Iron questions Flashcards
Hereditary haemochromatosis is due to a mutation in which gene?
HFE gene 85% of the time
C282Y is the most common
then H63D
then H65C
Mechanism of illness secondary to HFE gene mutation
Normally: HFE protein forms 1:1 complex with beta 2 microglobulin then that complex interacts with the transferrin receptor to decrease affinity of receptor for transferrin
Also get variable hepcidin defects-quality or quantity. Hence no regulation of absorption. Not always related to the HFE.
Mutation c282Y disrupts this complex so that there is increased Fe transfer into stores and increased DMT1 on intestinal cells leading to increased absorption
Why is iron overload a problem in thalassaemia and congenital sideroblastic anaemia
Even in absence of transfusion can become profoundly iron overloaded as there is a very high erythropoetic drive. This blocks hepcidin synthesis
Haemochromatosis features
“bronzed cirrhosis with diabetes”- diabetes insulin dependent, hepatomegaly without decompensation, diffuse hyperpigmentation
Rule of 3As
- Asthenia- fatigue, impotence
- Arthralgia - mimics OA, 2nd and 3rd MCPs often involved, radiologically see subchondral arthropathy and chondrocalcinosis. NOT related to degree of iron overload
- Aminotransferase elevation
Diagnosing iron overload
Ferritin but not specific, can be useful for close and frequent monitoring to indicated changes in iron burden when already diagnosed. Poor indicator of total body iron burden- though less than 800 unlikely to have significant risk of cardiac or liver loading
Transferrin saturation
Liver biopsy- direct measure but invasive- no longer for diagnosis but to show fibrosis. Still used for diagnosis if C282Y -/- apparently
MRI T2* (star)- expensive. Can look at heart and liver both; ACCURATELY PREDICTS total body iron stores. High liver iron concentration correlates with worsening prognosis, fibrosis
Also LFT, BSL
Causes of increased transferrin saturation
Causes of dyserythropoesis
Hepatitis
Hepatic failure
Iron overload
Causes of iron overload and normal or low transferrin saturation
Dysmetabolic hyperferritinaemia: AKA insulin resistance associated Fe overload- DM, hypertension, obesity, hyperlipidaemia- ferritin may be over 1000, normal transferrin saturation, hepatic iron less than three times the upper limit of normal
Ferroportin mutation
Hereditary aceruloplasminaemia
Venesection targets in iron overload
Weekly if Hb tolerates until ferritin under 50, saturation under 20%
Then maintain ferritin at less than 100
Do haemochromatosis symptoms/damage improve after venesection gets numbers under control?
good for enzymes, asthenia, increased pigmentation
Variable for arthralgias and can actually make it worse
Variable diabetes impact
bad for impotence
useless for cirrhosis or HCC
Acquired iron overload causes
Iron loading anaemias:
Thalassaemia intermedia
Sideroblastic anaemia
Chronic haemolytic anaemia
Transfusion related: Thal major Sickle cell MDS aplastic anaemia
What is the mechanism whereby the iron is actually toxic?
When serum iron exceeds transferrin’s binding capacity–>iron is bound to low molecular weight compounds as “non transferrin bound iron”- this is readily taken up by hepatocytes, cardiac myocytes, anterior pituitary cells, and pancreatic beta cells—> oxidant damage
In a thalassemia kid/adult, what do you look to assess results of disease?
Transfusion related infections Bone expansion-->hair on end skull hypopituitarism, hypothyroid, hypoparathyroid excessive skin pigmentation arthritis cardiomyopathy venous thrombosis cirrhosis venous thrombosis, pulmonary embolism, hypertension short DM splenomegaly delayed puberty and secondary sexual characteristics osteoporosis
What are the iron chelation options?
Desferrioxamine- subcut infusion 8 hours a day for 5-6 days a week
Deferasirox- oral but expensive and limited to thalassaemia and other congenital abnormalities on pbs
What is the basis and role of the soluble transferrin receptor in differentiating between ACD and Iron def?
This is the soluble component of the transferrin receptor- reflects the erythroid mass
Low if there is erythroid hypoplasia like in chronic renal failure or AA
HIgh if there is high erythroid hyperplasia like in chronic haemolysis or thalassaemia
IN THE ABSENCE OF ERYTHROID HYPERPLASIA, IRON DEFICIENCY IS THE PRINCIPAL CAUSE
Not elevated in ACD
Can increase predictive nature by dividing transferrin receptor over log ferritin- if over 4 then Fe def. If below 1 then ACD
What is the hepcidin level in haemochromatosis (HFE gene mutation vs ferroportin mutation)
In ferroportin mutation will be HIGH
In HFE will be LOW OR ABSENT (inappropriately)
