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Flashcards in Haemochromatosis Deck (12):
1

What does iron deficiency result in?

Low haemoglobin
Symptoms of anemia due to reduced O2 delivery

2

What is Haemochromatosis?

An autosomal recessive disorder of iron metabolism where there is increased iron absorption, excess iron accumulation
Multi-organ dysfunction due to iron deposition

3

When does Heaemochromatosis typically manifest?

It is a late onset disorder occurring once people are past age of 40
The incidence is equal in males and females, though females tend to have later presentation due low iron stores until they are post menopausal

4

What are the pathological findings associated with Haemochromatosis?

Heart degeneration (arrhythmias and cardiomyopathy)
Hepatomegaly (elevated liver enzymes and cirrhosis)
Diabetes mellitus due to pancreas damage
Endocrine caused damage including Testicular atrophy, hypothyroid
Arthritis
Fatigue and lethargy
There may be grey-bronze skin colouration

5

What is the pathology of haemochromatosis?

Organ damage occurs due to iron overload, initially this overload is harmless but once high enough concentrations accumulate then organ damage will occur through the interaction of reactive oxygen species and iron with DNA leading to lethal damage to cells and the stimulation of collagen formation

6

How was haemochromatosis diagnosed prior to the discovery of the gene responsible for this condition?

Detection of raised iron, iron transport protein and saturation
Rasied serum ferritin
A liver biopsy would show increased iron staining

7

What are the genetics of haemochromatosis?

There is linkage to chromosome 6 and in 1996 there was the isolation of the HFE gene
Which commonly has two point mutations the most common of which is Cys288Tyr which exists in 1 in 10 carriers and 90% of patients are homozygous for this mutation
And His63Asp this is less important present in 1 in 5 carriers with double heterozygotes potentially developing iron overload

8

What are the non-HFE causes of iron overload?

Juvenile haemochromatosis which is also known as type 2 haemochromatosis and may be due to 19q21 Haemojuvelin or 19q31 Hepcidin
Transferrin Receptor 2 linked haemochromatosis known as type 3 haemochromatosis
Ferroportin related Iron overload or type 4 hemochromatosis

9

How is normal iron homeostasis regulated?

Iron is absorbed from the diet by villus enterocytes and then passed out into the blood through the ferroportin transporter on its basolateral membrane
Ferroportin is also present on macrophage membranes and these may release some iron through this transporter
The liver regulates how much iron can be released through this transporter by the levels of hepcidin protein which binds to the ferraportin transporter

10

What are the three classes of genetic mutations that play a role in hemochromatosis?

Class I hepcidin gene mutations resulting in reduced levels of functional Hepcidin protein
Class II mutations HFE, TFR2 and haemojuvelin inactivate the signalling pathway which upregulates hepcidin
Class III mutations of ferroportin gene making it insensitive to Hepcidin regulation

11

What is the prevalence and penetrance of hemochromatosis?

It is found most commonly in northen eurpeans, Caucasians and celtic people
It is an autosomal recessive disease with a carrier rate of 1:10 and 1:400 homozygous however penetrance may not be as high as initially predicted with the phenotype varying depending on host factors such as growth, menses, pregnancy, alcohol intake and viral hepatitis
As well as the actions of modifier genes such as those encoding hepcidin, TfR2, haemojuvelin, genes involved in anti-oxidant defence and tissue repair

12

How is hemochromatosis managed?

Venesection is performed to deplete iron stores which causes the person to essentially lead a normal life unless the disease has already progressed to cirrhosis in which case there is also an increased risk of hepatocellular carcinoma