Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

stage 0 disease (C282Y homozygous)

1st line – observation and 3-yearly follow-up

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ONGOING
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stage 0 disease (C282Y homozygous)
1st line – 

observation and 3-yearly follow-up

Stage 0: C282Y homozygosity with normal serum transferrin saturation and ferritin, and no clinical symptoms.[6]

Patients should be monitored every 3 years with history, examination, and blood tests including serum ferritin level and serum transferrin saturation.[6]

Plus – lifestyle modifications

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ONGOING
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stage 0 disease (C282Y homozygous)
Plus – 

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

All patients should avoid iron-fortified foods or iron-containing supplements.[8][54]

Vitamin C-containing supplements should also be avoided, as vitamin C can lead to increased intestinal absorption of dietary iron.[4][7][8]​ Despite this, some physicians may recommend low doses of vitamin C in patients who are started on parenteral iron chelation therapy. This is because it increases the availability of iron for chelation with desferrioxamine.

Patients should be advised to avoid excess alcohol (or avoid altogether if hepatic disease is present).[8]

Raw/undercooked shellfish and wound contact with seawater should be avoided, due to susceptibility of patients with haemochromatosis to rare but serious systemic bacterial infection by Vibrio vulfinicus.[8]

Consider – hepatitis A and hepatitis B vaccination

Back
ONGOING
|
stage 0 disease (C282Y homozygous)
Consider – 

hepatitis A and hepatitis B vaccination

Additional treatment recommended for SOME patients in selected patient group

Can be considered in patients not exposed to hepatitis.[58][59]

stage 1 disease (C282Y homozygous)

1st line – observation and 1-yearly follow-up

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ONGOING
|
stage 1 disease (C282Y homozygous)
1st line – 

observation and 1-yearly follow-up

Stage 1: C282Y homozygosity with increased transferrin saturation (>45%), normal ferritin, and no clinical symptoms.[6]

Patients should be monitored every year with history, examination, and blood tests including serum ferritin level and serum transferrin saturation.​[6][54]

Plus – lifestyle modifications

Back
ONGOING
|
stage 1 disease (C282Y homozygous)
Plus – 

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

All patients should avoid iron-fortified foods or iron-containing supplements.[8][54]

Vitamin C-containing supplements should also be avoided, as vitamin C can lead to increased intestinal absorption of dietary iron.[4][7][8]​ Despite this, some physicians may recommend low doses of vitamin C in patients who are started on parenteral iron chelation therapy. This is because it increases the availability of iron for chelation with desferrioxamine.

Patients should be advised to avoid excess alcohol (or avoid altogether if hepatic disease is present).[8]

Raw/undercooked shellfish and wound contact with seawater should be avoided, due to susceptibility of patients with haemochromatosis to rare but serious systemic bacterial infection by Vibrio vulfinicus.[8]

Consider – hepatitis A and hepatitis B vaccination

Back
ONGOING
|
stage 1 disease (C282Y homozygous)
Consider – 

hepatitis A and hepatitis B vaccination

Additional treatment recommended for SOME patients in selected patient group

Can be considered in patients not exposed to hepatitis.[58][59]​​

stage 2, 3, or 4 disease (C282Y homozygous)

1st line – phlebotomy or erythrocytapheresis

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ONGOING
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stage 2, 3, or 4 disease (C282Y homozygous)
1st line – 

phlebotomy or erythrocytapheresis

Stage 2: C282Y homozygosity with both increased transferrin saturation (>45%) and serum ferritin (>674 picomols/L [>300 nanograms/mL] in men; >449 picomols/L [>200 nanograms/mL] in women), but no clinical symptoms.[6]

Stage 3: C282Y homozygosity with increased transferrin saturation (>45%) and serum ferritin (>674 picomols/L [>300 nanograms/mL] in men; >449 picomols/L [>200 nanograms/mL] in women), as well as clinical symptoms affecting the quality of life that are attributed to this disease (e.g., asthenia, impotence, and arthropathy).[6]

Stage 4: C282Y homozygosity with increased transferrin saturation (>45%) and serum ferritin (>674 picomols/L [>300 nanograms/mL] in men; >449 picomols/L [>200 nanograms/mL] in women), and clinical symptoms manifesting organ damage predisposing to early death (e.g., cirrhosis with risk of hepatocellular carcinoma, insulin-dependent diabetes, and cardiomyopathy).[6]​​

Patients should be started on a phlebotomy regimen.[6][8]​​[54] This starts with weekly (or biweekly) phlebotomy in an induction phase, and then transitions to a maintenance phase of intermittent phlebotomy (variable frequency: usually 2 to 6 phlebotomies/year) with a goal to maintain a serum ferritin level of 50-100 micrograms/L.[4][7][8][54]​ In patients who have pre-existing cardiovascular disease or hypotension, it is recommended to start therapy every 14 days and then increase the frequency to weekly as tolerated.​

By removing blood, the patient's bone marrow is stimulated to make new red cells using the iron they have in storage.

Each 1 mL of packed red cells contains approximately 1 mg of iron, so removing 500 mL of blood with a haematocrit of 40% removes approximately 200 mg of iron.

Each unit of phlebotomised blood should decrease the ferritin by approximately 67 picomols/L (30 nanograms/mL).

Phlebotomy should be initiated by removing 7 mL/kg body weight of blood per session (maximum 550 mL per session) weekly.[6] Patients should be instructed to maintain proper hydration prior to phlebotomy and avoid strenuous exercises for at least 24 hours post-phlebotomy.​

The Hb and MCV should be measured before each treatment and the treatment postponed if the Hb is <110 g/L (<11 g/dL).

Serum ferritin should be checked after the initial 10 to 12 phlebotomies. More frequent testing may be required as the patient’s serum ferritin approaches the target range, to prevent the development of iron deficiency.[54]

Transferrin saturation levels usually remain elevated until iron stores are depleted.[54]

Patients willing to adhere to a low iron diet may reduce annual phlebotomy requirements during the maintenance phase by 0.5 to 1.5 litres.[60]​ Patients with haemochromatosis, but who do not have significant organ damage, can become regular blood donors during the maintenance phase.[8]

In asymptomatic middle-aged C282Y homozygotes whose initial ferritin is only mildly elevated (e.g., <500 micrograms/L), it may be reasonable to monitor without treatment.[56]​ If phlebotomy is deferred, serum ferritin should be checked annually. Treatment should be instituted if the ferritin increases or if symptoms develop.

Erythrocytapheresis (an apheresis procedure in which red blood cells are separated from whole blood) is an alternative to phlebotomy.[4][7][8] Like phlebotomy, it involves an induction and maintenance phase, and has the same target ferritin levels.[8]​ It results in fewer haemodynamic changes, as well as fewer procedures and shorter treatment duration in the induction phase compared to phlebotomy.​[8]​ Mild citrate reactions are common.[8]

Plus – lifestyle modifications

Back
ONGOING
|
stage 2, 3, or 4 disease (C282Y homozygous)
Plus – 

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

All patients should avoid iron-fortified foods or iron-containing supplements.[8][54]

Vitamin C-containing supplements should also be avoided, as vitamin C can lead to increased intestinal absorption of dietary iron.[4][7][8]​ Despite this, some physicians may recommend low doses of vitamin C in patients who are started on parenteral iron chelation therapy. This is because it increases the availability of iron for chelation with desferrioxamine.

Patients willing to adhere to a low iron diet may reduce annual phlebotomy requirements by 0.5 to 1.5 litres.[60]

Patients should be advised to avoid excess alcohol (or avoid altogether if hepatic disease is present).[8]

Raw/undercooked shellfish and wound contact with seawater should be avoided, due to susceptibility of patients with haemochromatosis to rare but serious systemic bacterial infection by Vibrio vulfinicus.[8]

Consider – proton-pump inhibitor

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ONGOING
|
stage 2, 3, or 4 disease (C282Y homozygous)
Consider – 

proton-pump inhibitor

Additional treatment recommended for SOME patients in selected patient group

Proton-pump inhibitors (e.g., omeprazole, pantoprazole) could be useful in some patients. They increase gastric pH, which in turn reduces non-haeme iron absorption, which may potentially reduce the number of phlebotomies required to maintain serum ferritin targets.[4][7][8]​​ However, taking into account the relatively modest effects of PPIs, they may be considered as a supporting treatment rather than first-line or second-line.[8]

Primary options

omeprazole: 20-40 mg orally once daily

OR

pantoprazole: 40 mg orally once daily

Consider – hepatitis A and hepatitis B vaccination

Back
ONGOING
|
stage 2, 3, or 4 disease (C282Y homozygous)
Consider – 

hepatitis A and hepatitis B vaccination

Additional treatment recommended for SOME patients in selected patient group

Can be considered in patients not exposed to hepatitis.[58][59]​​

2nd line – iron chelation therapy

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ONGOING
|
stage 2, 3, or 4 disease (C282Y homozygous)
2nd line – 

iron chelation therapy

In general, iron chelation therapy should be reserved for patients in whom phlebotomy/erythrocytapheresis is contraindicated or is not feasible/available (i.e., anaemia, severe heart disease, or severe problems with venous access).[6][8]​​​ It should only be used after careful risk assessment by a consultant; iron chelation is associated with adverse effects such as hepatic and renal toxicity.[4]​​[7][8]

Treatment with the parenteral iron chelator desferrioxamine, and the oral iron chelators deferasirox and deferiprone have been reported.[8]

Most evidence in haemochromatosis is with oral deferasirox, which has been shown to effectively reduce ferritin levels in patients with type 1 haemochromatosis.​[8][61][62]​ However, deferasirox should not be used in patients with advanced liver disease, and can be associated with gastrointestinal adverse effects and impairment in kidney function.[4][7][8]​ Use of an oral chelating agent may improve compliance compared with a parenteral formulation.[4][7]​ Use of these agents may be off-label for haemochromatosis.

In some circumstances, iron-chelation therapy may be used in combination with phlebotomy/erythrocytapheresis, (e.g., in cases of severe clinical manifestation of juvenile haemochromatosis).[8]

Iron chelation therapy can be associated with visual and auditory changes, and vision and hearing should be checked at least yearly.

Primary options

deferasirox: consult specialist for guidance on dose

OR

desferrioxamine: consult specialist for guidance on dose

OR

deferiprone: consult specialist for guidance on dose

Plus – lifestyle modifications

Back
ONGOING
|
stage 2, 3, or 4 disease (C282Y homozygous)
Plus – 

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

All patients should avoid iron-fortified foods or iron-containing supplements.[8][54]

Vitamin C-containing supplements should also be avoided, as vitamin C can lead to increased intestinal absorption of dietary iron.[4][7][8]​ Despite this, some physicians may recommend low doses of vitamin C in patients who are started on parenteral iron chelation therapy. This is because it increases the availability of iron for chelation with desferrioxamine .

Patients should be advised to avoid excess alcohol (or avoid altogether if hepatic disease is present).[8]

Raw/undercooked shellfish and wound contact with seawater should be avoided, due to susceptibility of patients with haemochromatosis to rare but serious systemic bacterial infection by Vibrio vulfinicus.[8]

Consider – hepatitis A and hepatitis B vaccination

Back
ONGOING
|
stage 2, 3, or 4 disease (C282Y homozygous)
Consider – 

hepatitis A and hepatitis B vaccination

Additional treatment recommended for SOME patients in selected patient group

Can be considered in patients not exposed to hepatitis.[58][59]​​

not C282Y homozygous

1st line – individualised management

Back
ONGOING
|
not C282Y homozygous
1st line – 

individualised management

Patients who are heterozygous for C282Y/H63D (or homozygous for H63D), should be managed based on their phenotypic presentation and the presence of additional risk factors.[8] If they have evidence of iron overload, they should be investigated for other causes of this overload, and may be treated with phlebotomy, but this requires patient-specific clinical assessment.[8]

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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