Congenital Hyperbilirubinemias Flashcards by whitney hohman

Inherited hyperbilirubinemia disorders

Various inherited disorders

Hyperbilirubinemia in setting of normal liver function tests

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Categories of inherited hyperbilirubinemia

Unconjugated hyperbilirubinemia (Gilbert & Crigler-Najjar Type I/Type II)
Conjugated hyperbilirubinemia (Dubin-johnson syndrome, Rotor syndrome)

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Gilbert syndrome (unconjugated)

inherited unconjugated hyperbilirubinemia

2/2 mutations of bilirubin uridine diphosphate glucuronosyltransferase

Benign AR condition

Absent detectable functional or structural liver disease

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Gilbert syndrome (unconjugated)

Epidemiology

Puberty; males&raquo_space;

Related to increased Hb turnover & inhibition of bilirubin glucuronidation by endogenous steroid hormones

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Gilbert syndrome (unconjugated)

Molecular

Extra TA in TATA box of UGT1A1 promoter (UGT1A1*28)

Gene transcription decreases to 20% of normal levels

Decreased conjugation of bilirubin w/ glucuronic acid & some drugs

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Gilbert syndrome (unconjugated)

Associated

Decreased RBC life span,
HA, impaired hepatic bilirubin uptake

Fasting, illness, dehydration, cholelithiasis,

Hereditary spherocytosis

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Gilbert syndrome (unconjugated)

Presentation

Low hepatic UDP-GT activity –> isolated unconjugated hyperbilirubinemia

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Gilbert syndrome (unconjugated)

Risk fx –>

Toxicity from drugs metabolized by UGT

Decreased conjugation of some drugs (irinotecan, atazanavir, TAS-103, indinavir, tolbutamide, rifamycin)

Might be predisposed to acetaminophen toxicity

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Gilbert syndrome (unconjugated)

Misdiagnosis

Chronic hepatitis

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Gilbert syndrome (unconjugated)

Lab tests

Mild unconjugated hyperbilirubinemia –> increased proportion of bilirubin monoglucuronide

Normal: alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl trasnpeptidase

Rifampin admin & caloric restriction –> causes disproportionate hyperbilirubinemia relative to normal

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Crigler-Najjar Syndrome (type I) unconjugated hyperbilirubinemia

Complete absence of UDP-DT

Bilirubin glucuronides virtually absent from bile

No detectable constitutive expression of UGT1A1 in hepatic tissue

Serum unconjugated bilirubin >25 mg/dL

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Crigler-Najjar Syndrome (type I) unconjugated hyperbilirubinemia

Presentation

Die from encephalopathy (kernicterus) w/in first year of life

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Crigler-Najjar Syndrome (type I) unconjugated hyperbilirubinemia

Treatment

Liver transplant –> only effective therapy

Phenobarbital w/o effect –> cytochrome p450 inducer –> upregulates expression of UDPGT –> decreases levels of unconjugated bilirubin

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Crigler-Najjar Syndrome (type II) unconjugated hyperbilirubinemia

Partial deficiency of UDP-GT

Can be induced by infection, anesthesia, drug use

Serum bilirubin 5-20 mg/dL

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Crigler-Najjar Syndrome (type II) unconjugated hyperbilirubinemia

Treatment & Prognosis

Tx: Phenobarbital

Prog: Normal life expectancy

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Dubin-Johnson Syndrome (conjugated)

Molecular

Mutations in CMOAT/MRP2/ABCC2 –> codes for ATP-dependent organic anion transport localized to canalicular membrane

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Dubin-Johnson Syndrome (conjugated)

Pathogenesis

Conjugated hyperbilirubinemia

Result in impaired biliary canalicular transport of organic anions, including conjugated bilirubin

Impaired glutathione excretion –> reduces bile salt-independent bile flow

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Dubin-Johnson Syndrome (conjugated)

Micro

Coarse granular pigment in centrilobular hepatocytes

Deposition of brown-black melanin-like pigment in hepatocytes –> leads to blackening of liver

Iron stain NEGATIVE – not hemosiderin

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Dubin-Johnson Syndrome (conjugated)

Diagnosis

Immunohistochem –> MRP2: negative staining of canalicular membrane

Electron micro –> membrane-bound, electron dense lysosomal granules w/in cytoplasm of hepatocytes

Liver cells do not synthesize melanin –> reflects oxidation of anionic metabolites, possibly epi

Dubin-Johnson Syndrome (conjugated)

Differential

Erythropoietic protoporphyria (grossly pigmented liver)

Dubin-Johnson Syndrome (conjugated)

Presentation

Asymptomatic
2.Chronic/intermittent jaundice
RUQ pain
Serum bile acids not increased –> no pruritus
Urine darker than normal
Neonates –> hepatomegaly
Extreme –> can be precipitated by pregnancy/drugs that decrease hepatic excretion of organic anions (OCPs)

Dubin-Johnson Syndrome (conjugated)

Lab
Treatment
Prognosis

Conjugated hyperbilirubinemia, normal ALK phosphatase & gamma-glutamyl transpeptidase

Tx: none necessary

Prog: Excellent

Rotor Syndrome (Conjugated)

Benign, similar to Dubin-Johnson syndrome

Defect in organic anion storage

Normal liver pigmentation

Rotor Syndrome (Conjugated)

Pathogenesis

Hepatic venous outflow obstruction (HVOO)

Can occur at different levels of hepatic venous outflow

Sinusoidal obstruction syndrome (SOS)
Budd-chiari syndrome
Right heart or pericardial disease

Hepatic venous outflow obstruction (HVOO) Sinusoidal obstruction syndrome (SOS)

Formerly veno-occlusive Sinusoids or small hepatic veins

Hepatic venous outflow obstruction (HVOO) Budd-chiari syndrome

Large hepatic or IVC

Hepatic venous outflow obstruction (HVOO) Right heart or pericardial disease

Lead to liver failure RHF, tricuspid valve disease, cardiac amyloidosis, constrictive pericarditis

Rotor Syndrome (Conjugated) Role of liver biopsy

Liver changes result from hepatic venous congestion --> increase hepatic/sinusoidal pressure & necrosis --> secondary sinusoidal thrombosis into hepatic/portal veins --> parenchymal damage/fibrosis Liver biopsy confirms diagnosis --> determines degree of hepatocellular damage

Rotor Syndrome (Conjugated) Micro: Centrizonal-based changes

-Sinusoidal dilatation & congestion → compresses hepatocytes → hepatic plate atrophy - Increase in sinusoidal pressure → RBC extravasation in space of Disse - Hepatocellular necrosis in acute/subacute - Pericentral & sinusoidal fibrosis in chronic → bridging fibrosis/cirrhosis

Rotor Syndrome (Conjugated) Micro: Portal-based changes

- Lymphocyte infiltration - Portal & peripheral fibrosis

Rotor Syndrome (Conjugated) Possible vignette

Sinusoidal injury as a result of chemotherapy (following BMT w/ drugs like oxaliplatin)

Rotor Syndrome (Conjugated) Clinical Issues: Subacute (<6 mo)

Painful hepatomegaly, mild jaundice, ascites

Rotor Syndrome (Conjugated) Clinical Issues: Chronic

Chronic liver disease/cirrhosis

Rotor Syndrome (Conjugated) Clinical Issues: Fulminant

Rare, active liver failure

Rotor Syndrome (Conjugated) Lab tests

Mild elevation of transaminases, marked increase in acute Alkaline phosphatase elevation common

Rotor Syndrome (Conjugated) Treatment

Decompression procedure in BCS Cardiac --> tx Liver transplant --> advanced fibrosis Hematologic workup: identify cause of thrombosis

Budd-Chiari Syndrome Etiology

1. Polycythemia vera (<40%) 2. Myeloproliferative disorders 3. Hypercoagulable states (assoc w/ malignant tumors) 4. Use of OCPs 5. Pregnancy, chronic infections, chronic inflammatory disease 6. Metastatic & primary tumors in liver (hepatocellular carcinoma) 7. Surgical trauma 8. Congenital membranous obstructions (segment of IVC absent)

Budd-Chiari Syndrome

Venous obstruction of large hepatic veins or IVC

Budd-Chiari Syndrome Gross

Liver necrosis Splenomegaly

Sinusoidal obstruction syndrome (SOS) Most common clinical settings

Graft v host (allogenic SCT, w/in 3 wks) Cancer pts receiving certain chemos Ingestion of crotalaria & scenecio genera (bush tea)

Sinusoidal obstruction syndrome (SOS) Pathogenesis

Toxic injury to sinusoidal endothelium Injured, sloughed endothelium obstruction sinusoidal blood flow --> assoc debris accumulates in terminal hepatic veins Red cells enter space of Disse in disrupted sinusoids & cessation of blood flow --> necrosis of perivenular hepatocyte

Sinusoidal obstruction syndrome (SOS) Classifications

Right heart/pericardial disease with chronic passive congestion Left heart cardiac failure/shock--> acute passive congestion ("nutmeg liver")

Sinusoidal obstruction syndrome (SOS) Right heart/pericardial disease with chronic passive congestion

Right-sided cardiac decompensation --> passive congestion to liver 1. CHF 2. Increased peripheral venous circulation 3. Decreased venous outflow from liver 4. Chronic passive hepatic congestion

Sinusoidal obstruction syndrome (SOS) Right heart/pericardial disease with chronic passive congestion Gross/Micro

G: Liver enlarged, tense, cyanotic, rounded edges M: Congestion of dilated centrilobular sinusoids --> become atrophic w/ time

Sinusoidal obstruction syndrome (SOS) Left heart cardiac failure/shock--> acute passive congestion ("nutmeg liver")

Left-sided cardiac failure or shock --> hepatic hypoperfusion & hypoxia of hepatocytes around central veins

Sinusoidal obstruction syndrome (SOS) Left heart cardiac failure/shock--> acute passive congestion ("nutmeg liver") Gross/Micro

G: Nutmeg liver, variegated mottled appearance (hemorrhage & necrosis in centrilobular regions) Alternating areas of hemorrhagic area & pale parenchyma Hemorrhagic areas corresponding to centrizonal areas --> pale areas relatively unaffected periportal parenchyma

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Congenital Hyperbilirubinemias Flashcards

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