21. Haemochromatosis

Question 1

Haemochromatosis

Answer 1

Heterogeneous Clinical Disorder
Characterised by excess accumulation of iron in many different tissues

Question 2

Hereditary Haemochromatosis

Answer 2

an inherited disorder of iron metabolism where excess dietary iron is absorbed by the gastrointestinal mucosa (lining of the gastrointestinal tract)

Question 3

as a result of HH iron is depositied where ?

Answer 3

progressive desposition of iron containing cells on the
- liver
- joints
- pancreas
- skin and heart

Question 4

what is the biology of iron in humans

Answer 4

iron is a essential co factor for many enzymatic processes
crucial element in structure and function of hemoglobin

Question 5

level of iron in the body

Answer 5

• the total body content is 2-6mg
• daily intake of iron is 10-20mg orally
• about 10% of this is absorbed

Question 6

how does the body lose iron

Answer 6

• intestinal and skin cell losses
• menstruation in women
• increased demand in pregnancy

Question 7

what is the body content of iron for you to develop haemochomatosis

Answer 7

body content of over 20gm

Question 8

Transferrin

Answer 8

a protein produced by the liver which plays a crucial role in the transportation of iron around the body
- primary function is to bind to iron in the bloodstream and transport iron from gut to liver
- usually only 20-40% transferrin has bound iron

Question 9

Ferritin

Answer 9

iron in tissues is stored as Ferritin

ferritin levels can vary
- ferritin binds to excess iron ions and stores them preventing iron overload and potential damage to cells and tissues.
- when iron levels are low, ferritin releases stored iron to meet the bodies needs

Question 10

what is the commonest form of haemochromatosis
- how common is it

Answer 10

primary adult onset hereditary haemochromatosis
- 1 in 1,000 affected

Question 11

what is the predisposition to hereditary haemochomatosis and clincal symptoms

Answer 11

inherited in an autosomal recessive manner

• adult insidious onset of chronic fatigue
• joint pains
• malaise (general feeling of discomfort, uneasiness, or illness without any specific symptoms.)

Question 12

what does penetrance depend on

Answer 12

• importance of the function of the encoded protein
• functional importance of the mutation
• interaction with the environment
• interaction with other genes
• existence of alternative pathways that can compensate for loss of function

Question 13

potential complications of advanced haemochromatosis

Answer 13

• cirrhosis (liver disease)
• hepatoma (liver cancer)
• diabetes
• Cardiomyopathy (disease of the heart muscle)
• Pituitary gonadotrophins
• increased pigmentation

Question 14

pathology of haemochromatosis to do with the liver

Answer 14

iron overload causes chronic liver damage leading to cirrhosis
- cirrhosis is a liver disease that can increase the risk of hepatocellular carcinoma (type of liver cancer)
- excess amount of iron has accumulated in the Kupffer cells within the liver tissue

Question 15

pathology of haemochromatosis to do with the heart

Answer 15

in the heart, iron overload can lead to cardiomyopathy, the weakening and enlargement of the heart muscle. This can result fatigue, shortness of breath, palpitations, and eventually heart failure

Question 16

pathology of haemochromatosis - pancreas

Answer 16

excess iron deposition can damage the insulin-producing beta cells, leading to insulin resistance and diabetes mellitus

Question 17

pathology of haemochromatosis - skin

Answer 17

can cause a grey or bronze discoloration due to iron deposition in the skin cells

Question 18

haemochromatosis diagnosis

Answer 18

• examination to access for signs and symptoms
• lab tests: liver function test, test levels of transferrin and ferritin
• liver biopsy

Question 19

in haemochromatosis, what are the serum ferritin level

Answer 19

in males > 300 ng/ml
in females >200ng/ml

Question 20

pathogenic steps of HH

Answer 20

• HH is primarily caused by mutation in the HFE gene, particularly C282Y and H63D mutations
• Uncontrolled uptake of dietary iron
• Transferrin becomes saturated with iron
• Excess iron transportation by transferrin is deposited in various tissues, can lead to tissue damage and dysfunction over time
  Can go on to give you organ failure

Question 21

why is penetrance difficult to define in HH

Answer 21

• lack of agreement on clinical features
• other influencing factors (alcohol, age, sex, diet)
• biochemical versus clinical
• ascertainment biases in populations screened

Question 22

what are the two common gene variants for this condition

Answer 22

C282Y and H63D

Question 23

Treatment

Answer 23

major organ damage is preventable
phlebotomy: taking 500-800ml blood weekly
- aim is to reduce ferritin to less than 50ng per ml

Question 24

what are some other treatments available

Answer 24

reduce iron overload with a low iron diet

treat arthritis with physio, joint replacement

treat heart failure with diuretics

Question 25

what is population genetic screening

Answer 25

a search in a population to identify individual who may have, or may be susceptible to a serious genetic disease or to identify people who may not be at risk themselves as gene carriers may be at risk of having children with that genetic disease

Question 26

criteria for a population screening programme

Answer 26

- disease must be common - diagnosed by avaiable blood test - positive result must predict and prevent morbidity and mortality - must be treatable - socially and ethically acceptable - test must have high sensitivity - benefits must outweigh costs

Question 27

population genetic screening for HH - the case against

Answer 27

many people must be screened to prevent severe disease in only a few as penetrance is low progressive iron overload infrequently seen in untreated C282Y homozygotes decreases the incremental benefits of screening may miss individuals with iron overload due to other causes

Question 28

the case for screening

Answer 28

- it is a preventable disease - effective treatment if started early - is a common disease - Ireland has the highest frequency of HH gene in the world

Question 29

if you were to screen, who should you screen

Answer 29

- those with family history - sibs have 1 in 4 chance of being predisposed - but, most people diagnosed with HH are not known previously to have had the condition in their family

Question 30

is screening currently taking place

Answer 30

- some private medical screening services in IRL offer transferrin saturation and ferritin - some US health maintenance organizations run HH screening by transferrin - no whole population screening yet

Question 31

for effective screening you need to test the whole population, how could you go about this

Answer 31

- test all newborn babies - test secondary school children - offer voluntary test to adults through electoral register

Question 32

what test should you use, Transferrin saturation or Genetic test

Answer 32

transferrin saturation - no use in infants or children - in adults will need serial testing Genetic test - only needs to be done once - will pick up carriers as well