Natural History of Hemochromatosis

Natural History of Hemochromatosis

Mayo Clin Proc, March 2004, Vol 79 Editorial 305 March 2004 Mayo Clinic Proceedings Volume 79 Number 3 Editorial Natural History of Hemochromat...

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Mayo Clin Proc, March 2004, Vol 79

Editorial

305

March 2004

Mayo Clinic Proceedings

Volume 79 Number 3

Editorial

Natural History of Hemochromatosis

U

nderstanding the natural history of a disease is critical to its intelligent management. However, the severity of a disease state and its rate of progression are typically overestimated simply because it is the most ill patients who present to a physician. Histoplasmosis was once regarded as a uniformly fatal infection; most patients with factor V Leiden were believed to be at high risk for venous thrombosis, and patients with Gaucher disease were expected to show relentless progression. The situation is no different with hereditary hemochromatosis. Because hereditary iron storage disease can present with cirrhosis, diabetes, and cardiomyopathy, many physicians have assumed that this end stage would ultimately occur in most patients with the homozygous hemochromatosis genotype if they were not so fortunate as to have a diagnosis made by an alert physician and early treatment with phlebotomy. Indeed, this concept is intrinsic to an often cited study1 that showed that noncirrhotic persons with hemochromatosis have a normal life span if they undergo phlebotomy. Such patients were characterized as being “precirrhotic,” as if one could assume that without intervention they would surely become cirrhotic. There is now ample evidence that homozygotes for hemochromatosis also have a normal life span even if they do not undergo phlebotomy.2,3 The misconception that these patients were saved by treatment was due to a lack of understanding of the natural history of the disease. How does one define the clinical course in a disease such as hemochromatosis? It is essential that an unbiased sample of patients be studied. In hemochromatosis, this involves genotyping a large number of persons in the general population at a broad range of ages and comparing the

health of “at-risk” individuals to that of well-matched controls. Of course, one must make certain that the sickest patients have not died or are so ill that they are not represented in the sample studied. This can be achieved by determining whether the number of identified hemochromatosis-susceptible homozygotes meets the HardyWeinberg expectation at all ages. In hemochromatosis this is the case. After one is certain that the study population is not biased, a “cross-sectional” assessment of the course of the disease is possible by stratifying the population by age. Two major3,4 and many smaller studies have shown that, except for minor abnormalities in liver function or histology, the actual disease does not progress measurably throughout many decades. However, minor increases in serum ferritin and in transferrin saturation values have been documented in some studies. See also page 309. Another approach is to monitor individual patients over a lengthy period. In general, this strategy should provide the same information on the natural course of the disease as the cross-sectional approach, but it can also provide some information about variability within a patient. In hemochromatosis, it is difficult to obtain such data because, once the diagnosis is established, phlebotomy is typically performed to remove the excess iron, especially in severely affected patients. In this issue of the Mayo Clinic Proceedings, Olynyk et al5 performed such a longitudinal assessment of a limited number of subjects enrolled in the Busselton population studies of Western Australia. This could be accomplished because the subjects were first diagnosed as being homozygous for the C282Y mutation of the HFE gene in 1998. Stored blood samples were available, making it possible to document changes, principally in the transferrin saturation and serum ferritin levels. In the small number of subjects studied, it appeared that the transferrin saturation value tended to rise with time, but no such trend

This work was supported by grants DK53505-04 and RR00833 from the National Institutes of Health and by the Stein Endowment Fund. Address reprint requests and correspondence to Ernest Beutler, MD, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (e-mail: [email protected]). Mayo Clin Proc. 2004;79:305-306

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Editorial

could be discerned with the ferritin levels, which fluctuated widely between measurements. Although the latter finding may surprise those who believe that the ferritin level closely tracks the body iron stores, the fact is that serum ferritin is an acute phase protein and is a poor indicator of iron stores. It is simply the best we have. Since some of the homozygotes who had normal transferrin saturation values when initially examined had elevated levels with the passage of time, Olynyk et al suggest that phenotypic screening of persons younger than 40 years may be insufficient to detect all patients at risk. The study by Olynyk et al falls short in the same respect as many of the studies that misled us into believing that the penetrance of clinical hemochromatosis in homozygous individuals was much higher than we now recognize it to be. The Olynyk study lacks controls. It would have been valuable to know what happened to ferritin and transferrin saturation levels in Busselton residents who were not homozygous for hemochromatosis and how many of them would develop arthritis, hepatomegaly, or diabetes over a 17-year time span. Although those who cling to the idea that the hemochromatosis genotype does have a high penetrance might interpret the development of arthritis and the appearance of hepatic fibrosis in several patients as supporting such a view, no interpretation is possible without a proper control population. For example, NHANES II (Second National Health and Nutrition Examination Survey) showed that the prevalence of arthritis in the general US population is 5.6% in the 17 to 39 age group, 19.1% in the 40 to 59 age group, and 43.5% in the 60 to 84 age group.6 Hence, the development of arthritis in the Busselton subjects is probably a reflection of the fact that they aged 17 years during the course of the study. Notably, the only subject who developed cirrhosis was the one who ingested more than 6 alcoholic drinks per day. The association between alcohol and cirrhosis in hemochromatosis is well known.7 The number of persons who drink this amount of alcohol daily who do not have hemochromatosis but who develop cirrhosis is unknown. Although the opportunity of monitoring the natural history of hemochromatosis does not arise often, a group from Denmark recently followed up 14 C282Y homozygous patients for 25 years.8 This study also had controls, matched not only for age and sex but also for alcohol consumption. The results are similar to those reported by Olynyk et al in that ferritin values were highly variable,

Mayo Clin Proc, March 2004, Vol 79

with average values increasing with age in female patients and decreasing with age in male patients. Like the Olynyk study, there was a slight tendency for transferrin saturation values to increase. Interestingly, the ferritin levels increased more in the wild-type controls than in the homozygous patients. Notably, none of the homozygotes developed overt clinical hemochromatosis in the 25 years of follow-up, and there was no increase in the prevalence of arthritis in the homozygous patients compared with the controls. Both of these studies cast further doubt on the need for or effectiveness of population-based screening for hemochromatosis. The progressive rise in ferritin levels that many physicians assumed to be characteristic of this disease is confirmed neither by cross-sectional nor by longitudinal studies. This implies that, at least in most patients, iron stores, the size of which is reflected by serum ferritin levels, do not increase appreciably over many decades. The histological demonstration of hepatic fibrosis in a few patients with the C282Y/C282Y genotype does not seem to presage clinical illness or shortening of life span. Hemochromatosis is a serious disease, but fortunately it is rare. Ernest Beutler, MD Department of Molecular and Experimental Medicine The Scripps Research Institute La Jolla, Calif 1.

2. 3. 4. 5. 6. 7. 8.

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;313:1256-1262. Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of the 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet. 2002;359:211-218. Waalen J, Felitti V, Gelbart T, Ho NJ, Beutler E. Prevalence of hemochromatosis-related symptoms among individuals with mutations in the HFE gene. Mayo Clin Proc. 2002;77:522-530. Asberg A, Hveem K, Kruger O, Bjerve KS. Persons with screeningdetected haemochromatosis: as healthy as the general population? Scand J Gastroenterol. 2002;37:719-724. Olynyk JK, Hagan SE, Cullen DJ, Beilby J, Whittall DE. Evolution of untreated hereditary hemochromatosis in the Busselton population: a 17-year study. Mayo Clin Proc. 2004;79:309-313. McDowell A, Engel A, Massey JT, Maurer K. Plan and operation of the Second National Health and Nutrition Examination Survey, 1976-1980. Vital Health Stat 1. 1981:69. Fletcher LM, Powell LW. Hemochromatosis and alcoholic liver disease. Alcohol. 2003;30:131-136. Andersen RV, Tybjaerg-Hansen A, Appleyard M, Birgens H, Nordestgaard BG. Hemochromatosis mutations in the general population: iron overload progression rate. Blood. December 4, 2003 [Epub ahead of print].

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.