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Genetics > 21. Haemochromatosis > Flashcards

21. Haemochromatosis Flashcards

1
Q

Haemochromatosis

A

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

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2
Q

Hereditary Haemochromatosis

A

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

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3
Q

as a result of HH iron is depositied where ?

A

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

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4
Q

what is the biology of iron in humans

A

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

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5
Q

level of iron in the body

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

how does the body lose iron

A
  • intestinal and skin cell losses
  • menstruation in women
  • increased demand in pregnancy
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7
Q

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

A

body content of over 20gm

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8
Q

Transferrin

A

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

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9
Q

Ferritin

A

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

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10
Q

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

A

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

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11
Q

what is the predisposition to hereditary haemochomatosis and clincal symptoms

A

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.)
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12
Q

what does penetrance depend on

A
  • 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
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13
Q

potential complications of advanced haemochromatosis

A
  • cirrhosis (liver disease)
  • hepatoma (liver cancer)
  • diabetes
  • Cardiomyopathy (disease of the heart muscle)
  • Pituitary gonadotrophins
  • increased pigmentation
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14
Q

pathology of haemochromatosis to do with the liver

A

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

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15
Q

pathology of haemochromatosis to do with the heart

A

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

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16
Q

pathology of haemochromatosis - pancreas

A

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

17
Q

pathology of haemochromatosis - skin

A

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

18
Q

haemochromatosis diagnosis

A
  • examination to access for signs and symptoms
  • lab tests: liver function test, test levels of transferrin and ferritin
  • liver biopsy
19
Q

in haemochromatosis, what are the serum ferritin level

A

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

20
Q

pathogenic steps of HH

A
  • 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
21
Q

why is penetrance difficult to define in HH

A
  • lack of agreement on clinical features
  • other influencing factors (alcohol, age, sex, diet)
  • biochemical versus clinical
  • ascertainment biases in populations screened
22
Q

what are the two common gene variants for this condition

A

C282Y and H63D

23
Q

Treatment

A

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

24
Q

what are some other treatments available

A

reduce iron overload with a low iron diet

treat arthritis with physio, joint replacement

treat heart failure with diuretics

25
Q

what is population genetic screening

A

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

26
Q

criteria for a population screening programme

A
  • 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
27
Q

population genetic screening for HH - the case against

A

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

28
Q

the case for screening

A
  • 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
29
Q

if you were to screen, who should you screen

A
  • 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
30
Q

is screening currently taking place

A
  • 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
31
Q

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

A
  • test all newborn babies
  • test secondary school children
  • offer voluntary test to adults through electoral register
32
Q

what test should you use, Transferrin saturation or Genetic test

A

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

Genetics (23 decks)

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