Approach

The risk of iron-overload-related disease (IORD) in people with a baseline serum ferritin of <1000 micrograms/L is low.[21] Studies have also shown that over the course of a decade, only about 1 in 3 untreated middle-aged C282Y homozygotes with a baseline ferritin below 1000 micrograms/L will progress to a ferritin exceeding this threshold.[48] These findings suggest that observation with monitoring of the serum ferritin may be a reasonable strategy for the management of some patients with asymptomatic hemochromatosis with mild ferritin elevations.[48]

Although many patients with hemochromatosis report subjective improvement in well-being after phlebotomy, others find the procedure burdensome because of the need for venous access, time required, etc.[49] Notwithstanding the lack of evidence, expert opinion and practice guidelines recommend phlebotomy for any patients with hemochromatosis with evidence of expanded body iron stores on the premise that the treatment is safe, effective, and simple to perform. The objective of initial treatment is to deplete body iron stores and the objective of maintenance treatment is to prevent reaccumulation.[8]​​

Lifestyle modifications

In general, patients should follow a normal, healthy diet.[8]​ All patients should be advised to avoid iron-fortified foods or iron-containing supplements.[8][44]

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 deferoxamine.

Patients should be advised to avoid excess alcohol (or avoid altogether if hepatic disease is present). Raw/undercooked shellfish and wound contact with seawater should be avoided, due to susceptibility of patients with hemochromatosis to rare but serious systemic bacterial infection by Vibrio vulfinicus.

Hepatitis A and B vaccinations could be considered in patients not exposed to hepatitis.[50]​​[51]

Staging for management of type 1 (HFE-related) hemochromatosis

The following staging system can be used to guide therapy:[6]

  • Stage 0: C282Y homozygosity with normal serum transferrin saturation and ferritin and no clinical symptoms

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

  • Stage 2: C282Y homozygosity with both increased transferrin saturation (>45%) and serum ferritin (>300 micrograms/L in men, >200 micrograms/L in women), but no clinical symptoms

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

  • Stage 4: C282Y homozygosity with increased transferrin saturation (>45%) and serum ferritin (>300 micrograms/L in men, >200 micrograms/L 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).

Stage 0 disease

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

Stage 1 disease

Patients should have the same monitoring regimen as stage 0 patients, but yearly.​[6][44]

Stage 2, 3, and 4 disease

Patients should be started on a phlebotomy regimen.[6][8]​​[44]​ 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][44] In patients who have preexisting 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 stored iron. Each 1 mL of packed red cells contains approximately 1 mg of iron, so removing 500 mL of blood with a hematocrit of 40% removes approximately 200 mg of iron. Each unit of phlebotomized blood should decrease ferritin by approximately 30 micrograms/L. 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 exercise for at least 24 hours post-phlebotomy. Hemoglobin and mean corpuscular volume should be measured before each treatment, and the treatment should be postponed if the hemoglobin is <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.[44]​

Transferrin saturation levels usually remain elevated until iron stores are depleted.[44]

Patients willing to adhere to a low-iron diet may reduce annual phlebotomy requirements during the maintenance phase by 0.5 to 1.5 liters.[52]​ Patients with hemochromatosis, 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.[48] 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 hemodynamic changes, as well as fewer procedures and shorter treatment duration in the induction phase compared to phlebotomy.[8]​ Mild citrate reactions are common.[8]

Proton-pump inhibitors (PPIs) could be useful in some patients. They increase gastric pH, which in turn reduces non-heme 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 an adjunct treatment rather than first-line or second-line.[8]

Stage 2, 3, and 4 disease where phlebotomy/erythrocytapheresis is contraindicated

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

Treatment with the parenteral iron chelator deferoxamine, and the oral iron chelators deferasirox and deferiprone has been reported.[8]​ Most evidence in hemochromatosis is with oral deferasirox, which has been shown to effectively reduce ferritin levels in patients with type 1 hemochromatosis.[8][53][54] 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 hemochromatosis.​

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

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

Management of patients with hemochromatosis who are not C282Y homozygous

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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