This document provides information about haemochromatosis, an iron overload disorder. It discusses the types of haemochromatosis including the classical type caused by a mutation in the HFE gene. Organs that are commonly affected include the liver, heart, and pancreas. Symptoms may include fatigue, joint pain, and abdominal pain. Diagnosis involves tests such as serum ferritin levels, liver biopsy, and genetic testing. Treatment options include therapeutic phlebotomy to reduce iron levels and chelation therapy with medications like deferoxamine. The conclusion emphasizes that haemochromatosis is caused by a genetic mutation and can affect multiple organs if left untreated.

1. BLOOD DISORDERS
HAEMOCHROMATOSIS
BY
ADO MUHAMMAD DAKATA (famlsn)
M.Sc., B.Sc., ACMLS, FCMLS, PGDE
Human Leucocyte Antigen and Immunogenetics Laboratory,
Department of Haematology,
Aminu Kano Teaching Hospital,
Kano State.
Nigeria.

2. GUIDELINES
❖ INTRODUCTION
❖ WHAT IS HAEMOCHROMATOSIS
❖ TYPES OF HAEMOCHROMATOSIS
❖ CAUSES OF HAEMOCHROMATOSIS
❖ ORGANS COMMONLY AFFECTED BY HAEMOCHROMATOSIS
❖ SYMPTOMS OF HAEMOCHROMATOSIS
❖ DIAGNOSIS
❖ BLOOD IRON TEST
❖ SERUM FERRITIN ESTIMATION AND MONITORING
❖ GENETIC TEST
❖ LIVER BIOPSY
❖ MRI

3. GUIDELINE CONTINUED
❖ TREATMENT
❖ THERAPEUTIC PHLEBOTOMY
❖ USE OF CHELATING AGENTS
❖ CONCLUSION
❖ REFERENCES

4. HAEMOCHROMATOSIS
o Is an iron disorder in which the body simply load too much iron
o Also called iron storage disease
o Use to designate an increase of tissue iron resulting in a disease state
o Was first describe by Trousseau in 1865
o Massive accumulation of iron is its hallmark
o Some investigators though the toxic metal might be copper
o Gene located near the HLA-A and HLA-B

5. EPIDEMIOLOGY
❑ At one point Haemochromatosis was rare,
❑ Male to Female ratio was 18:1
❑ Gene mutation C282Y and S65C mutation are almost entirely confined to people of European ancestry
❑ H63D mutation is wide spread geographically
❑ Within Europe highest gene frequencies are encountered in southern British isles and Northern France
❑ Prevalence of other forms of Haemochromatosis is low compared to the classical Haemochromatosis
❑ It has low frequency in Africa

6. ETIOLOGY AND PATHOGENESIS
❑ Accepting and releasing electrons is the main basis of the importance of iron to living organism
❑ The capacity to undergo oxidation –reduction reaction appears to be the basis of the harm caused by
excessive amount of iron
❑ One of the pathways considered to be of great importance is the Haber-Weiss reaction
❑ Fe++ + H2O2 → Fe+++ +OH. + .HO
❑ O..
2 + Fe+++ → O2 + Fe++
❑ The sum of these two reactions is the Fenton reaction:
❑ O..
2 + H2O2 → O2 + OH. + .HO

7. ETIOLOGY AND PATHOGENESIS CONTINUED
❑ The (.HO) is second in reactivity only to atomic oxygen and has been implicated in damaging
polysaccharide, DNA and enzyme causing lipid peroxidation
❑ Even though no direct evidence exists that (.HO) generation is the pathway of tissue damage in
Haemochromatosis
❑ A possible role of ferryl ions (FeO2
+ ) in mediating tissue damage has been suggested

8. CAUSES OF IRON OVERLOAD
➢ Because body iron content is maintained by regulating absorption
➢ Excess body iron can accumulate only when absorption is dysregulated(Dysfunctional) or
➢ When iron is injected into the body,
➢ Either in the form of medicinal iron or transfused erythrocytes

9. DYSREGULATION OF IRON ABSORPTION
❖ A variety of mutations caused an increase in iron absorption in experimental animals and man.
❖ Mutation of the genes encoding HFE, TRANSFERRIN RECEPTOR -2, ferroportin-1 and hepcidin all has
been associated with iron overload.
❖ But the actual mechanism remains unknown.
❖ Haemochromatosis resulting from HFE mutations is linked with the expression of Hepcidin as was
established.
❖ Hepcidin is up-regulated when body iron increases.

10. INEFFECTIVE ERYTHROCYTOSIS
❖ Existence of a strong relationship between ineffective erythrocytosis and total iron burden.
❖ Amount of body iron may greatly exceed the quantity that can be accounted for through blood
transfusion
❖ But the mechanism through which active erythrocytosis and destruction of red cell precursor in the
bone marrow stimulate iron absorption is unknown.
❖ Of note, iron storage disease is particularly common in disorders such as thalassemia, hereditary
dyserythropoietic Anaemia pyruvate kinase defiency.

11. TRANSFUSION OR IRON THERAPY
❑ Iron overload can be iatrogenic (induced) in origin
❑ Because erythrocytes contain 1mg of iron per milliliter,
❑ So transfusion of 450ml of whole blood or 200ml of red cells add 200mg of total iron to the body.
❑ This iron will not be excreted.
❑ So if a patient requires 2U of blood per month will accumulate 4.8g of iron per day.

12. PATHOLOGY
❑ Affected tissues and organ exhibit a deep brown color
❑ Histologic examination reveals prominent Haemosiderin in many tissues and organ.
❑ The Liver
❑ Is often enlarged
❑ After cirrhosis develop become granular of coarsely nodular
❑ Haemosiderin is found in hepatocytes of patients with juvenile Haemochromatosis
❑ Also in bile duct epithelium, in Kupffer cells to lesser degree
❑ Haemosiderin accumulates primarily in periportal hepatocytes and is less toward central vein.

13. MARROW
❑ Iron in the marrow of patient with classical hereditary Haemochromatosis is only modestly increased,
if at all
❑ Iron is characteristically distributed into small equal size granules
❑ Located in endothelial lining cells rather than macrophages
❑ In type 1 Haemochromatosis both macrophages and intestinal mucosal cells are relatively iron poor.

14. OTHER TISSUES
❑ More iron than normal is found in intestinal mucosal cells
❑ In relation to total iron burden as indicated by serum ferritin level, the amount of iron is strikingly
decreased
❑ The same relationship was found in a knockout mice.
❑ In contrast patients with transfusion iron overload, macrophages are heavily laden with iron
presumably derived from Transfused red cells.
❑ Myocardium is thickened and often enlarged and testis often atropic

15. TYPES OF HAEMOCHROMATOSIS AND CAUSES
➢ There are two types
❑ First is called primary/classical/Hereditary
❑ Second is called Secondary/ Non-classical/Acquired
❑ Type1 Haemochromatosis-caused as a result of mutation
❑ Mutation is in the HFE genes at short arm of chromosome 6.
❑ Mutation in C282Y H63D, S65C (but barely perceptible)
❑ There are other wild copies of mutated genes over 19,000 but functionally not fully established or
known.

16. GENETIC HAEMOCHROMATOSIS CONTINUED
❑ Juvenile Haemochromatosis type 2A (HFE2)
❑ Juvenile Haemochromatosis type 2B Hepcidin (HFE2B)
❑ Type 3 Haemochromatosis Transferrin receptor 2 (TRF2 or HFE3)
❑ Type 4 African Haemochromatosis (Ferroportin)
❑ Neonatal Haemochromatosis (mutation not yet identified)
❑ Aceruloplasminemia (Autosomal recessive) ceruloplasmin is a ferroxidase enzyme encoded by CP
gene.
❑ Gracile syndrome BSC 1 gene
❑ Atransferrinaemia (Transferrin) encoded by TF gene

17. SECONDARY HAEMOCROMATOSIS AND CAUSES
❑ Severe Chronic Haemolysis (Intravascular, ineffective erythropoiesis)
❑ Multiple frequent blood transfusion (In Haemoglobinopathies)
❑ Iron poisoning because of excessive iron intake of parenteral iron supplement.
❑ Excess dietary iron
❑ Other predisposing factors such as alcohol porphyria cutanea Prolong haemodialysis etc.

18. ORGANS COMMONLY AFFECTED BY HAEMOCHROMATOSIS
❑ Liver
❑ Heart
❑ Kidney
❑ Pancreas
❑ Muscles and Bones
❑ Brain
❑ Gall Bladder
❑ Testis etc

19. SYMPTOMS
❑ Chronic fatigue and joint pain
❑ Pain in the knuckles of the pointer and middle finger, (collectively called “The iron fist” is the only sign
or symptom specific o Haemochromatosis).
❑ Lack of Energy
❑ Abdominal pain
❑ Memory fog
❑ Loss of sex drive
❑ Heart Flutters
❑ Irregular heart beat

20. DISEASE THAT CAN DEVELOP IF LEFT UNTREATED
❑ Bone and Joint: Osteoarthritis or Osteoporosis in knuckles, ankles and liver
❑ Liver: enlarged liver, cirrhosis and liver failure diabetes
❑ Skin: abnormal colour (bronze, reddish or ashen-gray)
❑ Heart: irregular heartbeat, enlarged heart, congestive heart failure
❑ Endocrine: diabetes, hypothyroidism, hypogonadism, (infertility, importance), hormone imbalances
❑ Spleen: enlarged spleen

21. WHAT TESTS ARE NEEDED TO OBTAIN A DIAGNOSIS
❑ Liver Biopsy
❑ TIBC
❑ Serum Ferritin (50-150ng/ml)
❑ Serum Iron
❑ MRI
❑ Genetic testing

22. SOME HISTOLOGIC PICTURE OF LIVER WITH IRON DEPOSIT IN
HAEMOCHROMATOSIS

23. PHYSICIANS WHO CAN HELP DIAGNOSE HAEMOCHROMATOSIS
❑ Cardiologist
❑ Endocrinologist
❑ Gastroenterologist
❑ Gynaecologist
❑ Haematologist/Oncologist

24. PHYSICIANS WHO CAN HELP DIAGNOSE HAEMOCHROMATOSIS
CONTINUED
❑ Hepatologist
❑ Internist (Doc. In internal medicine)
❑ Rheumatologist
❑ Urologist
❑ Psychiatrist

25. TREATMENT
❑ It is important to get iron levels down to normal
❑ Therapeutic blood removal or phlebotomy same as regular blood donation.
❑ Each milliter of packed red cell contains approximately 1mg of Iron
❑ So removal of 500mg of HCT 40% removes approximately 200mg of Iron
❑ Haemochromatosis patient can give blood about 8 times in a month
❑ Transferrin saturation and serum ferritin level need to be measured every 2 or 3 months.
❑ When Transferrin saturation is less 10% and serum ferritin less than 10ng/ml discontinue phlebotomy.

26. CHELATION THERAPY
❑ Deferoxamine
❑ Is a bacterial siderophore produce by streptomyces pilosus
❑ Act by binding free iron in the bloodstream and enhance its elimination through urine.
❑ Given as subcutaneous injection over a period of 8- 12 hours.

27. CHELATION THERAPY
❑ Deferasirox (Exjade)
❑ Oral Iron chelating agent
❑ Use to reduce chronic iron overload
❑ Remove iron from cells (cardiac myocytes and hepatocytes) and blood

28. CHELATION THERAPY
❑ Deferiprone (Trade name Ferriprox)
❑ Oral drug that chelate iron and use to treat thalassaemia major
❑ FDA approved to treat patients with iron overload due to blood transfusion in patient with
thalassaemia.

29. TREATMENT CONTINUED
❑ Treatment can be dietary also
❑ Humans consume two types of iron
❑ Heme and non-heme
❑ Heme iron is the most easily absorbed form of iron
❑ Highest in heme iron is red meat such as beef vension, lamb and Buffalo
❑ Additionally, blue fin tuna is higher in heme iron than most other type of fish
❑ All meat and fish also contain non-heme iron,
❑ Mostly in vegetables, fruits, nuts, grains and most over-the- counter iron supplement.

30. TREATMENT CONTINUED
❑ Patients can take a normal balance diet without avoiding iron provided they are undergoing effective
therapeutic phlebotomy
❑ Patients should avoid alcohol consumption since it increases the risk of developing Liver cirrhosis.
❑ Avoid ingestion of high doses of Vitamin C as it can lead to fatal abnormal heart rhythms in iron
overload
❑ Advisable to avoid vitamin C supplement until adequately treated.
❑ Avoid raw seafood since patient may be at risk of acquiring bacterial infections that flourish in rich
environment.

31. WHAT IS NEW
❖ Data from both cohorts confirm the high prevalence of joint symptoms in Haemochromatosis
❖ Which predate the diagnosis by many years
➢ Discriminatory features of the arthropathy include the involvement of MCP joints
➢ Ankles at a relatively young age in the absence of trauma
➢ All of which are unusual features of primary osteoarthritis (A0)
➢ The finding of this presentation should prompt diagnosis tests for haemochromatosis

32. ARE WE TREATING DISEASE, PREVENTING DISEASE OR TREATING
NUMBER
➢ These association beg the question that hyperferritinaemia is associated with a particular disease
state, then does treating hyperferritinaemia improve outcomes in such conditions? Unfortunately, the
answer to this question is not entirely clear.
➢ Because a large multicentre, randomized control trial was conducted to
➢ Evaluate iron reduction phlebotomy as a treatment for patients with symptomatic but stable peripheral
artery disease (PAD)
➢ But no significant differences were noted between the two groups for either the primary outcomes of
all-cause mortality or secondary outcomes of death plus nonfatal myocardial infarction and stroke.

33. ISTHERE A RATIONALE FOR PHELOBOTOMY IF IT IS NOT LIKELY TO BE
IRON OVERLOAD
➢ Unfortunately there is still no answer.
➢ The short answer is likely to be no
➢ Whereas the role of phlebotomy remain controversial in the absence of true iron overload
➢ But phlebotomy is likely answer in patients with demonstrable iron excess
➢ It is clear that iron cannot be accurately diagnosed based solely on elevated serum ferritin.
➢ So it is recommended that the presence of tissue iron deposition be confirmed by at least one of the
following modalities
➢ Iron staining in liver biopsy
➢ Measurement of liver iron Concentration (LIC)

34. ISTHERE A RATIONALE FOR PHELOBOTOMY IF IT IS NOT LIKELY TO BE
IRON OVERLOAD CONTINUED
➢ Alternatively, MRI which offers an accurate noninvasive alternative to liver biopsy.
➢ In cases where iron excess is confirmed in the setting of high ferritin, research to date support a
beneficial effect of iron reduction therapy

35. CONCLUSION
❖ Haemochromatosis is an iron overload disease cause as a result of genetic mutation by HFE gene
(C282Y, H63D, S65C)
❖ Can also be caused by secondary factors such as blood transfusion and haemolytic anaemia e.g.
Thalassaemia
❖ Is more common in people of European ancestry (Welsh, Britain, France and UK)
❖ Is less common in Africa but more data is needed to established full facts.
❖ Can be diagnose using serum ferritin, TIBC, TS%, liver biopsy and MRI.

36. CONCLUSION CONTINUED
❖ Treatment can be by phlebotomy, using different form of chelating agent e.g. Deferoxamine etc. and
also by dietary method.

37. THANK YOU FOR LISTENING

38. SOME QUOTED REFERENCES
❖ MELANIE D. BEATON AND PAUL C. ADAMS (2012)
Treatment of hyperferritinaemia, Annals of Hepatology, 11(3), pp. 294-300
❖ Richardson A., Prideaux A. AND Kiely P. (2016)
Haemochromatosis; unexplained metacarpophalangeal or ankle arthropathy should prompt diagnostic
tests: finding from two UK observational cohort studies Scandinavian journal of rheumatology. Available
from http:// www.scanjrheumatol.dk
❖ Erhabor O. and Adias T. (2013) Haematology made easy
1663 Liberty drive Bloomington, IN 47403: Authorhouse
❖ Williams et al. (2006) Hematology 7th edition McGraw-Hill New York.
❖ Haemochromatosis.org (2016) provided by iron disorder institute. [online] Available from
http://www.irondisorders.org