Flashcards in 7 - Liver Genes and the Genetic Diseases of the LIver Deck (45)
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1
Genetic Predisposition to Fibrosis
ARLD
NAFLD
Viral Hepatitis
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Hereditary Hyperbilirubinemias
Gilbert
Criggler-Najjar
Dubin Johnson
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Hereditary Cholestatic Disorders
PFIC/BRIC
CF
Hereditary Tyrosinemia
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Storage Diseases
Glycogen Storage Diseases
Lipid Storage Diseases
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Hereditary Hemochromatosis - Genes
Group of inborn errors of metabolism
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Hereditary Hemochromatosis - Mechanism
Excessive intestinal absorption of iron
Distinct from secondary iron overload
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Hereditary Hemochromatosis - Pathophys
Iron deposition causes tissue fibrosis
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Hereditary Hemochromatosis - Manifestations
Liver Disease
DM
Arthropathy
Cardiomyopathy
Testicular Atrophy
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Hereditary Hemochromatosis - Inheritance: Chromosome 6
HLA Locus - Chromosome 6
Most common cause
HFE Gene
Most patients homozygous for C282Y amino acid substitution
Only C282Y homozygotes or C282Y/H63D compound heterozygotes are at risk for significant Fe overload
Variable penetrance (few C282Y homozygotes have hepatic Fe overload
Common in Celtic/European populations
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Hereditary Hemochromatosis - H63D substitution
Less severe
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Hepcidin
Hormone produced in the liver
Negative feedback when Fe overload sensed
Downregulates intestinal iron absorption
Secreted when transferrin saturation is high
Decreased when iron deficient
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Hepcidin - Mechanism
Travels to duodenal enterocyte
Internalizes and degrades Ferroportin
Also binds to ferroportin on macrophages
Prevents mobilization of stored iron
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HFE Protein
Element of liver cell plasma membrane complex
(where liver takes up circulating iron)
If any part of this complex is absent or non-functional, liver can't secrete hepcidin
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Hereditary Hemochromatosis - HFE-related
C282Y/C282Y
C282Y/H63D
Other HFE mutations
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Hereditary Hemochromatosis - Non-HFE related
Hemojuvelin (HJV)
Transferrin receptor-2 (TfR2)
Ferroportin (SLC40A1)
Hepcidin (HAMP)
African iron overload
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Secondary Iron Overload
Iron-loading anemias
Thalassemia major
sideroblastic
Chronic hemolytic anemia
Aplastic anemia
Pyruvate kinase deficiency
Pyroxidine-responsive anemia
Parenteral iron overload
Red blood cell transfusions
Iron-dextran injections
Long-term hemodialysis
Chronic liver disease
Hepatitis C
Hepatitis B
Prophyria cutanea tarda
Alcoholic liver disease
Nonalcoholic fatty liver disease
Following protocaval shunt
Dysmetabolic iron overload syndrome
Miscellanenous
Neonatal iron overload
Aceruloplasminemia
Congenital atransferrinemia
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Hereditary Hemochromatosis - Pathogenic Steps
Mutant HFE
High Plasma Iron ->Elevated transferrin saturation
High Tissue Iron -> Elevated serum ferritin
Organ Damage -> Serum ferritin>1000 ng/ml (abnormal results on hepatic, glucose, endocrine tests)
Variable progression to cirrhosis
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Hemochromatosis - Clinical Aspects
Iron accumulates gradually (over decades)
Transferrin saturation (Iron/TIBC) > 45%
Serum ferritin rises
Women somewhat protected (menstruation)
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Untreated Hemochromatosis - Causes of Death
Cirrhosis
Hepatocellular Carcinoma (HCC)
Diabetes
Cardiomyopathy
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Hemochromatosis Testing - Symptomatic Patients
Unexplained manifestations of liver disease
Presumably known cause of liver disease with abnormality of 1 or more indirect serum iron markers
Type 2 DM, particularly with hepatomegaly, elevated liver enzymes, atypical cardiac disease, or early-onset sexual dysfunction
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Hemochromatosis Testing - Asymptomatic Patients
First-degree relatives of a confirmed case of hemochromatosis
Individuals with abnormal serum iron markers discovered during routine testing
Individuals with unexplained elevation of liver enzymes or serendipitous finding of asymptomatic hepatomegaly or radiologic detection of enhanced computed tomography attenuation of the liver
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Hemochromatosis Diagnosis
Iron Levels - Lack specificity (PPV 61% NPV 87%)
Transferrin Saturation (TS):
Iron/TIBC>50% (women)
Iron/TIBC>60% (men)
Ferritin - Non-specific, used with TS
TS>45 has 97% NPV
But those with HFE hemochromatosis with ferritin>1000 more likely to develop symptomatic iron overload
Genetic Testing
If TS or Ferritin elevated
HFE genotype
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Hemochromatosis - Liver Biopsy
Not required in all
Allows you to stage degree of fibrosis
Intense iron deposition as hemosiderin (primarily in hepatocytes)
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Liver Biopsy - Secondary Iron Overload
Iron deposition in macrophages
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Hemochromatosis - Treatment
Phlebotomy is the mainstay (1 unit blood removed weekly or biweekly)
Goal - Ferritin 50 - 100
Complete depletion of iron stores may take a year or more
Removal of excess iron halts disease progression
Testicular atrophy and arthropathy DO NOT IMPROVE
Liver transplant for decompensated disease
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Wilson's Disease
Autosomal Recessive Disorder
Copper transport within hepatocyte impaired
Excess copper normally eliminated in bile
Failure of copper transport -> buildup of copper in hepatocytes
Copper released from injured hepatocytes can accumulate in brain and kidneys
Chelation depletes excess copper, can arrest disease progression
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Wilson's Disease - Inheritance
Gene - ATP7B
Codes for copper transporting p-type membrane ATPase in hepatocytes
ATP7B traffics copper to the canalicular membrane for biliary secretion
When absent, copper cannot be eliminated, accumulates in hepatocyte lysosomes
Also required for transporting copper within hepatocytes to assemble ceruloplasmin
LOW CERULOPLASMIN
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Ceruloplasmin
Copper-containing oxidoreductase
Produced and secreted in the liver
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Ceruloplasmin
Contains 95% of the Cu in plasma
Liver is the source of ceruloplasmin synthesis
Negative acute phase reactant (limits its utility in diagnosis)
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Normal Copper Metabolism
Consume 2mg Cu daily
25% not absorbed, lost in the stool
50% forms a complex with metallothionein (eventually lost in stool)
25% transported to liver, incorporated into ceruloplasmin OR excreted in bile
Most of the Cu is excreted in the bile
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Wilson's Copper Metabolism
Normal Cu absorption
No incorporation into ceruloplasmin
No excretion into bile
Increased Cu in hepatocytes results in an overflow of Cu in blood. This means free Cu plasma concentration is increased.
Leads to increased urinary Cu concentration
Decreased stool concentration of Cu
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Wilson's Disease - Clinical
Most symptomatic between ages 5 - 45
Rate of accumulation related to severity of gene defect
ATP7B complete ABSENCE = Childhood presentation
Everyone else presents later
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Wilson's Disease Liver Injury - Clinical
Acute:
Mainly young females
Acute hepatitis
Can get acute liver failure
Acute kidney injury
(LOW alkaline phosphatase)
Chronic:
Adolescents and adults
Indolent progression to cirrhosis
Gradual extrahepatic deposition
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Wilson's Disease - Extrahepatic Manifestations
Renal
Bone - Arthritis Rickets
Haem - Hemolysis
CNS - Hella shit
Eye - Kayser Fleischer Rings
Cardiac
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Wilson's Disease - Diagnosis
Clinical AND Laboratory
Low ceruloplasmin 250mcg/g tissue
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Untreated Wilson's Disease
UNIFORMLY FATAL
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Wilson's Disease - Treatment
Timely treatment = Good Progrnosis
Chelation (D-penicillamine, trientine) - binds tissue Cu and facilitates excretion
Zinc - Prevents absorption of dietary copper in intestinal epithelial cells
Liver Transplant - ALF or decompensated cirrhosis
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α-1-Antitrypsin Deficiency
α1At is a circulating protease inhibitor
Synthesized and secreted by the liver
Protects lung from injury by neutrophil elastase and other serine proteases
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α-1-Antitrypsin Deficiency - Inheritance
α1AT is produced by the SERPINA1 (SERine Protease INhibitor A1) gene
PI*M is normal allele
PI*Z is associated with SEVERE deficiency circulating α1At
PI*S more modest reduction
Genotypes associated with liver disease:
ZZ
Some SZ
Occasionally SS
PI*null-null homozygotes
No α1AT
Severe lung disease BUT NO LIVER DISEASE
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α-1-Antitrypsin Deficiency - Clinical Aspects
Neonatal Hepatitis (Some ZZ homozygotes, can get jaundiced)
Most homozygotes present in adulthood with complications of liver or lung disease
Elevated transaminases -> Fibrosis -> Cirrhosis -> Can develop HCC
Many with liver disease little to no lung disease (converse also true)
Lung disease - Early emphysema, disproportional involvement of lung bases, worse with smoking
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α-1-Antitrypsin Deficiency - Liver Biopsy
PAS positive distase resistant cytoplasmic globular inclusions
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α-1-Antitrypsin Deficiency - Treatment
Avoid alcohol and tobacco
Augmentation therapy: human
Slows progression of lung disease
No benefit in liver disease
No specific therapy for liver disease
LIVER TRANSPLANT cures the gene defect
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Hereditary Hemochromatosis - Key Points
Iron overload related to genetic mutations in the HFE gene (C282Y and H63D)
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Wilson's Disease - Key Points
Autosomal recessive
Disorder of copper excretion into bile
Can manifest as acute or chronic liver disease
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