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GI / Hepatology > 7 - Liver Genes and the Genetic Diseases of the LIver > Flashcards

7 - Liver Genes and the Genetic Diseases of the LIver Flashcards

1
Q

Genetic Predisposition to Fibrosis

A

ARLD
NAFLD
Viral Hepatitis

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2
Q

Hereditary Hyperbilirubinemias

A

Gilbert
Criggler-Najjar
Dubin Johnson

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3
Q

Hereditary Cholestatic Disorders

A

PFIC/BRIC
CF
Hereditary Tyrosinemia

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4
Q

Storage Diseases

A

Glycogen Storage Diseases

Lipid Storage Diseases

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5
Q

Hereditary Hemochromatosis - Genes

A

Group of inborn errors of metabolism

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6
Q

Hereditary Hemochromatosis - Mechanism

A

Excessive intestinal absorption of iron

Distinct from secondary iron overload

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7
Q

Hereditary Hemochromatosis - Pathophys

A

Iron deposition causes tissue fibrosis

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8
Q

Hereditary Hemochromatosis - Manifestations

A 
Liver Disease
DM
Arthropathy
Cardiomyopathy
Testicular Atrophy
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9
Q

Hereditary Hemochromatosis - Inheritance: Chromosome 6

A

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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10
Q

Hereditary Hemochromatosis - H63D substitution

A

Less severe

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11
Q

Hepcidin

A

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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12
Q

Hepcidin - Mechanism

A

Travels to duodenal enterocyte
Internalizes and degrades Ferroportin

Also binds to ferroportin on macrophages
Prevents mobilization of stored iron

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13
Q

HFE Protein

A

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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14
Q

Hereditary Hemochromatosis - HFE-related

A

C282Y/C282Y
C282Y/H63D
Other HFE mutations

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15
Q

Hereditary Hemochromatosis - Non-HFE related

A 
Hemojuvelin (HJV)
Transferrin receptor-2 (TfR2)
Ferroportin (SLC40A1)
Hepcidin (HAMP)
African iron overload
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16
Q

Secondary Iron Overload

A 
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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17
Q

Hereditary Hemochromatosis - Pathogenic Steps

A

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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18
Q

Hemochromatosis - Clinical Aspects

A

Iron accumulates gradually (over decades)
Transferrin saturation (Iron/TIBC) > 45%
Serum ferritin rises
Women somewhat protected (menstruation)

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19
Q

Untreated Hemochromatosis - Causes of Death

A

Cirrhosis
Hepatocellular Carcinoma (HCC)
Diabetes
Cardiomyopathy

20
Q

Hemochromatosis Testing - Symptomatic Patients

A

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

21
Q

Hemochromatosis Testing - Asymptomatic Patients

A

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

22
Q

Hemochromatosis Diagnosis

A

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

23
Q

Hemochromatosis - Liver Biopsy

A

Not required in all
Allows you to stage degree of fibrosis
Intense iron deposition as hemosiderin (primarily in hepatocytes)

24
Q

Liver Biopsy - Secondary Iron Overload

A

Iron deposition in macrophages

25
Q

Hemochromatosis - Treatment

A

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

26
Q

Wilson’s Disease

A

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

27
Q

Wilson’s Disease - Inheritance

A

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

28
Q

Ceruloplasmin

A

Copper-containing oxidoreductase

Produced and secreted in the liver

29
Q

Ceruloplasmin

A

Contains 95% of the Cu in plasma
Liver is the source of ceruloplasmin synthesis
Negative acute phase reactant (limits its utility in diagnosis)

30
Q

Normal Copper Metabolism

A

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

31
Q

Wilson’s Copper Metabolism

A

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

32
Q

Wilson’s Disease - Clinical

A

Most symptomatic between ages 5 - 45
Rate of accumulation related to severity of gene defect
ATP7B complete ABSENCE = Childhood presentation
Everyone else presents later

33
Q

Wilson’s Disease Liver Injury - Clinical

A 
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

34
Q

Wilson’s Disease - Extrahepatic Manifestations

A 
Renal
Bone - Arthritis Rickets
Haem - Hemolysis
CNS - Hella shit
Eye - Kayser Fleischer Rings
Cardiac
35
Q

Wilson’s Disease - Diagnosis

A

Clinical AND Laboratory

Low ceruloplasmin 250mcg/g tissue

36
Q

Untreated Wilson’s Disease

A

UNIFORMLY FATAL

37
Q

Wilson’s Disease - Treatment

A

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

38
Q

α-1-Antitrypsin Deficiency

A

α1At is a circulating protease inhibitor
Synthesized and secreted by the liver
Protects lung from injury by neutrophil elastase and other serine proteases

39
Q

α-1-Antitrypsin Deficiency - Inheritance

A

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

40
Q

α-1-Antitrypsin Deficiency - Clinical Aspects

A

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

41
Q

α-1-Antitrypsin Deficiency - Liver Biopsy

A

PAS positive distase resistant cytoplasmic globular inclusions

42
Q

α-1-Antitrypsin Deficiency - Treatment

A

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

43
Q

Hereditary Hemochromatosis - Key Points

A

Iron overload related to genetic mutations in the HFE gene (C282Y and H63D)

44
Q

Wilson’s Disease - Key Points

A

Autosomal recessive
Disorder of copper excretion into bile
Can manifest as acute or chronic liver disease

45
Q

α-1-Antitrypsin Deficiency

A

Hepatic accumulation of the misfolded protein and lung emphysema
Often indolent and causes chronic liver disease

GI / Hepatology (28 decks)

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