7 - Liver Genes and the Genetic Diseases of the LIver Flashcards
Genetic Predisposition to Fibrosis
ARLD
NAFLD
Viral Hepatitis
Hereditary Hyperbilirubinemias
Gilbert
Criggler-Najjar
Dubin Johnson
Hereditary Cholestatic Disorders
PFIC/BRIC
CF
Hereditary Tyrosinemia
Storage Diseases
Glycogen Storage Diseases
Lipid Storage Diseases
Hereditary Hemochromatosis - Genes
Group of inborn errors of metabolism
Hereditary Hemochromatosis - Mechanism
Excessive intestinal absorption of iron
Distinct from secondary iron overload
Hereditary Hemochromatosis - Pathophys
Iron deposition causes tissue fibrosis
Hereditary Hemochromatosis - Manifestations
Liver Disease DM Arthropathy Cardiomyopathy Testicular Atrophy
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
Hereditary Hemochromatosis - H63D substitution
Less severe
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
Hepcidin - Mechanism
Travels to duodenal enterocyte
Internalizes and degrades Ferroportin
Also binds to ferroportin on macrophages
Prevents mobilization of stored iron
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
Hereditary Hemochromatosis - HFE-related
C282Y/C282Y
C282Y/H63D
Other HFE mutations
Hereditary Hemochromatosis - Non-HFE related
Hemojuvelin (HJV) Transferrin receptor-2 (TfR2) Ferroportin (SLC40A1) Hepcidin (HAMP) African iron overload
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
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
Hemochromatosis - Clinical Aspects
Iron accumulates gradually (over decades)
Transferrin saturation (Iron/TIBC) > 45%
Serum ferritin rises
Women somewhat protected (menstruation)
Untreated Hemochromatosis - Causes of Death
Cirrhosis
Hepatocellular Carcinoma (HCC)
Diabetes
Cardiomyopathy
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
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
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
Hemochromatosis - Liver Biopsy
Not required in all
Allows you to stage degree of fibrosis
Intense iron deposition as hemosiderin (primarily in hepatocytes)
Liver Biopsy - Secondary Iron Overload
Iron deposition in macrophages
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
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
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
Ceruloplasmin
Copper-containing oxidoreductase
Produced and secreted in the liver
Ceruloplasmin
Contains 95% of the Cu in plasma
Liver is the source of ceruloplasmin synthesis
Negative acute phase reactant (limits its utility in diagnosis)
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
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
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
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
Wilson’s Disease - Extrahepatic Manifestations
Renal Bone - Arthritis Rickets Haem - Hemolysis CNS - Hella shit Eye - Kayser Fleischer Rings Cardiac
Wilson’s Disease - Diagnosis
Clinical AND Laboratory
Low ceruloplasmin 250mcg/g tissue
Untreated Wilson’s Disease
UNIFORMLY FATAL
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
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
α-1-Antitrypsin Deficiency - Inheritance
α1AT is produced by the SERPINA1 (SERine Protease INhibitor A1) gene
PIM is normal allele
PIZ 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
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
α-1-Antitrypsin Deficiency - Liver Biopsy
PAS positive distase resistant cytoplasmic globular inclusions
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
Hereditary Hemochromatosis - Key Points
Iron overload related to genetic mutations in the HFE gene (C282Y and H63D)
Wilson’s Disease - Key Points
Autosomal recessive
Disorder of copper excretion into bile
Can manifest as acute or chronic liver disease
α-1-Antitrypsin Deficiency
Hepatic accumulation of the misfolded protein and lung emphysema
Often indolent and causes chronic liver disease
