i____l EDITORIAL

Hereditary Iron Overload and African Americans David Baer, MD, Oak/and, California

I ron absorption from the gut is highly regulated, and feedback mechanisms inhibit further absorp-

tion after about 800 to 1200 mg of storage iron have accumulated.’ When an inherited defect exists in this homeostatic control mechanism, toxic levels of iron can accumulate and cause various ailments, includ- ing cirrhosis, diabetes, cardiomyopathy, skin pig- mentation, arthritis, and pituitary dysfunction.

The first case report associating the syndrome of diabetes, cirrhosis, and skin pigmentation has been credited to Trousseau and was published in 186L2 In 1889, Von Recklinghausen named this disease he- mochromatosis.3 In a 1935 monograph,4 Sheldon thoroughly catalogued clinical manifestations of he- mochromatosis, suggested that at least some cases were familial, and speculated that the condition was due to an “inborn error of metabohsm.“4 However, it had not occurred to him that repeated phlebotomy could remove excess iron stores: “Th, relation of iron to the cells in haemochromatosis appears to be on all fours with that of the lobster to the lobster pot-easy to get in but supremely difficult to get out.“4 In 1955, when the topic was again reviewed,6 the central role of increased iron stores in producing tissue damage was more clearly understood, addi- tional support for inheritance was recognized, and encouraging results with phlebotomy therapy had been reported.6 Further follow-up has shown that when phlebotomy is initiated before cirrhosis devel- ops, survival is normal.7-g

In 1976, a truly remarkable observation was made by Simon et al: while studying 24 hemochromatosis sibships, they found that siblings with hemochro- matosis usually possessed the same 2 HLA haplo- types.” This phenomenon was due to the tight ge- netic linkage between the genes which code for HLA antigens and the gene for hemochromatosis. This re- lation established the recessive nature of the inher- itance of HLA-linked hemochromatosis (HH) and, more important, allowed investigators to identity, by methods entirely independent of acquired iron stores, HH family members who were homozygous, heterozygous, or unaffected.

1 From the Deoartment of Medicine, Division of HematolowOncolo~, Kaiser Permanknte Medical Center, ‘Oakland, California. -- --

1

Reouests for reprints should be addressed to David Baer, MD, Depart- ment ‘of Medicine,’ Kaiser Permanente Medical Center, 280 W. MacArthur Blvd., Oakland, CA 9461 l-5693.

Manuscript submitted April 1, 1996 and accepted May 30, 1996.

01996 by Excerpta Medica, Inc. All rights resewed.

This ability to recognize cases of HH, indepen- dently of stored iron, led to the observation that an elevated transferrin saturation test result, although imperfect, can best identify homozygotes.” In addi- tion, the hepatic iron index, a calculated ratio relat- ing quantitative hepatic iron concentration and the patient’s age, is the most definitive biochemical marker of homozygosity and is often required to dis- criminate among patients with mild homozygous dis- ease, heterozygotes, and patients with iron excess caused by alcoholic liver disease.‘2T’3 Populattion sur- veys have shown that as many as 0.5% of persons of European ancestry are homozygous for the condi- tion, r4-17 although probably only some of these ho- mozygotes would develop symptoms of iron over- load if they went undiscovered.”

The ability to effectively treat the complications of iron overload places this condition in a unique category of clinical entities. As emphasized by so many authors, the clinician must be alert to the diagnosis of HH be cause cirrhosis, diabetes, heart failme, arthritis, or im- potence can be easily attributed to other, more familiar causes. The frequency with which homozygotes can be discovered and the effectiveness of using prophylactic phlebotomy after the condition has been identified has prompted many commentators to recommend preven- tive routine screening of asymptomatic adults.lg-~ Screening efforts, if undertaken, might best be directed at persons of European ancestry.=

Relatively less attention has been directed at a dif- ferent iron overload syndrome, recognized for most of this century as clinically distinct from HH and de- scribed as occurring in Africa This syndrome usually is seen in middle-aged and older men with hepato- megaly or cirrhosis, less commonly with associated diabetes or cardiomyopathy. The syndrome has been attributed to high concentrations of iron found in the traditional home-brewed beer consumed in rural areas of Africa26 Beer is brewed in nongalvanized iron containers and is rich in highly absorbable iron.25 Pop u&ion surveys have shown that evidence o,f African iron overload (AIO) correlates strongly with heavy consumption of traditional beer.26 Serial autoqsy stud- ies further implicate dietary iron in the etiology of this syndrome. The prevalence of elevated levels of he- patic iron concentration in men aged >40 :years de- creased from 26% in 1962 to 13% in 1979.27 This de- crease coincided with the increasing replacement of iron-rich, home-brewed beer by commercially pre- pared products with low iron content.

0002-9343/(96)/~15.00 5 PlISOOO2-9343(96)00157-X

Interesting differences have been observed be- tween the syndromes of HH and AIO. In HH, hepatic iron stores are preferentially distributed to hepa- tocytes instead of macrophages of the reticuloen- dothelial system, and there is a unique gradient of hepatic iron deposition between hepatic venules and portal tracts.” In AIO, iron deposition is similar to that seen in transfusional overload: iron is de- posited equally in liver parenchyma and liver mac- rophages. In advanced HH, iron is deposited in the parenchyma of the pancreas, endocrine glands, and heart, but this deposition pattern is seen less com- monly in AIO. ” Conversely, in AIO, iron is depos- ited in bone marrow and spleen, but this pattern is minimal in HH.30 In HH, the transferrin saturation can become elevated at an early age, before serious iron overload develops. 31 In contrast, in African pa- tients with iron excess but no cirrhosis, iron levels are not increased and transfer-r-in saturation is nor- malzg In AIO, transferrin saturation increases only after cirrhosis develops.

Ascorbic acid deficiency and osteoporosis are commonly associated with AIO. Biochemical evi- dence of ascorbic acid deficiency is seen in virtually all black adults who have AIO, and clinical scurvy is common.2g~32 Osteoporosis, severe enough to pro- duce vertebral or femoral head collapse, is some- times found in black African men who have AlO.” Autopsy data have shown an inverse correlation of hepatic iron concentration and bone mineral density measurements, 33 and metabolic studies have sug- gested that alcohol, iron overload, and vitamin C de- ficiency all play a role in the development of osteo- porosis.34 However, osteoporosis and disorders of ascorbic acid may not be unique to iron overload in African men.35,36

Like HH among white Europeans, AI0 is quite common among black Africans. Studies from south- ern, western, and eastern Africa37 have all found that as many as 10% of adult black men have cirrhosis with excessive iron stores. Although most explana- tions of AI0 have focused on the high dietary iron content which results from drinking traditional beer, Gordeuk et al38 have proposed that another factor may exist. After carefully surveying the families of African beer drinkers with iron overload, they con- cluded that AI0 was associated with a familial (and therefore probably genetic) factor which interacts with the beer drinking. HLA typing studies of these families did not show any linkage to HLA pheno- types, and they postulated the existence of a gene, distinct from the gene responsible for HH, that was a contributing factor to the AI0 syndrome.38

If a genetic abnormality did predispose 10% of sub- Saharan African adult men to iron overload severe enough to result in cirrhosis, what does this imply

6 July 1996 The American Journal of Medicine8 Volume 100

for millions of Americans with similar ancestry? In the context of this important question, two recent articles have described iron overload in African Americans.

Barton et al% recently reported a series of 7 African- American patients in an Alabama community hema- tology and medical oncology practice who had symp- toms and laboratory abnormalities which could be consistent with iron overload. However, all of their pa- tients had associated conditions such as malignancy, hemoglobinopathy, or chronic active hepatitis C. In critically assessing the implications of these series,% it should be understood that the diagnosis of iron over- load can be problematic. Although it usually correlates well with total body iron stores, serum ferritin can be elevated disproportionately in states of inflammation, liver disease, or increased red-cell turnover.4o Elevated transfer-r-in saturation is useful in identifying persons with HH, but screening studies which use transfer-r-in saturation to screen asymptomatic persons have found that many who have elevated transfer&r saturation do not have HH or another identifiable iron storage prob- lem. 17rz4 Increased transferrin saturation levels may not serve as a useful marker of iron overload in other con- ditions than HH. Mild degrees of excess iron accumu- lation occur in forms of hemolytic anemia or thalas- semia However, severe iron loading associated with erythroid hyperplasia is often caused by undetected BH.4’,42 Chronic viral hepatitis and alcoholic liver dis- ease can masquerade as iron overload, and the distinc- tion from HH is often a challenge for clinicians.43,44 The hepatic iron index can distinguish HH from alcoholic liver disease, I3 but the index has not bee:n systemati- cally studied in African iron overload.

Attributing symptoms to iron overload in a patient is hazardous. Symptoms and diseases associated with iron overload (cirrhosis, diabetes, cardiomy- opathy, joint pains, and impotence) are all com- monly seen in a general clinical practice. Regardless of cause, severity of these conditions can vary over time. Improvement coincident with phlebotomy therapy is an important observation but must not be overinterpreted. The patients in the series of Barton et a13’ are intriguing and provocative, but the exis- tence of a new syndrome should not be assumed on the basis of these 7 cases.

In this issue of the Journal, however, Wurapa et al45 extend the observations of Barton et al. Wurapa et al describe the cases of 4 African Americans, each of whom had iron loading levels difficult to explain by currently understood etiology. Further, they re- viewed autopsy and hospital records of 326 unse- lected African Americans to estimate prevalence of iron overload in this ethnic group. Total body iron stores were estimated from measured hlepatic iron concentration with a calculated correction for his-

HEREDITARY IRON OVERLOAD AND AFRICAN AMERICANS/BAER

tory of blood transfusion. Four additional subjects were identified in this way who had unexplainable levels of iron loading and varying degrees of hepatic fibrosis. All 8 patients with iron overload in this se- ries had a history of heavy drinking.

Is it necessary to invoke a syndrome unique to Af- rican Americans to account for the cases described in these two reports? Are these cases simply highly selected individuals whose iron abnormality results from combinations of excess alcohol, mild erythroid hyperplasia, chronic diseases, or, perhaps a stray HLA-linked hemochromatosis gene? The authors have explained why they think not and have made a fairly persuasive case.

Yet several questions remain. Can a person who is genetically predisposed to AI0 accumulate toxic lev- els of iron while ingesting less than the 50 to 100 mg iron consumed daily by African beer drinkers?‘” What role does alcohol alone play in the syndrome of African iron overload? Does unrecognized expo- sure to toxic levels of dietary iron occur in this coun- try, or are the iron levels in an American diet suffi- cient to produce the syndrome in selected persons? Senba et al46 suggested that the iron accumulation in AI0 may be related to hepatitis B infection. What roles do hepatitis B and C have in African-American iron overload? Could viral hepatitis, a disease spread by vertical transmission in much of the world, ac- count for the familial distribution of iron overload seen by Gordeuk38 in Africa? How does one recon- cile the alleged genetic component of AI0 with the observation that white African volunteers absorb as much iron from traditional African beer as do black volunteers? 25

If iron overload exists as a distinct entity in Af- rican Americans, how common is it? How often is it severe enough to cause or contribute to clinical symptoms? How can it be diagnosed? Do African Americans with iron overload have disorders of as- corbic acid metabolism or bone mineralization? How can transferrin saturation or ferritin levels in African Americans be interpreted? Do hepatic iron concentration and the calculated value, hepatic iron index, distinguish iron overload in African Americans from alcoholic liver disease? While clin- ical investigators work to address these important questions, clinicians must use their good sense and caution in approaching this newly described and largely uncharacterized syndrome. The outlook for patients with iron overload is no longer as dismal as that of the lobster in the lobster pot; physicians are obliged to remain vigilant in identifying patients with this condition.

ACKNOWLEDGMENT The Medical Editing Department, Kaiser Foundahon Research Insbtute, provided

editorial assistance.

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