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Flashcards in CM- Genes, Cancer and the Liver Deck (52)
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Describe how iron is absorbed from the diet.

Hepcidin (a protein synthesized in the liver) controls the level of iron absorption from the diet through intestinal epithelial cells by blocking ferroportin on the basolateral membrane (thus not letting iron into the blood)


In iron overload states, how does excess iron enter the body?

1. the normal pathway (through epithelial cells in the intestine)
- classic hemochromatosis where too much is absorbed
- more iron in the diet/medication

2. Parenterally in blood transfusions (congenital and acquired anemia)


What 4 factors regulate hepcidin synthesis?

1. iron stores (high iron, increase hepcidin)
2. anemia (you need more iron so decrease H)
3. erythropoietic rate (higher rate= less H)
4. hypoxia (suppresses H)


Describe the path of iron when it get into the blood.

1. binds to circulating plasma transferrin which delivers it to cells
2. cells make heme or cellular enzymes
3. excess is stored as ferritin


What is the most common genetic mutation associated with iron overload?
Describe the mutation.

In Celtics-- classic hereditary hemochromatosis (type 1)

It is a mutation in an HLA-like molecule that results in increased iron absorption despite iron overload.
It is a failure of ferroportin to be regulated by hepcidin


How do blood transfusions cause iron overload?

1. there is no for normal pathway for the body to get rid of excess iron when it reaches the blood (regulation occurs at the level of the intestines)

2. underlying anemia my down-regulate hepcidin, thus allowing more iron to be absorbed from diet


You get lab tests back that are:
Iron: low
TIBC: high
Saturation: low
Transferrin receptor: high
Ferritin: low

What is the problem? What is the net effect in normal people?

This person has an iron deficiency. In normal individuals, hepcidin will decrease allowing ferroportin to take more iron in from the diet.

-increase iron absorption
-increase cell iron uptake


You get lab tests back that are:
Iron: high
TIBC: low
Saturation: high
Transferrin receptors: low
Ferritin: high

What is the problem? What is the net effect for normal people?

This person is iron overloaded. They need to upregulate hepcidin to:

1. decrease absorption from the intestines
2. decrease cell iron uptake


In what organs does iron accumulate? What is the negative sequelae associated with each organ? (6)

1. Liver- cirrhosis
2. Heart- cardiomyopathy
3. pancreas- DM
4. testes- hypogonadism
5. joints- calcium pyrophosphate crystal arthropathy (pseudogout)
6. skin- pigmentation (bronze skin)


Why is the liver disproportionately affected in iron overload from a dietary source?

because there is a first pass effect of dietary iron in portal blood.
When iron stores are saturated (ferritin), iron-mediated fibrosis develops.


What is the threshold for hepatic iron to demonstrate fibrosis/cirrhosis?
What happens to the threshold if there is concurrent viral/alcohol factors?

Between 20-30 mg/g dry weight hepatic iron is the threshold for fibrosis/cirrhosis

If there is alcohol or viral factors, the threshold drops to 10-20mg/g dry weight


How do most patients today present with iron overload?

Patients are likely to be asymptomatic with non-specific fatigue or arthralgia. They will have elevated Fe #s on standard testing.


What tests are used to assess iron overload?

Routine liver tests will vary with the stage of disease so you need to rely on:

1. transferrin, ferritin
2. genetic tests for hereditary hemochromatosis
3. non-invasive radiologic studies can suggest Fe but are not quantitative
4. biopsy if LFTs or enzymes are abnormal to stage the fibrosis
5. phlebotomy to get rid of excess Fe


What will the serum iron level be in:
1. Fe Overload
2. Inflammation
3. Iron deficiency

1. high
2. low-normal
3. low


What will the TIBC be for:
1. Fe overload
2. inflammation
3. Fe deficiency

1. low
2. low
3. high


What will Fe saturation be for:
1. Fe overload
2. inflammation
3. Fe deficiency

1. high
2. high
3. low


What will ferritin levels be for:
1. Fe overload
2. inflammation
3. Fe deficiency

1. normal early and high late
2. high
3. low


What will the hepcidin levels be for:
1. Fe overload
2. inflammation
3. Fe deficiency

1. low
2. high
3. low


What specific mutation accounts for the majority of patients with classic hereditary hemochromatosis?
What genetic test is available to confirm this?

Cys282Tyr - homozygous

Genetic test is for HFE


What is the difference between hemochromatosis and hemosiderosis?

Hemochromatosis = genetic iron overload
- cys282tyr homozygous or His63Asp heterozygous which interact with transferring receptor 1

Hemosiderosis = secondary iron overload
- transfusion
- hyperabsorption in response to anemia, hypoxia
- meds or diet
- advanced liver disease


What is the simplest way to manage excess iron? When is this challenging?

phlebotomy- this can be challenging if there is an underlying anemia.

It decreases serum ferritin to almost 0 by 8 months
Transferrin saturation drops at the 8 month mark


How is copper absorbed into the body?

It is absorbed from the diet. Normal is 1-5mg/day.
In intestinal epithelial cells it is either:

1. bound to metallothioneins
2. transported into the blood (25-60%)


What happens to copper when it reaches the blood?

It is bound to albumin and transported to hepatocytes where it is taken up.
A very little bit of copper can escape hepatic uptake and is excrete in urine (<40microns/day)


What happens to copper in the hepatocyte?

It is attached to chaperone proteins and transporters that:
1. prevent toxicity
2. facilitate incorporation into ceruloplasmin
3. facilitate excretion into the bile


Where is ceruloplasmin synthesized? How many copper atoms can be incorporated in it?

What happens to ceruloplasmin levels with inflammation?
What happens to ceruloplasmin with copper overload?

It is synthesized in the liver and 6-7 copper atoms can incorporate.
It accounts for the majority of serum copper.

Inflammation: increase
Copper overload : decrease ( also with protein losing states and advanced liver disease)


What happens to cells when there is copper overload?

1. deleterious oxidation of lipids and proteins
2. free radical formation


What is the defect in Wilson's disease?

There is an intra-cellular copper transporter defect so copper is not incorporated into ceruloplasmin OR excreted into bile.
The copper just builds in hepatocytes, oxidizing fat and protein and creating free radicals. This leads to cell damage and chronic cirrhosis. When excess copper is released to blood, it damages RBCs increasing bilirubin and leading to more liver problems


In addition to Wilson's disease, in what other two situations is copper excretion impaired?

1. PBC
2. PSC


How do patients present with Wilson's disease?
What age, what clinical presentation?

1. hepatic illness- can be abrupt or insidious
-hemolytic anemia (DAT negative)
- under age 5 or OVER age 40

(5-10 years later)

2. neuropsychiatric illness
-deposition in the basal ganglia and cerebellum
-parkinsons, dystonia, chorea, MS
-Corneal Kayser-Fleischer rings


What is used in the investigation to see if it is Wilson's disease?

Measurements of :
1. ceruloplasmin (low)
2. liver copper (high) - definitive diagnosis
3. urinary copper (high) - most cost-effective way to screen