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GEMS > Congenital Hyperbilirubinemias > Flashcards

Congenital Hyperbilirubinemias Flashcards

1
Q

Inherited hyperbilirubinemia disorders

A

Various inherited disorders

Hyperbilirubinemia in setting of normal liver function tests

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2
Q

Categories of inherited hyperbilirubinemia

A
  1. Unconjugated hyperbilirubinemia (Gilbert & Crigler-Najjar Type I/Type II)
  2. Conjugated hyperbilirubinemia (Dubin-johnson syndrome, Rotor syndrome)
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3
Q

Gilbert syndrome (unconjugated)

A

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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4
Q

Gilbert syndrome (unconjugated)

Epidemiology

A

Puberty; males&raquo_space;

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

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5
Q

Gilbert syndrome (unconjugated)

Molecular

A

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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6
Q

Gilbert syndrome (unconjugated)

Associated

A

Decreased RBC life span,
HA, impaired hepatic bilirubin uptake

Fasting, illness, dehydration, cholelithiasis,

Hereditary spherocytosis

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7
Q

Gilbert syndrome (unconjugated)

Presentation

A

Low hepatic UDP-GT activity –> isolated unconjugated hyperbilirubinemia

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8
Q

Gilbert syndrome (unconjugated)

Risk fx –>

A

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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9
Q

Gilbert syndrome (unconjugated)

Misdiagnosis

A

Chronic hepatitis

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10
Q

Gilbert syndrome (unconjugated)

Lab tests

A

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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11
Q

Crigler-Najjar Syndrome (type I) unconjugated hyperbilirubinemia

A

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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12
Q

Crigler-Najjar Syndrome (type I) unconjugated hyperbilirubinemia

Presentation

A

AR

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

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13
Q

Crigler-Najjar Syndrome (type I) unconjugated hyperbilirubinemia

Treatment

A

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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14
Q

Crigler-Najjar Syndrome (type II) unconjugated hyperbilirubinemia

A

Partial deficiency of UDP-GT

Can be induced by infection, anesthesia, drug use

Serum bilirubin 5-20 mg/dL

AD

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15
Q

Crigler-Najjar Syndrome (type II) unconjugated hyperbilirubinemia

Treatment & Prognosis

A

Tx: Phenobarbital

Prog: Normal life expectancy

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16
Q

Dubin-Johnson Syndrome (conjugated)

Molecular

A

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

AR

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17
Q

Dubin-Johnson Syndrome (conjugated)

Pathogenesis

A

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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18
Q

Dubin-Johnson Syndrome (conjugated)

Micro

A

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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19
Q

Dubin-Johnson Syndrome (conjugated)

Diagnosis

A

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

20
Q

Dubin-Johnson Syndrome (conjugated)

Differential

A

Erythropoietic protoporphyria (grossly pigmented liver)

21
Q

Dubin-Johnson Syndrome (conjugated)

Presentation

A
  1. Asymptomatic
    2.Chronic/intermittent jaundice
  2. RUQ pain
  3. Serum bile acids not increased –> no pruritus
  4. Urine darker than normal
  5. Neonates –> hepatomegaly
  6. Extreme –> can be precipitated by pregnancy/drugs that decrease hepatic excretion of organic anions (OCPs)
22
Q

Dubin-Johnson Syndrome (conjugated)

Lab
Treatment
Prognosis

A

Conjugated hyperbilirubinemia, normal ALK phosphatase & gamma-glutamyl transpeptidase

Tx: none necessary

Prog: Excellent

23
Q

Rotor Syndrome (Conjugated)

A

Benign, similar to Dubin-Johnson syndrome

Defect in organic anion storage

Normal liver pigmentation

AR

24
Q

Rotor Syndrome (Conjugated)

Pathogenesis

A

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

25
Q

Hepatic venous outflow obstruction (HVOO)

Sinusoidal obstruction syndrome (SOS)

A

Formerly veno-occlusive

Sinusoids or small hepatic veins

26
Q

Hepatic venous outflow obstruction (HVOO)

Budd-chiari syndrome

A

Large hepatic or IVC

27
Q

Hepatic venous outflow obstruction (HVOO)

Right heart or pericardial disease

A

Lead to liver failure

RHF, tricuspid valve disease, cardiac amyloidosis, constrictive pericarditis

28
Q

Rotor Syndrome (Conjugated)

Role of liver biopsy

A

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

29
Q

Rotor Syndrome (Conjugated)

Micro: Centrizonal-based changes

A

-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

30
Q

Rotor Syndrome (Conjugated)

Micro: Portal-based changes

A
  • Lymphocyte infiltration
    - Portal & peripheral fibrosis
31
Q

Rotor Syndrome (Conjugated)

Possible vignette

A

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

32
Q

Rotor Syndrome (Conjugated)

Clinical Issues: Subacute (<6 mo)

A

Painful hepatomegaly, mild jaundice, ascites

33
Q

Rotor Syndrome (Conjugated)

Clinical Issues: Chronic

A

Chronic liver disease/cirrhosis

34
Q

Rotor Syndrome (Conjugated)

Clinical Issues: Fulminant

A

Rare, active liver failure

35
Q

Rotor Syndrome (Conjugated)

Lab tests

A

Mild elevation of transaminases, marked increase in acute

Alkaline phosphatase elevation common

36
Q

Rotor Syndrome (Conjugated)

Treatment

A

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

37
Q

Budd-Chiari Syndrome

Etiology

A
  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)
37
Q

Budd-Chiari Syndrome

A

Venous obstruction of large hepatic veins or IVC

38
Q

Budd-Chiari Syndrome

Gross

A

Liver necrosis
Splenomegaly

39
Q

Sinusoidal obstruction syndrome (SOS)

Most common clinical settings

A

Graft v host (allogenic SCT, w/in 3 wks)

Cancer pts receiving certain chemos

Ingestion of crotalaria & scenecio genera (bush tea)

40
Q

Sinusoidal obstruction syndrome (SOS)

Pathogenesis

A

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

41
Q

Sinusoidal obstruction syndrome (SOS)

Classifications

A

Right heart/pericardial disease with chronic passive congestion

Left heart cardiac failure/shock–> acute passive congestion (“nutmeg liver”)

42
Q

Sinusoidal obstruction syndrome (SOS)

Right heart/pericardial disease with chronic passive congestion

A

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
43
Q

Sinusoidal obstruction syndrome (SOS)

Right heart/pericardial disease with chronic passive congestion

Gross/Micro

A

G: Liver enlarged, tense, cyanotic, rounded edges

M: Congestion of dilated centrilobular sinusoids –> become atrophic w/ time

44
Q

Sinusoidal obstruction syndrome (SOS)

Left heart cardiac failure/shock–> acute passive congestion (“nutmeg liver”)

A

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

45
Q

Sinusoidal obstruction syndrome (SOS)

Left heart cardiac failure/shock–> acute passive congestion (“nutmeg liver”)

Gross/Micro

A

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

GEMS (20 decks)

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