7 - Liver Genes and the Genetic Diseases of the LIver

Question 1

Genetic Predisposition to Fibrosis

Answer 1

ARLD
NAFLD
Viral Hepatitis

Question 2

Hereditary Hyperbilirubinemias

Answer 2

Gilbert
Criggler-Najjar
Dubin Johnson

Question 3

Hereditary Cholestatic Disorders

Answer 3

PFIC/BRIC
CF
Hereditary Tyrosinemia

Question 4

Storage Diseases

Answer 4

Glycogen Storage Diseases

Lipid Storage Diseases

Question 5

Hereditary Hemochromatosis - Genes

Answer 5

Group of inborn errors of metabolism

Question 6

Hereditary Hemochromatosis - Mechanism

Answer 6

Excessive intestinal absorption of iron

Distinct from secondary iron overload

Question 7

Hereditary Hemochromatosis - Pathophys

Answer 7

Iron deposition causes tissue fibrosis

Question 8

Hereditary Hemochromatosis - Manifestations

Answer 8

Liver Disease
DM
Arthropathy
Cardiomyopathy
Testicular Atrophy

Question 9

Hereditary Hemochromatosis - Inheritance: Chromosome 6

Answer 9

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

Question 10

Hereditary Hemochromatosis - H63D substitution

Answer 10

Less severe

Question 11

Hepcidin

Answer 11

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

Question 12

Hepcidin - Mechanism

Answer 12

Travels to duodenal enterocyte
Internalizes and degrades Ferroportin

Also binds to ferroportin on macrophages
Prevents mobilization of stored iron

Question 13

HFE Protein

Answer 13

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

Question 14

Hereditary Hemochromatosis - HFE-related

Answer 14

C282Y/C282Y
C282Y/H63D
Other HFE mutations

Question 15

Hereditary Hemochromatosis - Non-HFE related

Answer 15

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

Question 16

Secondary Iron Overload

Answer 16

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

Question 17

Hereditary Hemochromatosis - Pathogenic Steps

Answer 17

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

Question 18

Hemochromatosis - Clinical Aspects

Answer 18

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

Question 19

Untreated Hemochromatosis - Causes of Death

Answer 19

Cirrhosis
Hepatocellular Carcinoma (HCC)
Diabetes
Cardiomyopathy

Question 20

Hemochromatosis Testing - Symptomatic Patients

Answer 20

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

Question 21

Hemochromatosis Testing - Asymptomatic Patients

Answer 21

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

Question 22

Hemochromatosis Diagnosis

Answer 22

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

Question 23

Hemochromatosis - Liver Biopsy

Answer 23

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

Question 24

Liver Biopsy - Secondary Iron Overload

Answer 24

Iron deposition in macrophages

Question 25

Hemochromatosis - Treatment

Answer 25

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

Question 26

Wilson's Disease

Answer 26

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

Question 27

Wilson's Disease - Inheritance

Answer 27

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

Question 28

Ceruloplasmin

Answer 28

Copper-containing oxidoreductase | Produced and secreted in the liver

Question 29

Ceruloplasmin

Answer 29

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

Question 30

Normal Copper Metabolism

Answer 30

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

Question 31

Wilson's Copper Metabolism

Answer 31

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

Question 32

Wilson's Disease - Clinical

Answer 32

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

Question 33

Wilson's Disease Liver Injury - Clinical

Answer 33

``` 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

Question 34

Wilson's Disease - Extrahepatic Manifestations

Answer 34

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

Question 35

Wilson's Disease - Diagnosis

Answer 35

Clinical AND Laboratory | Low ceruloplasmin 250mcg/g tissue

Question 36

Untreated Wilson's Disease

Answer 36

UNIFORMLY FATAL

Question 37

Wilson's Disease - Treatment

Answer 37

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

Question 38

α-1-Antitrypsin Deficiency

Answer 38

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

Question 39

α-1-Antitrypsin Deficiency - Inheritance

Answer 39

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

Question 40

α-1-Antitrypsin Deficiency - Clinical Aspects

Answer 40

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

Question 41

α-1-Antitrypsin Deficiency - Liver Biopsy

Answer 41

PAS positive distase resistant cytoplasmic globular inclusions

Question 42

α-1-Antitrypsin Deficiency - Treatment

Answer 42

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

Question 43

Hereditary Hemochromatosis - Key Points

Answer 43

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

Question 44

Wilson's Disease - Key Points

Answer 44

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

Question 45

α-1-Antitrypsin Deficiency

Answer 45

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