Clinical Practice Guideline

for

HEMOCHROMATOSIS

Developed for the

Aerospace Medical Association

by their constituent organization

American Society of Aerospace Medicine Specialists

 

Overview: Hemochromatosis is an iron overload syndrome.  The hereditary nature was recognized in the 1930’s.  In 1996 the autosomal recessive form, known as hereditary hemochromatosis, was linked to amino acid substitutions on the short arm of chromosome 6 encoding HLA-A*3.  This “hemochromatosis gene,” is listed as HFE.  Since the discovery of the HFE gene, other genes related to the control of iron metabolism have been identified.  The Online Mendelian Inheritance in Man (OMIM) database has four types of hereditary hemochromatosis listed.4

 

The first of the four types is classic hereditary hemochromatosis, a HFE-related hemochromatosis.  The most common HFE mutation is a single substitution of tyrosine for cysteine at position 282 (C282Y); the other is a single substitution of aspartic acid for histidine at position 63 (H63D).  The second type, juvenile hereditary hemochromatosis (HjV), is associated with onset in early life and is much more fulminant.  It is also an autosomal recessive trait associated with the long arm of either chromosome 1 or 19.  The third type, like the first two, is autosomal recessive but is associated with the altered functioning of the transferring receptor 2 (TfR2) encoded by the long arm of chromosome 7.  The TfR2 is possibly responsible for hepatocyte iron uptake.  The final type is an autosomal dominant alteration in the long arm of chromosome 2 and alters ferroportin functioning.  Ferroportin is responsible for export of iron out of enterocytes, macrophages, placental cells and hepatocytes.

 

The predominant hereditary form, C282Y mutation, has a heterozygous frequency of about 10% in Caucasian populations in the United States and Western Europe and a homozygous frequency of about 5 per 1000 (0.5%).  Increasing transferrin saturation is the earliest detectable biochemical abnormality and is attributed to increased intestinal iron absorption.  The role of HFE in this pathophysiologic process is not fully clear.  Some patients with the HFE gene never progress beyond this biochemical abnormality.  However, progressive iron overload occurs in others.  Marked elevation of serum ferritin level has been associated with evidence of iron deposition.  The complications of hereditary hemochromatosis are the result of tissue deposition.6

 

Early presentation of symptomatic organ disease in the second or third decade of life, and fulminant course are the hallmark features of HjV that distinguish it from the other forms of hemochromatosis.  Symptoms in classic HFE hemochromatosis, and types 3 and 4 usually appear between the 4th and 5th decade of life.  Early non-specific symptoms may manifest as lethargy, fatigue, weakness, apathy, and weight loss.  The clinical manifestations of iron accumulation include liver disease, abdominal pain, skin pigmentation, diabetes mellitus, arthropathy, impotence in males and cardiac enlargement with or without heart failure or conduction defects.  The classic triad of cirrhosis, bronzed skin, and diabetes mellitus reflects severe end-organ damage, when total body iron content has reached as much as 20 grams (greater than five times normal).  This is fortunately an uncommon presentation due to increased awareness of the disease and improved diagnostic tests.  When hepatic dysfunction is present, over 50% will have diabetes mellitus.  Hepatic fibrosis is unusual in patients younger than 35 unless it is the HjV form or the individual is a heavy drinker.  Hemochromatosis is characterized by excess iron deposition in pituitary cells, leading to reduced serum levels of a number of trophic hormones.  Hypogonadism will occur in 25% of male patients and primary hypoaldosteronism in 10%.  Hypothyroidism or hyperthyroidism occurs in about 8% of hemochromatosis homozygotes.  Up to 50% of patients over 40-years-old have EKG irregularities and 43% of autopsied hearts from patients with hemochromatosis show iron deposits in the AV node and conduction system.  Arthropathy is present in 30-50% and is commonly present in the proximal interphalangeal and metacarpophalangeal joint.  Ten per cent of the patients have destructive arthropathy of the hip and knee joints.

 

Phlebotomy is the mainstay of treatment of hereditary hemochromatosis.  These patients often have body stores of 25 to 50 grams of iron.  A one-unit phlebotomy (500 ml of whole blood) will remove approximately 250 mg of iron.  This is continued weekly until the serum ferritin is less than 50 ng/ml and the transferrin-saturation drops to a value below 50%.  This is followed by maintenance phlebotomy of one unit of blood removed usually every 2-4 months with the intent to maintain the serum ferritin below 50 ng/ml, and the transferrin-saturation value below 50%.  This treatment will reduce the incidence of complications other than established cirrhosis, arthropathy and testicular atrophy.  Patients with hemochromatosis diagnosed in the precirrhotic stage and treated by venesection have a normal life expectancy, whereas cirrhotic patients have a shortened life expectancy and a high risk of liver cancer even when complete iron depletion has been achieved.

 

All first-degree relatives should be offered testing once an hereditary hemochromatosis proband is diagnosed.  If an adult relative of a C28Y homozygote is identified, and is either a C282Y homozygote or a compound heterozygote (C28Y/H63D) and if blood iron studies are abnormal then a presumptive diagnosis can be made and therapeutic phlebotomy can be initiated.  Early treatment can prevent complications.

 

Dietary supplements containing iron should be avoided.  It may be reasonable to recommend avoidance of vitamin C supplements due to its possible enhancement of free iron and the generation of reactive oxygen species.  Patients with hereditary hemochromatosis should be advised to avoid consumption of uncooked seafood because bacteria found in them can thrive on increased plasma iron concentrations.

 

Aeromedical Concerns: Hemochromatosis has the potential to affect numerous organ systems of the body through the deposit of iron in the tissue.  Some of the major aeromedical concerns include:  1) cardiac arrhythmias or cardiomyopathy, 2) cirrhosis of the liver and hepatocellular carcinoma, and 3) diabetes mellitus.  Arthropathy could become severe enough to interfere with controlling the aircraft.  Symptoms of hypogonadism and hypothyroidism would be of gradual onset and not likely to be suddenly incapacitating and treatment compatible with flying is available.

 

Medical Work-up: Prior to consideration for a waiver of hemochromatosis, the aeromedical summary should include the following information:

A.  Complete history of symptoms including pertinent negatives, complete physical and treatment plan

B.  Genetic testing

C.  Serum iron, serum ferritin, serum transferrin, and transferrin saturation

D.  CBC

E.  Liver function tests:  ALT, AST, bilirubin, alk phos

F.  Thyroid function tests

G.  Fasting electrolytes and glucose

H.  EKG, echocardiogram and Holter (reports, representative tracings and echo tape should be sent to ACS (ECG Library) for FC II)

I.  Liver biopsy if liver function tests abnormal or ferritin levels greater than 1000 ng/mL.

I.  Endoscopy for varices if evidence of liver involvement

J.  Copy of consults

 

Individuals once on maintenance phlebotomy should be followed with yearly serum transferrin saturation and ferritin.  These values should be included in the renewal aeromedical summary.  Further studies are dependent on symptoms.

 

 

Aeromedical Disposition (military): Hemochromatosis is disqualifying for all flying classes.  It is not waiverable in initial flying training.  It is potentially waiverable in trained aircrew if the individual has no aeromedically significant complications from the hemochromatosis and is on maintenance phlebotomy.  Maintenance phlebotomy to maintain control of iron stores will require a 72-hour grounding after each venesection.

 

Aeromedical Disposition (civilian): Hemochromatosis in an airman that has already progressed to organ system involvement would be disqualifying. The FAA does permit medical certification for all classes those cases that are heterozygous and are controlled with phlebotomies.  Those airmen are required to provide a yearly follow up report from their treating physician and a current complete blood count, serum transferrin saturation and ferritin level.

 

Waiver Experience (military): Review of a military waiver database showed six cases of hemochromatosis; five were granted waivers and one was disqualified (an initial flying training candidate).  The recommendation of the waiver is primarily contingent on the stage of the disease, the degree of complication(s) present, and treatment required.  Deferoxamine therapy is not compatible with granting of waiver.

 

Waiver Experience (civilian): Due to its current pathology coding system the FAA groups Hemochromatosis with other blood dsycrasias and thus an accurate count of those airmen who have been granted medical certification is not possible.

 

References:

 

1.  Adams, PC.  Hemochromatosis.  In Conn’s Current Therapy 2006.  Ed. by Rakel RE and Bope ET.  W.B. Saunders.  Philadelphia.  2006:  527-9.

 

2.  Alexander J, Kowdley KV.  Hereditary Hemochromatosis:  Genetics, Pathogenesis, and Clinical Management.  Ann Hepatology 2005; 4:240-7.

 

3.  Bacon, BR.  Iron Overload (Hemochromatosis).  In Cecil Textbook of Medicine, 22nd ed.  Ed. by Goldman, L. and Ausiello, D.  W.B. Saunders.  2004:  1302-1306.

 

4.  Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G.  Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis.  N Engl J Med 1985; 313:1256-62.

 

5.  Pietrangelo A.  Hereditary Hemochromatosis – A New Look at and Old Disease.  N Engl J Med 2004; 350:2383-97.

 

6.  Robson K, Merryweather-Clarke A, et.al.  Recent advances in understanding haemochromatosis:  a transition state.  J Med Genet 2004; 41:721-30.

 

7.  Schmitt B, Golub R, Green R.  Screening Primary Care Patients for Hereditary Hemochromatosis with Transferrin Saturation and Serum Ferritin Level:  Systematic Review for the American College of Physicians.  Ann Intern Med 2005; 143:522-36.

 

8.  Schrier SL., Bacon BR.  Clinical manifestations of hereditary hemochromatosis.  UpToDate.  Online version 14.3, August 14, 2006.

 

9.  Schrier SL., Bacon BR.  Treatment of hereditary hemochromatosis.  UpToDate.  Online version 14.3, February 23, 2006.

 

10.  Smith LH.  Overview of Hemochromatosis.  West

 

 

2/15/08