Module 2 Chapter 8: Genetic Liver Diseases

Question 1

Causes of heriditeray hemochromatosis and non-Heriditery hemochromatosis

Question 2

Causes of heriditeray hemochromatosis and non-Heriditery hemochromatosis

Question 3

crypt villous hypothesis for HH

Answer 3

HFE gene mutations decreased affinity of the transferrin receptor for transferrin. -leads to a false signal that body iron stores are low. - enterocytes in crypt synthesize more divalent metal transporters - enterocytes with more DMT migrate up from crypt to villi where more iron is absorbed, this leads to eventual iron overload in tissues.

Question 4

hepcidin hypothesis.

Answer 4

Hepcidin is the principle iron-regulatory hormone and is produced in hepatocytes Hepcidin binds ferroportin on macrophages (plays a role in anemia of chronic disease) and basolateral surface of enterocytes Hepcidin – ferroportin is internalized and degraded, inhibiting iron export by enterocytes and macrophages

Question 5

Diagnosing HH

Answer 5

• elevation of ALT or AST - Screening tests include transferrin saturation and ferreting. o TS % = Fe (iron) / TIBC (total iron binding concentration) is more specific o Ferritin is more sensitive, but less specific DDx for elevated ferritin includes 1) HH, 2) other chronic liver disease, 3) other inflammatory conditions (e.g. inflammatory bowel disease, rheumatoid arthritis) If TS% >45% then order HFE genetic testing Ferritin > 1000 ng/mL with TS% <45% should not necessary prompt HFE genetic testing

Question 6

crypt villous hypothesis for HH

Answer 6

HFE gene mutations decreased affinity of the transferrin receptor for transferrin. -leads to a false signal that body iron stores are low. - enterocytes in crypt synthesize more divalent metal transporters - enterocytes with more DMT migrate up from crypt to villi where more iron is absorbed, this leads to eventual iron overload in tissues.

Question 7

hepcidin hypothesis.

Answer 7

Hepcidin is the principle iron-regulatory hormone and is produced in hepatocytes Hepcidin binds ferroportin on macrophages (plays a role in anemia of chronic disease) and basolateral surface of enterocytes Hepcidin – ferroportin is internalized and degraded, inhibiting iron export by enterocytes and macrophages

Question 8

Diagnosing HH

Answer 8

• elevation of ALT or AST - Screening tests include transferrin saturation and ferreting. o TS % = Fe (iron) / TIBC (total iron binding concentration) is more specific o Ferritin is more sensitive, but less specific DDx for elevated ferritin includes 1) HH, 2) other chronic liver disease, 3) other inflammatory conditions (e.g. inflammatory bowel disease, rheumatoid arthritis) If TS% >45% then order HFE genetic testing Ferritin > 1000 ng/mL with TS% <45% should not necessary prompt HFE genetic testing

Question 9

what would you see on a histology slide of someone with HH

Answer 9

tons of iron. Brown of H and E stain, and blue on prussian blue stain.

Question 10

endocrine implications of HH

Answer 10

in addition to arthritis, hepatitis/cirrhosis/ HCC, and bronze pigmentation, there is an increased likihood of diabetes, impotence, and amenorrhea

Question 11

Natural history of HH

Answer 11

can progress to cirrhosis and associated wtih high risk of HCC unless phlebotomy is done

Question 12

T/F Phlebotomy can reverse many symptoms of HH, including testicular atrophy, and arthritis

Answer 12

false.

Phlebotomy will decreased tissue stores of Fe, and normalize live enezymes and increased cardiac function, and will have an increased chance of survival if phlebotomy is started before cirrhosis and diabetes. it will not cause an improvement in arthritis or testicular atrophy.

Question 13

treatment of HH

Answer 13

phlebotomy weekly. Check Hg and Fe afterwards.

• aavoid vitamin C supplements

Question 14

where is copper sbsorbed, and how are copper stores balanced?

Answer 14

stomach and duodenum. normal copperstores are maintained by balance of GI absorption and bile excretion

Question 15

Pathophysiology of wilsons disease

Answer 15

Within hepatocytes, high intracellular copper normally leads to increased biliary excretion of excess copper

• this requires vesicles prouced by the transgolgi network to carry copper to bile canaliculus for excretion into bile.

In the Golgi, free copper is bound
to apoceruloplasmin and is
released as ceruloplasmin into the circulation for transport of copper to other organs

ATP7B mutations of Wilson’s Disease leads to abnormal uptake of copper into the Golgi

This results in a lack of biliary
excretion of copper

Copper is also not bound to
apoceruloplasmin Apoceruloplasmin has a shorter
half-life (compared to copper
bound ceruloplasmin) and is
removed from circulation more
quickly

Question 16

clinical presentation and natural history of WD

Answer 16

Hepatic dysfunction usually occurs 10 years before neurologic symptoms

May be asymptomatic with abnormal liver tests (mild, moderate or severe )

They may have chronic hepatitis (with liver biopsy findings that can mimic NAFLD, AIH,
viral hepatitis) and it can progress to cirrhosis

Acute Liver Failure (ALF) presents with jaundice, severely elevated ALT, elevated
bilirubin (which may be partly unconjugated as copper is toxic to red blood cells and
leads to hemolytic anemia) with disproportionately low ALP

Parkinsonian features (Cu in basal ganglia), with dystonia (rigidity and contractures),
tremors, dysarthria and dysphonia, gait disturbance and choreiform movement

Kayser-Fleischer (KF) rings (copper deposits in limbus) seen as brown ring around iris, which is best seen on slit lamp examination

Natural History can progress to cirrhosis and its complications, acute liver failure always requires liver transplantation.

Question 17

diagnosing WD

Answer 17

1. Low serum ceruliplasmin
2. rasied 24 hr urine copper
3. liver biopsy for copper concentration
4. genetic studies to see mutations in ATP7B gene

Question 18

Treatment of WD

Answer 18

Chopper chelation to increase urinary copper excretion.

penicillamine, trientine, and Zinc for decreased copper absorption.

• monitor response with yearly 24 horu copper urine measurement.

Question 19

A1AT deficiency pathophysiology

Answer 19

people with A1AT def often have non-functional A1AT. side chain changes and it prevents A1At from being excreted into the plasma. This leads to globules being retained in the liver, and this disease of excess leads to abnormal autophagy with subsequent fibrosis and cirrhosis

The lack of A1AT in the circulation and the lungs (disease of deficiency) leading to an
inability to inhibit neutrophil elastase and results in emphysema

Question 20

A1AT def can occur in children in 20% of cases, causing neonatal cholestasis. In adults, it is seen usually though semi-mild ALT elevation. On a histological slide, how would you determine A1AT def?

There’s no treatment for A1At def. liver translant is also rare.

Answer 20

showing globules which periodic acid schiff PAS sticks to, but Diastase stain isn’t seen, causing cloudiness. PAS-D stain.