Haemochromatosis:
Key factors:
presence of risk factors, skin bronzing, diabetes mellitus
Other diagnostic factors:
fatigue, weakness, lethargy, arthralgias, impotence in males, loss of libido,
blood loss
Risk factors:
Middle age, Male gender, White ancestry, Famili history, Supplemental iron
Definition:
Haemochromatosis is a multisystem disorder of inappropriately increased dietary iron absorption and increased iron release from erythrophagocytosis which, if left untreated, can lead to life-threatening complications that include cirrhosis, hepatocellular cancer, diabetes and heart disease. It is one of the most common known genetic disorders in white patients but has variable penetrance
Disease is prevalent worldwide, but is more common in people of northern European descent where it has a prevalence close to 1 per 200 of the population
1st tests to order:
serum transferrin saturation: >45%
C-reactive protein: normal
HFE mutation analysis: C282Y mutation homozygosity (p.Cys282Tyr)
plasma ferritin: elevated; >674 pmol/L ( >300 ng/mL/ micrograms/L) in men; >449 pmol/L (>200 ng/mL/micrograms/L) in women
Tests to consider:
MRI liver liver to muscle signal intensity <0.88
liver biopsy iron content elevated
LFTs aminotransferase levels above normal
fasting blood sugar (FBS) elevated
echocardiogram mixed dilated-restrictive or dilated cardiomyopathy
ECG decreased QRS amplitude and T-wave flattening or inversion
testosterone, FSH and LH assays lower than normal levels
bone densitometry osteopaenia (T score <-1 SD) or osteoporosis (T score <-2.5 SD)
TFTs high TSH
Differential:
Dysmetabolic hyperferritinaemia
Hereditary aceruloplasminaemia
Excessive iron supplementation
Chronic hepatitis
French
recommendations for the management of HFE haemochromatosis. Haute Autorite de Sante [29]
The following staging system can be used to guide therapy:
Stage 0: C282Y homozygosity with normal plasma 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 (>674 pmol/L (>300 ng/mL/>300 micrograms/L in men) in men; >449 pmol/L (>200 ng/mL/>200 micrograms/L)in women)) but no clinical symptoms.
Stage 3: C282Y homozygosity with increased transferrin saturation (>45%) and serum ferritin (>674 pmol/L ( >300 ng/mL/>300 micrograms/L in men) in men; >449 pmol/L (>200 ng/mL/>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 (>674 pmol/L ( >300 ng/mL/>300 micrograms/L in men) in men; >449 pmol/L (>200 ng/mL/>200 micrograms/L)in women)), and clinical symptoms manifesting organ damage predisposing to early mortality (e.g., cirrhosis with risk of hepatocellular carcinoma, insulin-dependent diabetes and cardiomyopathy).
Treatment approach
The main goal of treatment is to avoid iron overload in early-stage disease, and remove excess iron from body stores in late-stage disease.
Lifestyle modifications
All patients should be instructed to avoid iron or iron-containing supplements.
Vitamin C or vitamin C-containing supplements should also be avoided as vitamin C can lead to increased intestinal absorption of dietary iron. 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 instructed to avoid excess alcohol (or avoid altogether if hepatic disease is present).
Hepatitis B vaccination is recommended for patients who have not been exposed to hepatitis.
Stage 0 disease
Patients should be monitored every 3 years with history, examination and blood tests including serum ferritin level and serum transferrin saturation.
Stage 1 disease
Patients should have the same monitoring regimen, as with stage 0 patients, but yearly.
Stage 2, 3 and 4 disease
Should be started on a phlebotomy regimen. Start with weekly phlebotomy in an induction phase, and then transition to a maintenance phase of intermittent phlebotomy with a goal to maintain the serum ferritin level ≤112 pmol/L (≤ 50 ng/mL).
Stage 2, 3 and 4 disease where phlebotomy is contraindicated
Iron chelation therapy should be reserved for patients in whom phlebotomy is contraindicated (i.e., anaemia, severe heart disease or technically impossible blood-draw).
Traditionally, a parenteral iron chelator was given; however, there is now an oral iron chelating agent available. Deferasirox may be considered as a first-line option, as an alternative to parenteral therapy, for type 1 (hereditary) haemochromatosis patients who are unable to receive phlebotomy. Compliance is likely to be better with oral therapy compared with parenteral therapy.
Follow up:
Monitoring
The frequency of follow-up for patients in the maintenance phase of treatment for iron overload varies depending on the individual. However, a good rule of thumb may be to check laboratory work every 4 to 8 weeks with an FBC and serum ferritin assessment. Iron chelation therapy can be associated with visual and auditory changes, and so patients should have their vision and hearing checked at least yearly. Screening for hepatocellular carcinoma must be performed with liver ultrasound every 6 months in patients with documented cirrhosis. [38]
Patient Instructions
It might be advisable to consider referring patients to a dietician, especially if they have concomitant diabetes, hypertension or hyperlipidaemia. Patients should be instructed to avoid excess alcohol (or avoid all together if hepatic disease is present) and avoid supplements that contain iron or vitamin C. Natural sources of iron and vitamin C are considered safe. Note that some physicians may recommend low doses of vitamin C in patients on parenteral iron chelation therapy to increase the excretion of iron.
Complications
Complication Timeframe Likelihood
cirrhosis long term high
hepatocellular carcinoma long term medium
hypogonadism long term medium
bone loss long term medium
hypothyroidism long term medium
diabetes mellitus variable high
congestive heart failure, chronic variable high
Prognosis:
In a study of 251 patients, carried out over 33 years, the mean survival was 21 years. [36] If diagnosed and treated prior to the development of diabetes and cirrhosis, the life expectancy is virtually identical to that of age- and sex-matched controls. [36] The adjusted relative risk of death was 4.3 in patients with diabetes and 2.4 in patients with liver cirrhosis. Patients with haemochromatosis have an increased risk of dying from cancer (11%), especially hepatocellular carcinoma (7%), diabetes mellitus (2%), cardiomyopathy (2%), myocardial infarction (2%), and liver cirrhosis (6%). [36] Survival does seem to be improving as individuals are diagnosed at an earlier stage. Organ damage from iron overload does not typically occur until the patient is older than 40 years. [31]
Key articles:
Brissot P, de Bels F. Current Approaches to the management of hemochromatosis. Hematology Am Soc Hematol Educ Program. 2006;36-41.
Olynyk JK, Cullen DJ, Aquilia S, et al. A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med. 1999;341:718-724.
Haute Autorite de Sante. Management of patients with HFE-related haemochromatosis (Type 1 haemochromatosis). July 2005.
http://www.has-sante.fr/portail/display.jsp?id=c_432802 (accessed on 26 June 2007)
U.S. Preventive Services Task Force. Screening for hemochromatosis: recommendation statement. Ann Intern Med. 2006;145:204-208.
Niederau C, Fischer R, Purschel A, et al. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology. 1996;110:1107-1119.
El-Serag HB, Inadomi JM, Kowdley KV. Screening for hereditary hemochromatosis in siblings and children of affected patients. A cost-effectiveness analysis. Ann Intern Med. 2000;132:261-269.
