23^rd Annual Family Practice Review, Temple University Office of C.M.E. Philadelphia, P.A. 19140.  March 25^th, 1999. 

Lecture #58: HEMOCHROMATOSIS - SHOULD WE BE SCREENING ALL OUR PATIENTS FOR  THIS?

Prof. Victor Herbert, M.D., J.D., M.A.C.P., F.R.S.M. (London)                                                                      

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OBJECTIVES

Following the completion of this lecture participants should be able to:

                   1.  Explain why everyone should be tested for iron status.

                   2.  Explain why serum transferrin saturation and serum ferritin are the best

                        initial test for general population screening for iron overload disease.

                   3.  Explain why screening the general population for the hemochromatosis

                        gene can be misleading in 30% of cases so screened.

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CLINICAL PEARLS                                                      NOTES

1.  Contrary to the ubiquitous TV ads, of patients who complain of 

      weakness and tiredness, twice as many are in positive iron

      balance as are in negative iron balance.

2.  Supplements of synthetic Vitamin C (which 43% of Americans

     take daily) sharply speed up organ destruction and death from

     iron  overload.  This does not occur from the natural Vitamin C

     present in orange juice and other foods.

3.  15% who have the gene (the genotype) do not have the disease

      (the phenotype).  15% who have the disease (the phenotype)

      do not have the gene.

4.  Every patient diagnosed with diabetes, liver disease, sterility,

     heart disease, or arthropathy must be blood tested for iron

     overload.  Treating the overload early can cure the disorder,

     except for arthropathy. 

Figure 1 delineates the various standard tests used to stage iron status, including the test results in positive iron balance and in iron overload.

All North Americans should have determinations of both serum transferrin percent saturation with iron (derived from measurements of serum iron and of serum TIBC [total iron binding capacity] ) and serum ferritin.  A transferrin saturation greater than 45% suggests iron overload, and a serum ferritin greater than 200 µg/L confirms that iron overload is present.   A liver biopsy is desirable to quantitate the size of liver iron stores and the degree of liver fibrosis.  High liver iron stores and fibrosis eventually result in fatal liver cancer if the stores are not removed.  Removal of the stores by vigorous phlebotomy causes disappearance of all the fibrosis accumulated in the prior year, and a variable amount of further fibrosis removal.  Bottom line: liver biopsy is more a prognostic test than a diagnostic test.

The College of American Pathologists Practice Guidelines on Hereditary Hemochromatosis state that ìthe demonstration of increased stores of iron ó not waiting for iron storage disease to develop ó is the indication for treatment by the removal of ironî.   For patients who refuse liver biopsy, phlebotomize weekly for 10 weeks.  (Normal total  body iron  in adult males averages 4g, of which 2.5g are in hemoglobin,  and 1g is in stores [Figure 2] ).  Since each phlebotomy pint contains 0.25g of iron, 10 pints = 2.5g of iron.  If the patient has not  developed anemia after removal of 10 pints of blood, the diagnosis of iron overload is unequivocally confirmed.

In healthy adults, suffering no inflammation or other disorder, one can convert  g/L of ferritin to grams of body iron stores, by simply converting  g to grams, i.e. the average adult male has a serum ferritin of 100 µg/L and a body store of 1000mg (1g) ; the average fertile female has a serum ferritin of 30 µg/L and a body iron store of 30 µg. 

An excellent longitudinal review of diagnosing and treating 410 French-Canadians and people in France with hemochromatosis was published in 1997 by PC Adams, et al.  They found that serum ferritin was >300 µg/L in 96% of men and >200 µg/L in 97% of women, transferrin saturation was >55% in 90%, and iron removed by phlebotomy was >5g in 70% of men and 73% of women (see also Brittenham et al 1998).

Our new assay for ferritin iron, i.e., total number of iron atoms in every molecule of ferritin protein in 1 ml of serum, may prove as effective as liver biopsy in quantitating total body iron (See reference 10).  We are now engaged in a study comparing ferritin-iron, in thalassemics getting iron chelation therapy, with their liver biopsy iron (measured by Nancy Olivieri of The Hospital for Sick Children in Toronto, Canada), and with their SQUID liver iron (measured by Gary Brittenham of Columbia University College of Physicians and Surgeons in NYC).

Approximately 12% of Americans (and up to perhaps 30% of Afro-Americans) have heterozygous hemochromatosis (H) (moderate iron overload)  and approx. 1 in 100-200 (approx. 1 in 100 Afro-Americans) have homozygous hemochromatosis (HH).  H absorb approx. 50% more iron from their daily food as the rest of us, slowly piling up excess iron stores, and thus need approx. 4 to 6 therapeutic phlebotomies/yr to get rid of, and then keep normal,  their body iron.  While approximately 12% of Americans are in positive iron balance, only about 6% are in negative iron balance.

HH absorb about 300% more iron from their daily food as the rest of us, and thus need approx. 1 therapeutic phlebotomy/week for a year and (if their serum ferritin has then fallen to 50 or below, indicating that their body iron stores have fallen to or close to normal) phlebotomy every 2 to 4 weeks thereafter.

Most HH are not diagnosed until iron overload free radical damage to organs (gonads, pancreas, liver, heart, joints, etc.), produces chronic fatigue, sterility and/or diabetes and/or liver damage and/or cardiomyopathy and/or intractable arrythmias and/or arthropathy, and even then, despite the characteristic increased skin pigmentation and occasionally neurologic and psychological abnormalities, are often not diagnosed until autopsy, because so few think to routinely assess blood iron status in the initial work-up of every new patient, as every physician should know.

The first symptoms of iron overload are the same as the first symptoms of iron deficiency: feeling tired and run-down. Just as in iron deficiency, there may be mild anemia in iron overload.  This is due to excess iron literally ìcrushingî bone marrow erythroblasts.  Phlebotomy can correct this mild anemia, just as it can improve the anemia of sideroblastic anemia (see Bottomley).  Physicians who automatically treat with iron every new patient who presents with symptoms of being tired and run-down, even if they also have mild anemia, risk losing a 7-figure malpractice suit, as others have done (see Herbert, 1991), for not following what he/she learned in medical school: always diagnose before you treat.

We have all seen the ubiquitous ads: ìDo you love your husband? Maybe he needs Geritol.î  My comment is: Donít give him Geritol if you love him, since only one husband in 500 is iron deficient and can profit from Geritol, but between 1 in 100 (if heís Irish) or 1 in 250 (if heís French-Canadian) has HH, and Geritol will  maim and kill him faster. 

When the diagnosis of H or HH is made, the patient must be clearly informed that they must henceforth forswear alcohol and supplements containing iron and/or vitamin C, because any of the 3 will speed early organ destruction, liver cancer, and death. 

The gene test is useful in sorting out those who have iron overload solely from long-standing alcoholism, from those alcoholics who also have the HH phenotype.  Our own studies suggest there are more of the latter than the former. 

Vitamin C supplements, which 43% of all Americans take daily, are particularly pernicious.  They not only enhance absorption of iron, but, far more dangerously, they release billions of free radicals from harmless stored ferric iron by converting it to free radical-generating ferrous iron, as shown in Figure 3.  This does not occur with food vitamin C, as in orange juice, because that vitamin C is present in both oxidized and reduced forms, as are the well over a dozen other redox agents in all citrus and other fruits and vegetables.  All of these are absorbed together, and all go together through the 6 pores of the soccer-ball shaped ferritin protein into its interior, where they balance each other out, producing no conversion of the ferric iron to the ferrous form.  Vitamin C supplements, misrepresented by the buzz-word ìantioxidantsî, are in fact redox agents, antioxidant in some circumstances, and prooxidant in others (as in their release from ferritin protein of free radical-generating ferrous iron from harmless ferric iron).  The first evidence of this vitamin C-driven release was presented in our 1963 paper in the New England Journal of Medicine (Figure 4).  The whole subject was reviewed by Herbert et al in 1996.

The patient should also be tested for HFE (the C282Y mutation), the gene for hereditary hemochromatosis, as should every blood relative.  This commercially available test can be done on a serum sample or a buccal smear.

HLA-linked hereditary hemochromatosis is one of the most common inherited diseases in populations of European ancestry. The workers who isolated the gene marched down chromosome 6 from HLA to HFE, where they found it.

It is important to realize (and tell the patient) that commercially available serum assay for the hemochromatosis  gene (the genotype) is of less value than measuring the duo of  percent saturation of transferrin and serum ferritin protein.   In approx. 15% with phenotypic iron overload (i.e., the disease), the currently isolated relevant gene is not found, and in approx. 15% with the currently isolated relevant gene, the disease (i.e., the phenotype) is not found. 

We therefore should not, for ethical and legal reasons (i.e., losing a lawsuit to an improperly stigmatized plaintiff)  stigmatize genotypes (or adequately phlebotomized phenotypes) as having iron overload disease because about 15%of each group donít.  In young phenotypes, iron overload and fibrosis may disappear completely with adequate phlebotomy.

We are not yet sure why about 15% with the gene do not express it as disease.  The evidence is that this is due in part to incomplete penetrance of the gene, and partly due to the strong evidence that many of this 15% also have genes (IRE genes - iron regulatory element genes) which act to suppress the increased iron absorption which the hemochromatosis gene would otherwise produce( i.e., these genes cancel out the hemochromatosis gene). 

The desire of insurers and employers to stigmatize those who have a gene for iron overload, for breast cancer, or for any other disorder, is particularly inappropriate in view of the fact that many people with ìdefectiveî or ìharmfulî genes also have anti-genes which cancel expression of the ìbadî gene.  Since we have not yet completely isolated those ìgoodî genes, we can not yet test for them in patients with a ìbadî gene.