Natural History and Management of HFE-hemochromatosis

Eng K. Gan, M.B.B.S.; Lawrie W. Powell, M.B.B.S., M.D., Ph.D., F.R.A.C.P., F.R.C.P.; John K. Olynyk, B.Med.Sc., M.B.B.S., M.D., F.R.A.C.P.

Disclosures

Semin Liver Dis. 2011;31(3):293-301. 

In This Article

Management of Hemochromatosis

The primary goal in HH is to remove excess iron. This is usually achieved through phlebotomy, although rare cases may require consideration of chelation if phlebotomy is contraindicated or poorly tolerated. Secondary goals relate to management of hepatic and non-hepatic complications

Phlebotomy

Humans lack the capacity to excrete iron rapidly. The discovery of iron elimination through phlebotomy in 1950 has remained the cornerstone of therapy.[82] There are no evidence-based guidelines on therapeutic phlebotomy for HH. Treatment is conventionally commenced once serum ferritin exceeds the normal range; 200 μg/L in premenopausal women and 300 μg/L in postmenopausal women and men. The goal is to reduce the serum ferritin level to low normal range, usually 20–100 μg/L. In the induction phase, 1 unit (400–500 mL) of blood, equivalent to 200–250 mg of iron, can be safely removed weekly. Serum ferritin should be monitored after each 1–2 g of iron removed. Patients then undergo maintenance phlebotomy, which varies between individuals in frequency of requirement to keep serum ferritin levels in the range 20–100 μg/L.[3,21,50,83,84] Levels lower than this may be associated with symptoms of iron deficiency.[85]

The benefit of phlebotomy has been clearly demonstrated in cohort studies.[17,82] Survival of clinically diagnosed HH patients who have undergone phlebotomy therapy is greater than those who are not adequately de-ironed.[17] It is also thought that preemptive therapy prevents complications, although treatment efficacy has never been subjected to randomized controlled studies. In the absence of complications of cirrhosis or diabetes, the life expectancy of treated patients is similar to that of the age- and gender-matched general population.[16,86] Phlebotomy improves liver transaminases, skin pigmentation, and liver fibrosis. The majority of patients with biopsy-proven liver fibrosis show regression with optimal effect occurring when baseline fibrosis is mild.[70] Extrahepatic manifestations such as hypogonadism, cirrhosis, deforming arthropathy, and diabetes requiring insulin are usually irreversible.[87] Phlebotomy is generally accepted as being indicated in homozygotes with ferritin levels >1000 μg/L.[28] Recent studies indicate that progression of iron overload is not universal. In males, the highest risk of progression is in those individuals with ferritin levels >1000 μg/L and transferrin saturation >95%.[28] Females have a much lower risk of progression, with the likelihood being predominantly influenced by menopausal status.

The current American Association for the Study of Liver Diseases guidelines advocate regular phlebotomy to maintain the serum ferritin between 50 and 100 μg/L in asymptomatic individuals with homozygous HH, markers of iron overload, and histological evidence of potentially toxic levels of hepatic iron.[21] However, more recent Australian data suggests an alternative approach might be to monitor HH patients with serum ferritin levels between the upper limit of normal and 1000 μg/L.[27,28] These studies demonstrated that the risk of development of iron-overload disease in C282Y homozygous individuals with ferritin levels in the range between the upper limit of normal and 1000 μg/L was no greater than that observed in C282Y homozygotes with normal ferritin or wild-type controls.[28,29] The proportion of C282Y homozygotes with SF <1000 μg/L progressing to levels >1000 μg/L is unknown.

In patients who are intolerant to phlebotomy such as those with anemia or heart failure, oral iron chelators such as deferasirox may be safe alternatives as a therapeutic strategy. A recent phase 1/2 study of dose escalation of daily oral deferasirox demonstrated efficacy at reducing serum ferritin in non-cirrhotic C282Y homozygotes, with tolerable dose-dependent side effects.[88]

Decompensated end-stage liver disease is treated with orthotopic liver transplantation (OLT).[89] Survival post-liver transplantation is generally poorer compared with other OLT indications, and is predominantly due to infection and cardiac complications.[90] This may be secondary to impairment of immunity in iron overload.[91] Thus, careful preoperative care, including de-ironing therapy and careful attention to cardiac and other comorbidities are required to optimize survival.[92,93]

Non-liver-related Complications

Cardiomyopathy is an important and potential reversible cause of heart failure, which is characterized by development of diastolic dysfunction and arrythmias as the severity of dilated cardiomyopathy deteriorates.[94,95] The mainstay of therapy is careful phlebotomy as left ventricular dysfunction can be reversed even in advanced iron overload.[96] Other general management principles are the same as for patients with dilated cardiomyopathy and heart failure of any causation.[94] Early use of angiotensin-converting enzyme inhibitors and β – adrenergic blockers together with cardiac resynchronization device therapy for severe heart failure are routine.[97] In cases of severe therapy-refractory iron-overload cardiomyopathy, a combined heart and liver transplant may be considered.[98]

Arthritis or arthralgia can be difficult to manage and may severely impact on quality of life. Iron load is likely the major determinant of arthropathy in HH independent of occupational factors.[99] Unfortunately, this recalcitrant symptom may not be alleviated by phlebotomy treatment.[87] Anti-inflammatory therapy may be used, but is often ineffective. Orthotic devices may help alleviate foot pain. Ultimately, total joint replacement may be necessary.[100]

There is anecdotal evidence suggesting that the consumption of tannin-rich tea may possibly reduce the increase in iron stores.[101] Individuals who consume more than two servings of non-citrus fruits per day have lower serum ferritin levels compared with those who do not consume non-citrus fruits.[40] Over-the-counter supplementation of vitamin C should be limited to 500 mg/day.[102] Excessive alcohol ingestion should be avoided.[41,42] Screening for colorectal or breast malignancy should be considered given the emerging evidence of a role for HFE gene mutations in carcinogenesis.[46,47,103–105]

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