increased alk phos 2/2 Trimester see increased alk phos 2/2

developing placenta (not liver)developing placenta (not liver)

Intrahepatic Cholestasis of Intrahepatic Cholestasis of Pregnancy (IHCP)Pregnancy (IHCP)

Incidence 0.1% - 1% of pregnanciesIncidence 0.1% - 1% of pregnancies Recurrence in subsequent pregnanciesRecurrence in subsequent pregnancies Pruritis develops in late 2Pruritis develops in late 2ndnd and 3 and 3rdrd

trimestertrimester High transaminases - 40% > 10 x High transaminases - 40% > 10 x

(Hay)(Hay) Bilirubin < 5mg/dLBilirubin < 5mg/dL Total bile acids increase 100 foldTotal bile acids increase 100 fold

Intrahepatic Cholestasis of Intrahepatic Cholestasis of Pregnancy (IHCP)Pregnancy (IHCP)

Pathogenesis: genetic, hormonalPathogenesis: genetic, hormonal– Women who develop clinical cholestasis Women who develop clinical cholestasis

during pregnancy during pregnancy or with oral or with oral contraceptives contraceptives likely have genetic likely have genetic polymorphisms in the genes responsible polymorphisms in the genes responsible for bile formation and flowfor bile formation and flow

– Familial - 10% occurrence in 1Familial - 10% occurrence in 1stst degree degree relativesrelatives

– Hormonal – timing in pregnancy, twinsHormonal – timing in pregnancy, twins

ICHP Clinical FeaturesICHP Clinical Features Pruritis is the defining characteristicPruritis is the defining characteristic About 50% develop jaundiceAbout 50% develop jaundice Disappears rapidly after deliveryDisappears rapidly after delivery Severity is variableSeverity is variable Rarely see a familial, progressive Rarely see a familial, progressive

course to cirrhosiscourse to cirrhosis

IHCPIHCPTherapyTherapy

Ursodeoxycholic acid 10mg- Ursodeoxycholic acid 10mg- 10mg/Kg/day10mg/Kg/day

Cholestyramine Cholestyramine Vitamin K p.r.n.Vitamin K p.r.n. Reassurance and supportReassurance and support Consider early delivery in severe casesConsider early delivery in severe cases

– Unbearable maternal pruritis or risk of fetal Unbearable maternal pruritis or risk of fetal distress/deathdistress/death

– Deliver at 38 weeks if mild, at 36 weeks for Deliver at 38 weeks if mild, at 36 weeks for severe cases – if jaundicesevere cases – if jaundice

Summary Summary Normal pregnancy is associated w/ Normal pregnancy is associated w/

characteristic, benign changes in characteristic, benign changes in liver physiologyliver physiology

Several unique diseases occur during Several unique diseases occur during pregnancy and all resolve following pregnancy and all resolve following deliverydelivery

Implications are disorder specificImplications are disorder specific

Case StudyCase Study

What is the ProblemWhat is the Problem

Abnormal LFTsJaundice, pruritis,abdominal pain,

and vomiting

UltrasoundR/O Gallstones Family Hx Co-morbidities

Case studyCase study(Hay)(Hay)

32 year old Para 1 @ 24 weeks32 year old Para 1 @ 24 weeks– two weeks of severe pruritistwo weeks of severe pruritis– Pruritis and abnormal LFTs in last Pruritis and abnormal LFTs in last

pregnancypregnancy– Known gallstones – no biliary dilatation Known gallstones – no biliary dilatation

on ultrasoundon ultrasound– No abdominal pain, fever, rashNo abdominal pain, fever, rash– Exam normal apart from pregnancyExam normal apart from pregnancy– AST 277 ALT 655 Bili 2.1 Alk Phos 286 AST 277 ALT 655 Bili 2.1 Alk Phos 286

Case StudyCase Study Hepatitis A, B, C serologies non Hepatitis A, B, C serologies non

reactivereactive Negative autoimmune markersNegative autoimmune markers Urso 300 mg t.i.d. is prescribedUrso 300 mg t.i.d. is prescribed 32 weeks - feels well; D/C Urso32 weeks - feels well; D/C Urso 33 weeks - pruritis - resume Urso33 weeks - pruritis - resume Urso 37 weeks - delivery healthy baby; D/C 37 weeks - delivery healthy baby; D/C

UrsoUrso 2 weeks postpartum - LFTs normal2 weeks postpartum - LFTs normal

Questions?Questions?

Inherited and PediatricInherited and PediatricLiver DiseaseLiver Disease

A Brief OverviewA Brief Overview

Inherited and Pediatric Liver Inherited and Pediatric Liver DiseasesDiseases

Wilson DiseaseWilson Disease Hereditary hemochromatosisHereditary hemochromatosis Alpha 1 Antitrypsin DeficiencyAlpha 1 Antitrypsin Deficiency Inborn errors of metabolismInborn errors of metabolism Fibrocystic diseasesFibrocystic diseases Pediatric cholestatic diseasesPediatric cholestatic diseases Porphyria Porphyria

Wilson DiseaseWilson Disease Autosomal recessive pattern of inheritanceAutosomal recessive pattern of inheritance Defective gene: ATP7B on chromosome 13Defective gene: ATP7B on chromosome 13 Leads to copper overload in liver, other Leads to copper overload in liver, other

organsorgans World wide distributionWorld wide distribution Incidence 1:30,000Incidence 1:30,000 Carrier state 1:90Carrier state 1:90 Higher in Sardinians and Chinese, Higher in Sardinians and Chinese,

infrequent in Africainfrequent in Africa

Wilson DiseaseWilson DiseaseVariable PresentationVariable Presentation

Liver, brain damage due to oxidative Liver, brain damage due to oxidative stressstress

Age of onset between 6 to 45Age of onset between 6 to 45 May present as chronic liver disease May present as chronic liver disease

or acute liver failure, progressive or acute liver failure, progressive neurological disorder without liver neurological disorder without liver involvement or as a psychiatric involvement or as a psychiatric illnessillness

Wilson DiseaseWilson DiseaseVariable PresentationVariable Presentation

Neurological sequelae occur 2Neurological sequelae occur 2ndnd – 3 – 3rdrd decade:decade:– Increased or abnormal motor disorder w/ Increased or abnormal motor disorder w/

tremor/dystoniatremor/dystonia– Loss of movement w/ rigidityLoss of movement w/ rigidity

Psychiatric sequelaePsychiatric sequelae– DepressionDepression– PhobiasPhobias– PsychosisPsychosis

Wilson DiseaseWilson DiseaseOcular FeaturesOcular Features

Classic finding: Kayser-Fleisher ring, Classic finding: Kayser-Fleisher ring, a golden-brown deposit at the outer a golden-brown deposit at the outer rim of the cornearim of the cornea

Sunflower cataract, less frequent. Sunflower cataract, less frequent. Copper deposition in the lensCopper deposition in the lens

Wilson DiseaseWilson DiseaseInvolves Other OrgansInvolves Other Organs

Hemolytic anemia 2/2 sporadic release Hemolytic anemia 2/2 sporadic release of copper into the bloodof copper into the blood

Renal involvement w/ Fanconi Renal involvement w/ Fanconi syndrome, microscopic hematuria, syndrome, microscopic hematuria, stonesstones

Arthritis 2/2 copper deposit in synovial Arthritis 2/2 copper deposit in synovial jointsjoints

Osteoporosis, Vitamin D resistant Osteoporosis, Vitamin D resistant rickets 2/2 renal damagerickets 2/2 renal damage

Wilson DiseaseWilson DiseaseInvolves Other OrgansInvolves Other Organs

CardiomyopathyCardiomyopathy Muscles: RhabdomyolysisMuscles: Rhabdomyolysis PancreatitisPancreatitis Endocrine disordersEndocrine disorders

Wilson DiseaseWilson DiseaseDiagnosis and TreatmentDiagnosis and Treatment

Lab findings: Decreased ceruloplasmin Lab findings: Decreased ceruloplasmin and serum copper, excess urinary and serum copper, excess urinary coppercopper

24 hour urine x 3 to confirm diagnosis24 hour urine x 3 to confirm diagnosis Histology: Hepatic copper depositionHistology: Hepatic copper deposition Treatment is chelation:Treatment is chelation:

– penicillamine, which increases urinary penicillamine, which increases urinary copper excretion copper excretion

– ammonium tetrathiomolybdateammonium tetrathiomolybdate

Wilson DiseaseWilson DiseaseTreatmentTreatment

Zinc interferes w/ copper binding, Zinc interferes w/ copper binding, decreasing absorptiondecreasing absorption

Elimination of copper-rich foods from Elimination of copper-rich foods from the diet:the diet:– Organ meats, shellfish, nuts, chocolate, Organ meats, shellfish, nuts, chocolate,

mushroomsmushrooms– Check drinking water supplyCheck drinking water supply

Liver transplantation if ALFLiver transplantation if ALF

Wilson DiseaseWilson Disease Prognosis is good on chelation Prognosis is good on chelation

therapy if diagnosed promptlytherapy if diagnosed promptly Affected sibling diagnosed and Affected sibling diagnosed and

treated prior to symptom onset has treated prior to symptom onset has the best prognosisthe best prognosis

Pediatric Cholestatic SyndromesPediatric Cholestatic Syndromes

Neonatal jaundice is common, Neonatal jaundice is common, transient, usually due to immature transient, usually due to immature glucouronosyl transferase or to breast glucouronosyl transferase or to breast feedingfeeding

If jaundice persists after 14 days, If jaundice persists after 14 days, investigateinvestigate

Extrahepatic biliary atresia requires Extrahepatic biliary atresia requires urgent surgical repair of abnormal urgent surgical repair of abnormal hepatic or common bile ductshepatic or common bile ducts

Pediatric Cholestatic SyndromesPediatric Cholestatic Syndromes Neonatal hepatitis 2/2 infection, Neonatal hepatitis 2/2 infection,

idiopathicidiopathic Intrauterine infections i.e., TORCH: Intrauterine infections i.e., TORCH:

toxoplasmosis, rubella, toxoplasmosis, rubella, cytomegalovirus, herpes simplexcytomegalovirus, herpes simplex

Alagille Syndrome – few bile ducts, Alagille Syndrome – few bile ducts, congenital heart disease, skeletal congenital heart disease, skeletal abnormalities abnormalities – Autosomal dominant, Incidence: 1:70,000 Autosomal dominant, Incidence: 1:70,000

Pediatric Cholestatic SyndromesPediatric Cholestatic Syndromes

Progressive Familial Intrahepatic Progressive Familial Intrahepatic Cholestasis, another group of Cholestasis, another group of autosomal recessive disorders autosomal recessive disorders involved w/ errors in bile acid involved w/ errors in bile acid synthesis and bile acid transportsynthesis and bile acid transport– Byler Disease now called PFIC1Byler Disease now called PFIC1– Byler Syndrome now called PFIC 2Byler Syndrome now called PFIC 2

Case StudyCase Study