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SBM GI > 03-18 Metab Liver Dz > Flashcards

03-18 Metab Liver Dz Flashcards

• Discuss the clinical presentation including laboratory testing, and pathogenesis of the following conditions: Alpha 1 Antitrypsin Deficiency, Hereditary Hemochromatosis and Wilson's disease • Discuss the management of the above conditions • Describe glycogen storage diseases and their effect on the liver and selected other less common metabolic inherited liver diseases

1
Q

OBJECTIVE: Clinical Presentation w/ labs of A1AT Deficiency; Acquired or Inherited?

A

Inherited, A.D. w/ co-dom expression (as common as CF; ~1% of COPD pts)

—only 10-15% of ZZ allelic individuals present w/ clinical dz

CLINICAL PRESENTATION: CHILD ≠ ADULT

Children: Liver > Lung

most common pedi liver dz

—Neonatal jaundice, hepatomegaly, failure to thrive, or acute liver failure

Adults: Lung > Liver

  • Emphysema/COPE
  • ZZ: 8X risk of cirrhosis, 20X risk of HCC
  • SZ/MZ: heterozygotes w/ cirrhosis usually have another co-founding risk factor
  • Lesson common:
    • Necrotizing panniculitis- painful localized necrosis of subQ fat
    • Anti-proteinase-3-positive vasculitis (painful bruising w/ serosanguinous weeping) [seen here]

LAB FINDINGS

  • Low A1AT
  • Protein geno- or phenotyping: MZ, SZ or ZZ A1AT alleles
  • Consider bx to r/o other causes

CHILDREN: 25% w/ ↑ liver enzymes

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2
Q

OBJECTIVE: Pathogenesis of A1AT deficiency

A

A1AT Inhibits proteases, specifically neutrophil elastase released during inflammation

  • 2 main organs involved w/ 2 very different Mechs
  1. Lung: Inability to inhibit neutrophil elastase leads to destruction of lung parenchyma → lung disease and COPD
    • A1AT is responsible >90% of anti-elastase activity in alveolar lavage fluid
  2. Liver: Accumulation of aberrant folded A1AT protein in ER → apoptosis, mitochondrial injury, hepatic necrosis leading to fibrosis and cirrhosis
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3
Q

OBJECTIVE: Management of A1AT deficiency.

A

LIVER TX

  • stop smoking (it makes liver dz worse, too)
  • correct modifiable risk factors: wt, DM, HTN, etc.
  • Liver transplant, PRN
  • Experimental:
    • Gene therapy
    • Carbamezapine and Rifamycin

LUNG TX

  • replace the A1AT w/ a functioning version to stop destruction of lung tissue by elastase
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4
Q

A1AT deficiency relatives

A

Other serine protease inhibitors

  • C1 Inhibitor (hereditary angioedema)
  • Antithrombin III (thrombosis)
  • α1-antichymotrypsin (COPD)

Can be inherited with A1AT b/c close proximity on Chromosome 14

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5
Q

What are the 3 iron-regulating compounds? What are their fxns?

A

Hepcidin (hepatic bactericidal protein)

  • Hormone produced in the liver that responds to serum iron levels
  • Stimulates iron transportation into cells (M0s, enterocytes, hepatocytes)
  • Binds ferroportin (iron exporter on M0s and basolateral enterocyte), internalizes it and targets it for degradation
  • Acute phase reactant: ↑ in inflamm

Ferroportin

  • Main iron export protein
  • Found on enterocytes, hepatocytes, M0s
  • Regulated by hepcidin binding

HFE protein

  • HFE = Human hemochromatosis protein
  • encoded by HFE gene
  • Iron sensor found on hepatocytes
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6
Q

OBJECTIVE: Clinical presentation w/ labs of Hereditary Hemochromatosis; Acquired or Inherited?

A

CLINICAL PRESENTATION

  • ♂ : ♀ = 8 : 1; Avg onset 40-50 y/o
  • Most common s/sx:
    • weakness, lethargy, arthralgias, abdominal pain, and ↓ libido or potency in ♂
  • Exam:
    • hepatosplenomegaly
    • ascites, edema, and jaundice, may be present.
    • Bronzed or slate-gray skin (Fe in basal epidermis)
  • Other
    • hypothyroid
    • hypogonadotrophic hypogonadism
    • cardiomyopathy, valvulopathy
    • Arthropathy of 2nd/3rd MCPs w/ joint space narrowing, chondrocalcinosis, subchondral cyst formation, osteopenia, and swollen joints
    • Infections in iron-loaded patients (Vibrio vulnificus, Listeria **monocytogenes, Yersinia enterocolitica, and Yersinia pseudotuberculosis)

LABS

  • ↑ liver enzymes
  • ↑ transferrin
  • ↑ tranferrin sat
  • ↑ iron index = age-adjusted serum Fe
  • HFE genotype
    • bad one = C282Y
    • more minor = H63D
    • (others S65C)
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7
Q

OBJECTIVE: Pathogenesis of Hereditary Hemochromatosis

A
  1. Mutation of hepatic Fe-sensor proteins (e.g. HFE)
  2. Hepatocytes “see” low iron → therefore they stop hepcidin synth
  3. ferroportin goes regulating pumping iron absorbed by enterocytes into the blood and allow its uptake by M0s, etc.
  4. Increased iron levels & transferrin saturation
  5. Deposition in the liver, heart, spleen and endocrine organs
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8
Q

OBJECTIVE: Management of Hereditary Hemochromatosis + Prognosis

A
  • Routine phlebotomy
  • If can’t tolerate: Rx = deferoxamine (iron-chelator)
  • avoid Fe-rich food, Vit C (↑ absorption)
  • avoid raw shellfish (vibrio risk)

Normal life span if tx’d before cirrhosis

  • Arthritis, liver fibrosis, risk of HCC and hypogonadism do not improve, however
  • Prognosis depends on genotype homozygous C282Y is the bad one RR of developing HCC = 120
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9
Q

OBJECTIVE: Clinical presentation w/ labs of Wilson’s disease

A

Kids - hepatic presentation

  • Sx: fatigue, anorexia, or abdominal pain.
  • High LFTs, hepatomegaly, fatty liver on bx
  • Kayser-Fleischer rings (on slit lamp exam) [seen here]

Adults - neuro presentation

  • movement: Tremors, ↓ coordination, + lose fine motor control
  • rigid dystonia: Mask-like facies, rigidity, and gait disturbance + pseudobulbar (drool/dysarth) involvement

20% Have Pure Psychiatric Presentation

  • Depression is common
  • Phobias or compulsive behavior
  • Aggressive or antisocial behavior

LAB FINDINGS

  • ↑ 24hr urine Cu
  • ↑ serum Cu
  • ↓ ceruloplasmin
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10
Q

OBJECTIVE: Pathogenesis of Wilson’s disease

A

A.R. inherited disease of defective biliary Cu excretion protein ATP7B

  • cannot excrete Cu into bile normally
  • Cu builds up and accumulates in
    • brain
    • liver
    • eyes
    • heart
    • kidneys
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11
Q

OBJECTIVE: Management of Wilson’s disease

A

Dietary

  • eliminate copper-rich food such as organ meats, shellfish, nuts, chocolate, and mushrooms
  • Analyze drinking water

Rx

  • D- penicillamine = gold std
  • Trientine - for neuro sx
  • Zinc (maintenancy therapy)
  • Liver transplant
  • Genetic screening for family members
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12
Q

DDx for Kayser Fleischer Rings

A

Kayser-Fleischer rings are not specific for Wilson disease.

  • Primary Biliary Cirrhosis
  • Primary Sclerosing Cholangitis
  • Autoimmune Hepatitis
  • or familial cholestatic syndromes.
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13
Q

OBJECTIVE: Describe glycogen storage diseases and their effect on the liver

A

Three types of glycogen storag disease

  1. GSD I = deficiency of glucose-6-phosphatase
  2. GSD III = amylo-1,6-glucosidase debranching enzyme
  3. GSD IV = Deficiency of the branching enzyme

Dx these w/ enzyme test on fresh liver tissue

Present w/ hepatomegaly, abd distention, hypoglycemia, failure to thrive, other liver-related things; subtle difference betwen them

Tx: low carb diet, give starch at night? transplant

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14
Q

Chart on slide 12

A

.

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15
Q

Crigler-Najjar vs. Dubin-Johnson and Rotor Syndrome

A

Crigler-Najjer Syndrome

  • Children
  • Defect in conjugation (glcuronyl transferease) of bilirubin
  • Unconjugated hyperbilirubinemia

Dubin Johnson and Rotor Syndrome

  • Defect in excretion of bilirubin
  • Conjugated hyperbilirubinemia
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16
Q

Gilbert’s syndrome 101

A

defect in uptake of bilirubin

  • cause Unconjugated Hyperbilirubinemia seen in 5% adults
  • in fact not a disease but a groups of humans with a slower than normal (the other 95%) handling of bilirubin that under stress circumstances may lead to an isolated ↑ bilirubin
17
Q

Tyrosinemia 101

A

defect of amino acid metabolism via deficiency of fumaryl acetoacetate hydrolase (FAH) associated with tyrosine degradation pathway

  • Highly associated with Hepatocellular carcinoma
18
Q

Gaucher’s Disease 101

A

defect in lipid metabolism via deficiency of glucocerebrosidase

19
Q

Progressive familial intrahepatic cholestasis (PFIC) syndromes 101

A

defect in the bile acid synthesis and transport in the liver

20
Q

Ornithine transcarbamylase (OTC) deficiency 101

A

Ornithine transcarbamylase (OTC) deficiency: most common defect in the Urea cycle in the liver

SBM GI (29 decks)

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