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

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

Flashcards in 7 - Liver Genes and the Genetic Diseases of the LIver Deck (45)
Loading flashcards...
1

Genetic Predisposition to Fibrosis

ARLD
NAFLD
Viral Hepatitis

2

Hereditary Hyperbilirubinemias

Gilbert
Criggler-Najjar
Dubin Johnson

3

Hereditary Cholestatic Disorders

PFIC/BRIC
CF
Hereditary Tyrosinemia

4

Storage Diseases

Glycogen Storage Diseases
Lipid Storage Diseases

5

Hereditary Hemochromatosis - Genes

Group of inborn errors of metabolism

6

Hereditary Hemochromatosis - Mechanism

Excessive intestinal absorption of iron
Distinct from secondary iron overload

7

Hereditary Hemochromatosis - Pathophys

Iron deposition causes tissue fibrosis

8

Hereditary Hemochromatosis - Manifestations

Liver Disease
DM
Arthropathy
Cardiomyopathy
Testicular Atrophy

9

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

10

Hereditary Hemochromatosis - H63D substitution

Less severe

11

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

12

Hepcidin - Mechanism

Travels to duodenal enterocyte
Internalizes and degrades Ferroportin

Also binds to ferroportin on macrophages
Prevents mobilization of stored iron

13

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

14

Hereditary Hemochromatosis - HFE-related

C282Y/C282Y
C282Y/H63D
Other HFE mutations

15

Hereditary Hemochromatosis - Non-HFE related

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

16

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

17

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

18

Hemochromatosis - Clinical Aspects

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

19

Untreated Hemochromatosis - Causes of Death

Cirrhosis
Hepatocellular Carcinoma (HCC)
Diabetes
Cardiomyopathy

20

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

21

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

22

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

23

Hemochromatosis - Liver Biopsy

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

24

Liver Biopsy - Secondary Iron Overload

Iron deposition in macrophages

25

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

26

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

27

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

28

Ceruloplasmin

Copper-containing oxidoreductase
Produced and secreted in the liver

29

Ceruloplasmin

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

30

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

31

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

32

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

33

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

34

Wilson's Disease - Extrahepatic Manifestations

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

35

Wilson's Disease - Diagnosis

Clinical AND Laboratory
Low ceruloplasmin 250mcg/g tissue

36

Untreated Wilson's Disease

UNIFORMLY FATAL

37

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

38

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

39

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

40

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

41

α-1-Antitrypsin Deficiency - Liver Biopsy

PAS positive distase resistant cytoplasmic globular inclusions

42

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

43

Hereditary Hemochromatosis - Key Points

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

44

Wilson's Disease - Key Points

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

45

α-1-Antitrypsin Deficiency

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