EASL Clinical Practice Guidelines

How should HFE-HC be managed?

There are very few data on the threshold of tissue iron excess at which tissue damage is seen. A study of the degree of lipid peroxidation has been done in treated and untreated HC patients, as well as in heterozygotes, suggesting changes at low levels of iron loading [207]; however, this study has not been confirmed. The relationship between liver iron concentration [208], serum ferritin (>1000 μg/L) [202], and hepatic damage do not help define when the treatment of iron overload should begin. Another marker of toxicity and tissue damage may be non-transferrin bound (ie. free or labile) plasma iron because of its potential for catalyzing the generation of reactive oxygen species in vivo [209].

How to manage iron overload in HFE-HC

How should HFE-HC be treated?

Three approaches have been used to remove excess iron. None have undergone randomized controlled trials. Phlebotomy is the mainstay of treatment. Iron chelators are avaliable and can be an option in patients who are intolerant or when phlebotomy is contraindicated. Erythrocytophoresis has been reported in treatment of HC, but is not widely practiced.

There are no studies addressing survival in genotyped C282Y homozygous HC patients. The benefit of phlebotomy has been demonstrated by case series of clinically diagnosed HC, and benefit shown by comparison with historical groups of patients not treated with phlebotomy [210], or inadequately treated with phlebotomy [211], based on measures of iron depletion. In the latter study, Kaplan–Meier analysis of survival at 5 years was 93% for adequately phlebotomized patients, compared to 48% for inadequately phlebotomized patients (10 year survival 78% vs. 32%).

There are studies on clinical and histopathological improvement by phlebotomy: two of these studies included HFE genotyped patients [[212], [213]]. Fatigue, elevated transaminases, and skin pigmentation improved [214]. Milman et al. [211] reported improvement in the stage of fibrosis on repeat liver biopsy in 15–50% of patients. In another study this was found in all cases (except when cirrhosis was present) [213]. Falize et al. [212] reported improvement in the METAVIR fibrosis score in 35–69% of cases depending upon the initial fibrosis score. In cirrhotic patients, improvement in or resolution of esophageal varices has also been reported [215].

It is recognized, however, that several clinical features are unlikely to improve with iron depletion, in particular arthralgia [[211], [214]]. Improvement in endocrinological disorders, including diabetes mellitus, and cardiological abnormalities varies, likely related to the degree of tissue/organ damage at the start of treatment.

The benefit of iron depletion by phlebotomy has therefore been established, despite the absence of randomized controlled trials, and is the accepted standard of care. Phlebotomy is well tolerated by patients [216] and the majority of patients comply with treatment [217]. Long-term unwanted effects of venesection have not been reported.

There are no studies providing data to direct the optimal time at which to start venesection. Current recommendations of when to initiate treatment are empirical. Survival of treated patients without cirrhosis and diabetes has been found to be equivalent to that of the normal population, whereas those with these complications have a significantly reduced survival [[211], [214]]. These data emphasize the early initiation of iron removal. The threshold of serum ferritin at which to start treatment is currently taken as above the normal range. There are no studies from which to give an evidence base to the protocol of therapeutic venesection (i.e. frequency, endpoint).

How to monitor HFE-HC:

Based on empirical and clinical experience, haemoglobin and haematocrit should be monitored at the time of each venesection. If anemia is detected, phlebotomy should be postponed until the anemia is resolved.

Serum ferritin is measured and is sufficient to monitor iron depletion. The frequency of measurements depends upon the absolute concentration. When ferritin levels are high, measurement is required less frequently (every 3 months or so); however, as ferritin approaches the normal range, measurements should become more frequent.

Endpoint of therapeutic phlebotomy:

There is no evidence base on which to direct the endpoint of therapeutic phlebotomy. The recommendations that exist are based upon (i) a theoretical argument that maintains it is necessary to achieve iron deficiency in order to lower tissue iron levels to normal, and (ii) that a stated target is better than a statement of 'to normal', which would likely lead to variable interpretation and practice. The standard clinical practice is to achieve a target of serum ferritin that is less than 50 μg/L.

Maintenance therapy

There are no data from which to base the optimal treatment regimen and target serum iron indices. Once iron depletion has been achieved, the aim is to prevent re-accumulation. The advocated standard practice is to maintain the serum ferritin at 50–100 μg/L. This is usually achieved with 3–6 months of venesection.

Patients may be offered the alternative approach of ceasing venesection with monitoring of serum ferritin, with the reinstitution of a short therapeutic program when the serum ferritin reaches the upper limit of the normal range [218].

After therapeutic phlebotomy, some patients may not show re-accumulation of iron at the expected rate. Some are taking proton pump inhibitors, which have been reported to be associated with reduced iron absorption and a reduced requirement for venesection [219]. Others may be on prescribed non-steroidal anti-inflammatory drugs. However, in older patients it is necessary to be alert to conditions that may lead to iron loss, such as peptic ulcers, colonic disease, and hematuria, which will need appropriate investigation.


There are no studies proving that dietary interventions and avoidance of dietary iron have an additional beneficial effect on the outcome in patients undergoing venesection. Although diets avoiding excess iron have been discussed, this panel considers that the important issue is maintaining a broadly healthy diet. Iron containing vitamin preparations and iron supplemented foods such as breakfast cereals should be avoided. Compliance with phlebotomy will prevent iron overload.

Tea drinking has been reported as possibly reducing the increase in iron stores in HC patients [220], but this finding was not confirmed in a subsequent study [221]. Non-citrus fruit intake has also been reported to be associated with a lower serum ferritin, but whether this truly reflects a biological effect on iron stores has not been shown [221].

Vitamin C has been reported to be potentially toxic in patients with iron overload [222]. However, there are no articles on the effect of vitamin C on iron absorption or iron stores in HFE-HC. A single case report in a genetically uncharacterized HC patient in whom vitamin C could have had a negative effect on cardiac function [223], has led to the recommendation that it is prudent to limit ingestion of vitamin C supplements to 500 mg/day [224].

As in many liver diseases, excess alcohol ingestion leads to increased hepatic damage in HFE-HC [225]. In addition, recent experimental studies show suppression of hepatic hepcidin expression by alcohol in experimental models [226]. This could account for the observation that there is a linear correlation between alcohol intake and serum iron indices and increased iron absorption in alcoholics [[227], [228], [229]].


A normal full term pregnancy removes around 1 g of iron from the mother [230]. Iron supplements should not be given routinely to pregnant women with HFE-related HC. Serum ferritin should be monitored. Iron deficiency should be treated according to the usual guidelines applied to pregnancy. If the ferritin is high, therapeutic phlebotomy should be deferred until the end of pregnancy unless there are cardiac or hepatic issues, in which case the appropriate specialist should be involved in the discussion of the positive and negative effects of treatment.

How to manage tissue/organ damage

Cirrhosis (US, AFP, transplant): It is important to define whether or not the patient with HFE-HC has cirrhosis. In newly recognized affected patients liver biopsy is recommended in order to assess liver architecture when serum ferritin >1000 μg/L. Transient elastography is a non-invasive tool that can be helpful for the determination of advanced fibrosis and liver cirrhosis [205].

HFE-HC patients with cirrhosis have a 100-fold greater chance of developing HCC than the normal population [214]. As in cases of cirrhosis from other causes (e.g. hepatitis C and B), screening to detect an early tumor is recommended using ultrasound examination and serum alpha fetoprotein measurement every 6 months. Despite some case reports of HCC in non-cirrhotic HC patients, this is very rare, and screening for HCC is not considered necessary in this group.

Hepatic decompensation with ascites, spontaneous bacterial peritonitis, encephalopathy, variceal haemorrhage, and early small tumor formation may require assessment for liver transplantation.

Early reports on the outcome of HFE-HC after liver transplantation for HFE-HC [[59], [231], [232]] have found that survival may be lower than in other groups. Survival for transplant patients is around 64% after 1 year, and 34% after 5 years [231]. Reduced survival compared to other aetiological groups was considered to be related to iron overload; few patients had iron depletion prior to transplantation. Causes of death were heart disease, infection, and malignancy [231].

Diabetes mellitus: Improvement in glucose control may occur during phlebotomy treatment, but insulin dependency is not reversed [214]. Diabetes mellitus is managed in the same way as for other patients with diabetes.

Arthralgia, arthritis: Physical and radiological evaluation is necessary. Unfortunately it is unusual for symptoms to be alleviated by phlebotomy treatment. Symptoms, such as joint destruction, often progress.

Anti-inflammatory agents are often ineffective but can be used. Podiatric assessment is valuable with use of insoles in shoes to help with foot pain. Joint replacement (hip and knee) may be necessary.

Cardiac disease: Although cardiac failure is a recognized complication of severe iron overload, it is clinically unusual (except in patients with juvenile HC). Electrocardiographic abnormalities have been reported in one third of patients [214], and in one third of these, there is improvement with phlebotomy.

However, any cardiac symptoms should be investigated by the cardiologist, if needed by electrocardiogram (ECG), echocardiography, and 24 h ambulatory ECG monitoring. There is no recognized ferritin level above which cardiac assessment is recommended.

Endocrine disease: Hypothyroidism has been reported in 10% of males with HC [233]. Hypogonadism with loss of potency is a recognized complication [214]. Thus the clinical history of patients with these symptoms should be obtained, and thyroid function tests and serum testosterone levels monitored.

Osteoporosis: Patients with HC are at risk of osteoporosis, and should undergo a DEXA scan and receive appropriate routine advice or treatment for osteoporosis if diagnosed [234].