Genetic haemochromatosis (Bsh 2017)



One of the most frequent genetic disorders in North Europeans

Continued absorption of iron from the small intestine despite normal/high total body iron levels leads to tissue iron deposition and subsequent organ dysfunction.


Life expectancy is normal when phlebotomy is started before cirrhosis and diabetes have developed


Normal Iron balance


Total body iron content is around 4g, of which:

  • 3g in haemoglobin

  • 1g in RES macrophages (stored as ferritin)

  • 100mg in tissue enzymes involved in respiration

  • 4mg bound to transferrin


There is no active excretion of iron, losses occur from:

  • 1mg/day via death of cells in the GI lumen

  • 15-40mg/period

  • 500mg/pregnancy


Transferrin (Tf)

  • Glycoprotein produced by the liver, responsible for delivering iron to cells via transferrin receptors

  • Tf levels are regulated by iron stores, rising in deficiency and falling in overload.

  • Each Tf has two iron binding domains and is capable of delivering 20-40mg of iron every 24 hours

  • In health, around 30% of transferrin is saturated with iron at any one time.

  • All cells receive iron via Tf. In addition to this, macrophages have a far greater supply via the ingestion of circulating red cells.

Iron toxicity

If serum iron levels rise --> Tf levels fall and the Tsat% rises --> non-transferrin bound iron (NTBI) starts to appear in the plasma, and is then transported into cells alongside Tf-iron.


NTBI is thought to damage cells via the Fenton reaction, free radical formation and lipid peroxidation.


HFE Gene Mutation

90% of patients with GH

Autosomal recessive inheritance of mutation in the HFE gene on chromosome 6

HFE gene codes for a glycoprotein which has complex interactions within the iron homeostasis pathways. HFE mutation results in suppression of hepcidin --> deregulation of iron efflux (see diagram above)


Two common mutations:

  • C282Y mutation: Cysteine --> Tyrosine at amino acid 282

  • H63D mutation: Aspartic acid --> Histidine at amino acid 63

(H63D mutation more common in general population, but does not usually cause iron overload)


Biochemical penetrance is variable and only 80%/50% (Male/female) of people with even the most high-risk genotype (C282Y homozygotes) will develop a raised SF/Tsat during their lifetime.


Clinical penetrance is even lower again, but from highest to lowest risk:

  •  C282Y homozygotes

  •  C282Y/H63D compound heterozygotes

  •  C282Y heterozygotes

  •  H63D homozygotes

  •  H63D heterozygotes


(Note: It is possible that other factors (Alcohol, Metabolic Syn) play a more important role in causing hyperferritinaemia in all but the C282Y homozygotes. Some would argue that H63D mutations should not be tested for, e.g. French laboratories are not reimbursed for running this test).



Unselected population screening for the HFE gene mutation is not recommended (as only 19/16% (male/female) of people with raised SF + raised Tsat are C282Y homozygotes).


Family members of patients diagnosed with HFE GH should be offered testing for:

  • FBC, LFT, SF, Tsat and HFE gene mutation


Family screening is not required for family of patients with C282Y/H63D compound heterozygosity


Clinical Features


Generalised weakness and lethargy

‘Bronzed Diabetes’ – type 2 diabetes with bronze skin pigmentation

Liver fibrosis / cirrhosis

Cardiomyopathy and conduction defects

‘Painful handshake sign’ – arthropathy affecting the 2nd and 3rd metacarpophalangeal joints


Hypogonadotrophic hypogonadism – results from severe iron loading in the pituitary



Patients with clinical features to suggest GH should be tested for:

  • FBC, LFT, serum ferritin (SF) and transferrin saturation (Tsat)


HFE gene mutation should then be tested for:

  • All adults >30 y.o. of North European descent with unexplained SF >300/>200 and Tsat >50%/>40% (Male/Female)


C282Y Homozygotes

  • SF <1000, normal LFT, normal examination --> no further investigation required

  • SF >1000 or abnormal LFT --> refer to hepatology for fibrosis/cirrhosis investigation

(Cirrhotic patients will then typically get 6 monthly liver USS + alpha-fetoprotein levels)


Non-C282Y Homozygotes

  • If significant iron loading is present by MRI/liver biopsy then rare causes of iron loading should be sought



All fit GH patients with biochemical iron loading:

  • Weekly venesection until SF 20-30 and Tsat <50% (check these monthly + weekly FBC inbetween)

  • Then maintain with PRN venesection, preferably as blood donation – target: normal FBC, SF <50, Tsat <50%


Homozygotes with normal iron studies, or compound heterozygotes with mild rise in iron:

  • Recommend regular blood donation and annual measurement of SF + Tsat


Who needs liver assessment?

Ferritin >1000 or any rise in transaminases --> refer to hepatology for fibrosis/cirrhosis assessment


Liver biopsy is no longer required for the diagnosis of HFE GH, but may still be used to assess severity of fibrosis.


Patients with liver cirrhosis are at 100-fold increased risk of primary liver cancer and require 6 monthly screening with USS and alpha-fetoprotein levels.


List of Rare Genetic Causes of iron overload


Type 2 Haemochromatosis (Juvenile Haemochromatosis)

HFE2 (syn. HJV) or HAMP gene mutations.

Causes severe iron overloading with cardiac failure and panhypopituitarism.


Type 3 Haemochromatosis (Transferrin receptor 2 deficiency)

TFR2 mutation.

European and Japanese ethnicities.

Clinical phenotype lies between Type 1 and Type 2 GH.


Type 4a Haemochromatosis (Ferroportin Disease)

Loss of function mutation in SLC40A1 (syn. FPN1) gene that encodes ferroportin

Reduced macrophage iron release --> RES iron overload.

Organ damage does not occur but patients develop iron deficiency anaemia with venesection.


Type 4b Haemochromatosis

Gain of function SCL40A1 mutation.

Similar phenotype to Type 1 GH.


Type 5 Haemochromatosis

FTH1 gene mutation.

Described in a single Japanese family.



CP gene mutation

Dystonia, ataxia, dementia (iron deposition in basal ganglia).


Hereditary Hyperferritinaemia Cataract Syndrome (HHCS)

Autosomal dominant

L-ferritin deposition in the ocular lens results in early-onset cataracts

There is no need to lower the SF level



TF gene mutation (Autosomal recessive)

Presents a birth with severe iron deficiency anaemia + paradoxical tissue iron overload


Benign Hyperferritinaemia

FTL gene mutation

Ferritin 400 - 6000 without tissue iron overload.