Genes, Cancer and Liver

Question 1

What is the normal regulation of iron in the body?

Answer 1

hepcidin synthesized in liver inhibits ferroportin (iron export protein on BL membrane) - decreases entry of iron into body

Question 2

What are the factors that regulate hepcidin synthesis?

Answer 2

iron stores
erythryopoietic rate
anemia
hypoxia

Question 3

What happens to iron once it has been absorbed by the body?

Answer 3

binds to circulating plasma transferrin - delivers to cells for heme or enzyme formation
excess stored as ferritin
regulatory proteins like hepcidin balance uptake with storage to maintain normal levels

Question 4

What are the causes of genetic iron overload?

Answer 4

classic hereditary hemochromatosis = type 1 - mutation in HLA like molecule HFE1 –> increased iron absorption despite overload - increased ferritin in liver
final common pathway is failure of ferroportin regulation by hepcidin

Question 5

What is the cause of parenteral iron overload?

Answer 5

no normal pathway for excretion of excess - transfusions –> secondary overload
underlying anemia can increase absorption from diet despite extra-intestinal stores

Question 6

What are the effects of iron mediated cell and tissue injury in iron overload states?

Answer 6

accumulates in liver, heart, pancreas –> cirrhosis, cardiomyopathy, diabetes
if excess from diet, liver disproportionately affected due to first pass
ferritin stores saturated, then iron-mediated fibrosis
hypogonadotropic hypogonadism

Question 7

What is the clinical presentation of iron overload?

Answer 7

usually asymptomatic, nonspecific fatigue or arthralgias, elevated iron found on standard tests

Question 8

What is the role of liver biopsy in investigation of iron overload?

Answer 8

only if liver function or enzymes abnormal because of risk of HCC
if biopsy contra-indicated –> phlebotomy

Question 9

What is the role of genetic diagnosis in hemochromatosis?

Answer 9

look for Cys282Tyr mutation
beneficial effects in heterozygotes –> high prevalence in Celtic
genetic test for HFE available

Question 10

What is the ddx of iron overload?

Answer 10

genetic - hemochromatosis - HFE related normally interacts with transferring receptor 1, other rare mutations in ferroportin and hepcidin
secondary = hemosiderosis - transfusion, hyperabsorption in response to anemia or hypoxia, meds or diet, advanced liver dz

Question 11

What is the management of iron overload?

Answer 11

remove excess iron - phlebotomy
outcome is normal life expectancy in non-cirrhotic
complications of heart failure, diabetes, or HCC reduces survival in cirrhotic
arthritis and hypogonadotropic hypogonadism not reversed

Question 12

What is the normal absorption of copper?

Answer 12

rapidly transported into epithelial cells of upper small intestine
bound to metallothioneins or transported across BL
25-60% dietary reaches circulation and bound to albumin - from albumin to hepatocytes
typically little escapes hepatic uptake and is excreted in urine

Question 13

What happens to copper once it reaches the hepatocyte?

Answer 13

apo-ceruloplasmin synthesized in liver - iron then incorporated - most serum copper
increased ceruloplasmin during inflammation - decrease during protein-losing states and in advanced liver dz

Question 14

How is copper excreted?

Answer 14

biliary excretion is major control mechanism

Question 15

How does copper overload happen?

Answer 15

impaired biliary excretion

Question 16

What is responsible for the copper overload in Wilson’s disease?

Answer 16

intra-cellular copper transporter defective - not incorporated into ceruloplasmin or excreted in bile

Question 17

How does Wilson disease present?

Answer 17

hepatic or neuropsychiatric illness (movement disorders) - hepatic 5-10 yrs earlier
hemolytic anemia - Cu injures RBCs
cirrhosis

Question 18

What investigations are seen in Wilson’s dz?

Answer 18

low ceruloplasmin
elevated urine copper in symptomatic
high hepatic copper
(could get false positives of urine and hepatic in cholestasis)
common markers flank gene on long arm of ch 13

Question 19

When can ceruloplasmin be low other than in wilsons?

Answer 19

low protein disorders, heterozygosity for Wilsons

Question 20

What is the management of wilsons?

Answer 20

copper chelation with D-penicillamine

Question 21

What are risk factors for dev of HCC?

Answer 21

Hep B (w/o cirrhosis) or C
cirrhotic liver dz - hemochromatosis, alcoholic, etc
carcinogen exposure - aflatoxin, hormones, smoke
hereditary tyrosinemia
males»>females

Question 22

What factors are determine if management for HCC can be operative?

Answer 22

sufficient liver function must remain for normal life

surgical resection not possible if patient has advanced liver dz - only transplant

Question 23

What are non-operative managements of HCC?

Answer 23

radio frequency ablation
chemoembolization
tyrosine kinase inhibitor sorafenib

Question 24

What are palliative managements for HCC?

Answer 24

narcotic analgesic regimens

Question 25

What, other than HCC, can cause elevated alpha fetoprotein?

Answer 25

regeneration

testicular cancer

Question 26

What lab tests are used to determine priority for liver transplantation?

Answer 26

bilirubin
INR
creatinine 
severity correlates w/ increased risk of death
MELD score - >16 means transplant