THE WESTERN JOURNAL OF MEDICINE THE
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OF
MEDICINE
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SEPTEMBER 1990 SEPTEMBER
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fasciitis with eosinophilia (Shulman's syndrome), which is characterized by clinical and histopathologic alterations of the integument indistinguishable from those found in EMS.5 Shulman's syndrome, however, is not associated with either the multisystem involvement or the presence of antinuclear antibodies frequently encountered in EMS. Because of the persistent eosinophilia, a relation of EMS to the idiopathic hypereosinophilic syndromes, a group of chronic diseases characterized by eosinophilic infiltration of the skin and various internal organs, has been suggested. In similarity with EMS, peripheral neuropathy, myositis, skin rash, endocardial fibrosis, and pulmonary infiltrates are common in this group of diseases.6 The eosinophilia-myalgia syndrome also resembles clinically and histopathologically the toxic epidemic syndrome, a multisystem disease associated with the ingesting of adulterated cooking oil that occurred in Spain in 1981.' A common pathogenetic mechanism for these two disorders has been postulated (see below). The role of tryptophan in the pathogenesis of EMS is not clear. Abnormalities in tryptophan metabolism have been suspected to play a role in various fibrotic diseases8 and have been shown in-some patients with EMS.9 Tryptophan, however, had been commonly used in the United States for more than a decade before the epidemic occurrence of EMS, suggesting that a contaminant(s) in the preparation rather than the amino acid may be the causative agent. Extensive studies to identify such contaminant(s) have not been conclusive to date. The possibility that aniline-related compounds may be involved in EMS has been suggested10 because aniline derivatives that have been implicated in the pathogenesis of the toxic oil syndrome are used in the production of tryptophan. The dramatic increase in peripheral blood eosinophils and their conspicuous presence in affected tissues suggest an important role for these cells in the development of the tissue damage of EMS. Eosinophils release a variety of toxic granule-associated proteins that have been shown to be present in affected tissues and are elevated in the blood of patients with the syndrome.4 As discussed in detail by Criswell and Sack,1 the presence of inflammatory cells in affected tissues in EMS suggests that these cells or their products may play a role in the pathologic manifestations of EMS. For example, degranulating mast cells are found in skin biopsy specimens of patients with early progressive cutaneous disease. Mast cell products interact with eosinophils and dermal fibroblasts and may stimulate the synthesis of extracellular matrix components, resulting in the development of fibrosis."1 We have recently demonstrated the widespread activation of collagen gene expression in EMS dermal fibroblasts employing in situ hybridizations with human complementary DNA. 12 Furthermore, transforming growth factor-i,3 (TGF,3J), one of the most potent signals to stimulate collagen production, has been shown to be present in fibroblasts and inflammatory cells in affected tissue (S.A.J. and collaborators, unpublished observations). Although cytokine-fibroblast interactions may play a major role in the development of EMS, the complex clinical characteristics of the syndrome and the variety of systems affected suggest that several factors may be involved in its pathogenesis. For example, peripheral nerve damage may be a toxic effect mediated by tryptophan metabolites, contaminants of the tryptophan preparations, or the toxic substances released from eosinophils. On the other hand, the cutaneous and visceral fibrosis may be related to the activation of T lymphocytes with the release of fibrogenic lym-
323
3
3
323
phokines such as TGFj,3 or to degranulation of mast cells with subsequent activation of fibroblasts. Understanding the mechanisms that result in the development of the various pathologic alterations of EMS should provide new insights into the pathogenesis of fibrotic diseases and may lead to the development of novel forms of therapy for these frequently crippling diseases. This work is supported in part by grant No. AR 19101 from the National Institutes of Health. SERGIO A. JIMENEZ, MD
Professor of Medicine and ofBiochemistry and Molecular Biology Director, Rheumatology Research JOHN VARGA, MD Assistant Professor of Medicine Jefferson Medical College of Thomas Jefferson University Philadelphia
REFERENCES
1. Criswell LA, Sack KE: Tryptophan-induced eosinophilia-myalgia syndrome. West J Med 1990 Sep; 153:269-274 2. Centers for Disease Control: Clinical spectrum of eosinophilia-myalgia syndrome-California. MMWR 1990; 39:89-91 3. Varga J, Heiman-Patterson TD, Emery DL, et al: Clinical spectrum of the systemic manifestations of the eosinophilia-myalgia syndrome. Semin Arthritis Rheum 1990; 19:313-328 4. Hertzman PA, Blevins WL, Mayer J, et al: Association of the eosinophiliamyalgia syndrome with the ingestion of tryptophan. N Engl J Med 1990; 322:869-873 5. Moutsopoulos HM, Webber BL, Pavlidis NA, et al: Diffuse fasciitis with eosinophilia-A clinicopathological study. Am J Med 1980; 68:701-709 6. Fauci AS, Harley JB, Roberts WC, et al: The idiopathic hypereosinophilic syndrome. Ann Intern Med 1982; 97:78-92 7. Toxic Epidemic Syndrome Study Group: Toxic epidemic syndrome, Spain 1981. Lancet 1982; 2:697-702 8. Stemnberg EM, Van Woert MH, Young SN, et al: Development of a scierodermalike illness during therapy with L-5-hydroxytryptophan and carbidopa. N Engl J Med 1980; 303:783-787 9. Silver R, Heyes MP, Maize JC, et al: Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan. N Engl J Med 1990; 322:874-881 10. Medsger TA Jr: Tryptophan-induced eosinophilia-myalgia syndrome (Editorial). N Engl J Med 1990; 322:926-928 11. Claman HN: Mast cells, T cells and abnormal fibrosis. Immunol Today 1985; 6:192-195 12. Varga J, Peltonen J, Uitto J, et al: Development of diffuse fasciitis with eosinophilia during L-tryptophan treatment: Demonstration of elevated type I collagen gene expression in affected tissues-A clinicopathologic study of four patients. Ann Intern Med 1990; 112:344-352
Hemochromatosis-Treatment Is Easy, Diagnosis Hard HEMOCHROMATOSIS HAS BEEN RECOGNIZED for about 40 years as an iron storage disease that could be arrested or reversed by iron removal through phlebotomy. The problem has been not with the treatment but with the recognition of the condition. The diagnostic triad of hepatomegaly, pigmentation of the skin, and diabetes mellitus was rarely seen. Laboratory tests for its detection were limited. In addition, its separation from a number of other iron-loading conditions was difficult. The situation has gradually changed in the past two decades. The course of the disease is now better defined. Hemochromatosis is a genetic disorder, the hallmark of which is excessive iron absorption. There is an additional failure of reticuloendothelial iron storage during the initial stage, resulting in the localization of the excess iron in the parenchymal cells of the liver. For many years there may be no tissue damage; then minor evidence of liver dysfunction may appear-the serum alanine aminotransferase (previously serum glutamic-pyruvate transaminase) liver function test being the most sensitive-and iron spills over into other parenchymal tissues. Initial symptoms are highly variable from patient to patient, but eventually the symptom complex expands into a more recognizable form.
324
The availability of laboratory measurements of plasma iron and iron-binding protein from which transferrin saturation could be calculated, the development of the plasma ferritin measurement, and a better understanding of the interpretation of these two screening tests have helped the diagnostic approach immeasurably. The recognition of the close relation between the hemochromatosis gene abnormality and the HLA complex has provided insight into the genetics of the disorder and has improved the diagnosis among siblings of a proband with the disease. Then, too, there is now a more detailed knowledge of the symptoms produced by parenchymal iron overload. Observations in the past decade place emphasis on gonadal failure and arthritis of the metacarpophalangeal joints of the second finger as early manifestations. It should also be appreciated that the presenting symptoms are modified by the rate of iron accumulation and the patient's age at the onset of symptoms. For example, gonadal and cardiac failure are particularly prominent in patients presenting with symptoms in their 20s and 30s. This is consistent with presenting symptoms in the more rapid iron loading of thalassemia and sideroblastic anemia. How common is hemochromatosis? Most practicing physicians have never recognized the disease in their practice. The best information suggests that one person in a few hundred may have the homozygous form of the disorder and therefore may have the potential of sufficient iron overload occurring to produce tissue damage. A nearly tenfold difference exists between these prevalence studies, which include the preclinical disorder, and the number of cases diagnosed clinically. Does this mean that we are missing the diagnosis nine times out of ten? There are undoubtedly several reasons for the disparity. Prevalence data are sparse. Much of our information may come from populations of high gene concentration that have evoked a special interest in the disease. Studies using screening tests on "unprejudiced," predominantly white populations are far more limited but suggest a lower prevalence of affected persons, perhaps 1 per 1,000. Another explanation is the discrepancy between the condition and its symptomatic state. We know that the genetic frequency is equal in men and women, yet symptomatic disease in women occurs only about a fifth as frequently as in men. In other words, four of five women do not accrue sufficient iron to be symptomatic. There is also a proportion of men who go through life without symptoms; others have symptoms that are so mild or nonspecific that the disorder is not recognized on clinical grounds. The final possibility is that physicians are not sufficiently astute in making the proper diagnosis. All of these elements undoubtedly explain the apparent discrepancy between reported prevalence and actual diagnosis. Since the number of practicing physicians approximates the number of symptomatic patients with hemochromatosis, the average physician will rarely, if ever, diagnose the condition. Yet even among the well informed, diagnosis is still a chancy matter because of the protean nature of presenting symptoms. At any rate, by the time recognizable symptoms appear, the "horse may be out of the barn." In recent years the public has expressed its displeasure with this state of affairs. Lay societies have been formed whose mission is to disseminate information about the "bronze killer." Participants often are family and relatives of a patient whose unfortunate death was related to a delay or a failure of proper diagnosis. Their members are aware that the disease can be "cured" only if treatment is started before tissue damage occurs or that the disease can be arrested
EDITORIALS
if recognized later on. Their information program has been
so effective that people they reach are sometimes far better
informed than their physicians. How can disease detection be improved? In the silent years of the disorder, there is an accumulation of iron bound to the iron transport protein of the plasma, and hepatic iron stores become excessive. These changes may be detected by laboratory tests that are characteristic of, but not specific for, parenchymal iron overload. The earliest indicator is an elevation of plasma transferrin saturation, at first intermittent and then constant. This merely indicates an imbalance between the iron loading of this iron transport protein and its delivery of iron to transferrin receptors on cell surfaces. Such an elevation does not necessarily mean an increase in iron stores; it may be due to an abnormality in erythropoiesis, for example, caused by chloramphenicol ingestion or other types of marrow damage. It may be due to liver disease, to damage to a ferritin-rich tissue, or simply to an instability in plasma iron in a normal healthy person. Repeated determinations will settle this last point. Plasma ferritin is the other useful screening test; its level will increase progressively in an affected patient in proportion to the increase in storage iron to values of several thousand micrograms per liter. Values of as high as 2,000 jg per liter in the elderly are more frequently due to other forms of liver disease or to chronic inflammation such as rheumatoid arthritis. Values elevated for age and sex, however, when linked to an elevated transferrin saturation, merit more definitive evaluation for iron storage disease. There are two points of attack on hemochromatosis. In the past the approach has been through the acumen of a practicing physician who, when faced with a patient whose symptoms suggest the disease, requests a liver biopsy. Difficulties persist in separating by biopsy the genetic disease from late-stage alcoholic or viral hepatic disease. In such patients the desferrioxamine iron excretion test may be helpful in separating the heavier iron load of idiopathic hemochromatosis; the test is only valid when cirrhosis is present. Quantitating hepatic iron from a liver biopsy specimen would be better, but a reliable iron determination on a fragment of tissue obtained by needle biopsy is not generally available. Results to date indicate the limitations of this clinical approach, especially when the time of diagnosis is considered. The average patient's age at the time of diagnosis is older than 50 in a disorder that is assumed to begin its pathologic iron storage in childhood. Furthermore, after symptoms occur, there is an average lag period of about six years to diagnosis. It is hoped that a greater familiarity with the clinical features of the disease so beautifully presented by Smith in this issue of the journal' would reduce this interval. Because certain cellular damage, particularly that of the myocardium, is completely reversible, prompt institution of phlebotomy can be life-saving. Damage to other tissues may not be reversible, however. While physicians should be prepared to suspect hemochromatosis when appropriate symptoms are present, their "batting average" will continue to be predictably low until the disease is advanced. The attack of the future will be preventing the disease by early detection of the disorder. Already, chance determinations of an elevated transferrin saturation or ferritin level have led to the detection of parenchymal iron loading in younger persons who show no evidence of tissue damage. It is in the preclinical years that a liver biopsy is uniquely diagnostic. There will be a generalized iron loading of parenchymal cells, but Kupffer's cells will be spared, and
THE WESTERN JOURNAL OF MEDICINE
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there will be no evidence of cellular damage. At this stage, the marrow hemosiderin levels will not be increased. It is thought that such persons, once their iron stores are returned to normal and kept there, will have no medical effects of their genetic disorder. A strong case can be made for incorporating measurements of the plasma iron, iron-binding capacity, and ferritin into the routine blood screen. A physician's role then will be to interpret these tests and to determine whether parenchymal iron overload is present. Without such a laboratory survey, there is little hope of recognizing hemochromatosis at the time when treatment has the greatest promise. CLEMENT A. FINCH, MD
Professor of Medicine Emeritus University of Washington School of Medicine
Seattle REFERENCES
1. Smith LH Jr: Overview of hemochromatosis. West J Med 1990 153:296-308
Sep;
Transcatheter Treatment of Congenital Heart Disease Past, Present, and Future SINCE THE 1950s, cardiac catheterization has been an impor-
tant tool in the management of congenital or acquired heart disease. Over this 40-year span, changes have occurred not only in the techniques and equipment used to perform a cardiac catheterization in a child, but also over the past 10 years in the indications for cardiac catheterization. In the past, the primary reason for doing a cardiac catheterization was to make an anatomic or physiologic diagnosis. Although the advent of two-dimensional echocardiography and color-flow Doppler has in part replaced this indication, other new indications for cardiac catheterization in pediatric patients have emerged. Two of the major new indications include the following: electrophysiologic studies and therapeutic catheterization. Therapeutic catheterization can be divided into two major types: catheter-based interventions and pharmacologic intervention. The vast majority of therapeutic catheterizations done in children involve catheter-based interventions. The report by Waldman and Swensson elsewhere in this issue clearly summarizes many of these catheter-based therapeutic procedures. I As the authors note, the birth of therapeutic catheterization can be traced to Dr William Rashkind's development of balloon atrial septostomy in the late 1960s.2 The recent development of interventional pediatric cardiology, however, can be linked to two papers published in the early 1980s. Lock and co-workers reported their results in dilating experimentally created peripheral pulmonary artery stenosis in late 1981,3 and about six months later, Kan and colleagues published their results on balloon valvuloplasty for the treatment of pulmonary stenosis.4 Following these and other reports on the use of balloon angioplasty to treat various types of congenital heart disease, it became apparent that more information was needed regarding the techniques, complications, and safety of these new interventional procedures. Therefore, in 1983, pediatric cardiologists from a number of institutions formed the Valvuloplasty and Angiography of Congenital Anomalies (VACA) Registry.5 More than 20 pediatric cardiology centers from around the world participated in this registry. The results of that registry have recently been published in the American Journal of Cardiology.6-10 Based on that report and a number
3
325
of other publications, including the current report of Waldman and Swensson, it is clear that balloon dilation is an effective, safe form of therapy for children with many forms of congenital heart disease, including valvar pulmonary, tricuspid, mitral, and aortic stenosis; coarctation of the aorta; peripheral pulmonary artery stenosis; and superior vena caval obstruction. There are, however, still a number of areas related to balloon angioplasty that need further evaluation. These include the following: long-term follow-up results, the use of these interventional techniques in infants, the socioeconomic benefits of these interventional techniques, and the combined use of interventional cardiology and cardiac surgery in the treatment of some forms of congenital heart disease. To date, most of the data regarding the efficacy of angioplasty to treat congenital heart disease relate to initial or short-term-less than two years after angioplasty-hemodynamic studies. There have been no long-term studiesmore than five years after intervention-that have documented that these interventional procedures provide long-lasting hemodynamic and angiographic correction of the congenital defect. To establish the efficacy of balloon angioplasty, these long-term studies will need to be done. With regard to the use of these interventional techniques in infants, available data suggest that balloon valvuloplasty is safe and efficacious for the treatment of critical pulmonary stenosis in neonates. The use of balloon valvuloplasty to treat critical aortic stenosis in neonates is less clear, however.11.12 Based on the findings of the VACA registry, valvuloplasty results in the same degree of aortic stenosis gradient reduction in children regardless of whether they are older or younger than 1 year. The incidence of significant complications, however, including death, aortic regurgitation, and femoral artery damage, is inversely related to the age of the child, with valvuloplasty performed during the first month of life having the highest rate of complications.' A major reason why infants and neonates have higher complication rates is thought to relate to the combination of the larger size (10 to 12 French) of the currently available valvuloplasty catheters and the relatively small size of infants' femoral vessels. In the future, with the development of new catheters with a smaller shaft size and lower balloon profile, valvuloplasty for aortic stenosis will be performed safely in most neonates and infants. As well summarized by Waldman and Swensson, there are both major socioeconomic benefits and problems associated with interventional pediatric cardiology. The major benefits include shorter hospital stays, less need for blood transfusion, the lack of a surgical scar and the psychological trauma that entails, and the potential for large financial savings in an already overspent health care market. Major new problems that interventional cardiology has created include obtaining acceptance from third-party payers that these interventional procedures are no longer experimental and are therefore reimbursable; the need to regulate the indications for performing these procedures; the need to develop standards regarding accreditation for training pediatric cardiologists in these interventional procedures; and the need to establish guidelines for regulating which hospitals should be permitted to do these procedures. The final area for which future research is needed relates to the interrelationship between interventional cardiology and cardiac surgery. In the past, before the use of a new interventional procedure was advocated, the catheter intervention was required to be able to replace surgical therapy as the treatment of choice; that is, the results of the intervention had to be as good or better than surgical treatment.
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JOURNAL
OF
MEDICINE
o *
SEPTEMBER 1990 SEPTEMBER
1990
o
*
153 153
o
fasciitis with eosinophilia (Shulman's syndrome), which is characterized by clinical and histopathologic alterations of the integument indistinguishable from those found in EMS.5 Shulman's syndrome, however, is not associated with either the multisystem involvement or the presence of antinuclear antibodies frequently encountered in EMS. Because of the persistent eosinophilia, a relation of EMS to the idiopathic hypereosinophilic syndromes, a group of chronic diseases characterized by eosinophilic infiltration of the skin and various internal organs, has been suggested. In similarity with EMS, peripheral neuropathy, myositis, skin rash, endocardial fibrosis, and pulmonary infiltrates are common in this group of diseases.6 The eosinophilia-myalgia syndrome also resembles clinically and histopathologically the toxic epidemic syndrome, a multisystem disease associated with the ingesting of adulterated cooking oil that occurred in Spain in 1981.' A common pathogenetic mechanism for these two disorders has been postulated (see below). The role of tryptophan in the pathogenesis of EMS is not clear. Abnormalities in tryptophan metabolism have been suspected to play a role in various fibrotic diseases8 and have been shown in-some patients with EMS.9 Tryptophan, however, had been commonly used in the United States for more than a decade before the epidemic occurrence of EMS, suggesting that a contaminant(s) in the preparation rather than the amino acid may be the causative agent. Extensive studies to identify such contaminant(s) have not been conclusive to date. The possibility that aniline-related compounds may be involved in EMS has been suggested10 because aniline derivatives that have been implicated in the pathogenesis of the toxic oil syndrome are used in the production of tryptophan. The dramatic increase in peripheral blood eosinophils and their conspicuous presence in affected tissues suggest an important role for these cells in the development of the tissue damage of EMS. Eosinophils release a variety of toxic granule-associated proteins that have been shown to be present in affected tissues and are elevated in the blood of patients with the syndrome.4 As discussed in detail by Criswell and Sack,1 the presence of inflammatory cells in affected tissues in EMS suggests that these cells or their products may play a role in the pathologic manifestations of EMS. For example, degranulating mast cells are found in skin biopsy specimens of patients with early progressive cutaneous disease. Mast cell products interact with eosinophils and dermal fibroblasts and may stimulate the synthesis of extracellular matrix components, resulting in the development of fibrosis."1 We have recently demonstrated the widespread activation of collagen gene expression in EMS dermal fibroblasts employing in situ hybridizations with human complementary DNA. 12 Furthermore, transforming growth factor-i,3 (TGF,3J), one of the most potent signals to stimulate collagen production, has been shown to be present in fibroblasts and inflammatory cells in affected tissue (S.A.J. and collaborators, unpublished observations). Although cytokine-fibroblast interactions may play a major role in the development of EMS, the complex clinical characteristics of the syndrome and the variety of systems affected suggest that several factors may be involved in its pathogenesis. For example, peripheral nerve damage may be a toxic effect mediated by tryptophan metabolites, contaminants of the tryptophan preparations, or the toxic substances released from eosinophils. On the other hand, the cutaneous and visceral fibrosis may be related to the activation of T lymphocytes with the release of fibrogenic lym-
323
3
3
323
phokines such as TGFj,3 or to degranulation of mast cells with subsequent activation of fibroblasts. Understanding the mechanisms that result in the development of the various pathologic alterations of EMS should provide new insights into the pathogenesis of fibrotic diseases and may lead to the development of novel forms of therapy for these frequently crippling diseases. This work is supported in part by grant No. AR 19101 from the National Institutes of Health. SERGIO A. JIMENEZ, MD
Professor of Medicine and ofBiochemistry and Molecular Biology Director, Rheumatology Research JOHN VARGA, MD Assistant Professor of Medicine Jefferson Medical College of Thomas Jefferson University Philadelphia
REFERENCES
1. Criswell LA, Sack KE: Tryptophan-induced eosinophilia-myalgia syndrome. West J Med 1990 Sep; 153:269-274 2. Centers for Disease Control: Clinical spectrum of eosinophilia-myalgia syndrome-California. MMWR 1990; 39:89-91 3. Varga J, Heiman-Patterson TD, Emery DL, et al: Clinical spectrum of the systemic manifestations of the eosinophilia-myalgia syndrome. Semin Arthritis Rheum 1990; 19:313-328 4. Hertzman PA, Blevins WL, Mayer J, et al: Association of the eosinophiliamyalgia syndrome with the ingestion of tryptophan. N Engl J Med 1990; 322:869-873 5. Moutsopoulos HM, Webber BL, Pavlidis NA, et al: Diffuse fasciitis with eosinophilia-A clinicopathological study. Am J Med 1980; 68:701-709 6. Fauci AS, Harley JB, Roberts WC, et al: The idiopathic hypereosinophilic syndrome. Ann Intern Med 1982; 97:78-92 7. Toxic Epidemic Syndrome Study Group: Toxic epidemic syndrome, Spain 1981. Lancet 1982; 2:697-702 8. Stemnberg EM, Van Woert MH, Young SN, et al: Development of a scierodermalike illness during therapy with L-5-hydroxytryptophan and carbidopa. N Engl J Med 1980; 303:783-787 9. Silver R, Heyes MP, Maize JC, et al: Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan. N Engl J Med 1990; 322:874-881 10. Medsger TA Jr: Tryptophan-induced eosinophilia-myalgia syndrome (Editorial). N Engl J Med 1990; 322:926-928 11. Claman HN: Mast cells, T cells and abnormal fibrosis. Immunol Today 1985; 6:192-195 12. Varga J, Peltonen J, Uitto J, et al: Development of diffuse fasciitis with eosinophilia during L-tryptophan treatment: Demonstration of elevated type I collagen gene expression in affected tissues-A clinicopathologic study of four patients. Ann Intern Med 1990; 112:344-352
Hemochromatosis-Treatment Is Easy, Diagnosis Hard HEMOCHROMATOSIS HAS BEEN RECOGNIZED for about 40 years as an iron storage disease that could be arrested or reversed by iron removal through phlebotomy. The problem has been not with the treatment but with the recognition of the condition. The diagnostic triad of hepatomegaly, pigmentation of the skin, and diabetes mellitus was rarely seen. Laboratory tests for its detection were limited. In addition, its separation from a number of other iron-loading conditions was difficult. The situation has gradually changed in the past two decades. The course of the disease is now better defined. Hemochromatosis is a genetic disorder, the hallmark of which is excessive iron absorption. There is an additional failure of reticuloendothelial iron storage during the initial stage, resulting in the localization of the excess iron in the parenchymal cells of the liver. For many years there may be no tissue damage; then minor evidence of liver dysfunction may appear-the serum alanine aminotransferase (previously serum glutamic-pyruvate transaminase) liver function test being the most sensitive-and iron spills over into other parenchymal tissues. Initial symptoms are highly variable from patient to patient, but eventually the symptom complex expands into a more recognizable form.
324
The availability of laboratory measurements of plasma iron and iron-binding protein from which transferrin saturation could be calculated, the development of the plasma ferritin measurement, and a better understanding of the interpretation of these two screening tests have helped the diagnostic approach immeasurably. The recognition of the close relation between the hemochromatosis gene abnormality and the HLA complex has provided insight into the genetics of the disorder and has improved the diagnosis among siblings of a proband with the disease. Then, too, there is now a more detailed knowledge of the symptoms produced by parenchymal iron overload. Observations in the past decade place emphasis on gonadal failure and arthritis of the metacarpophalangeal joints of the second finger as early manifestations. It should also be appreciated that the presenting symptoms are modified by the rate of iron accumulation and the patient's age at the onset of symptoms. For example, gonadal and cardiac failure are particularly prominent in patients presenting with symptoms in their 20s and 30s. This is consistent with presenting symptoms in the more rapid iron loading of thalassemia and sideroblastic anemia. How common is hemochromatosis? Most practicing physicians have never recognized the disease in their practice. The best information suggests that one person in a few hundred may have the homozygous form of the disorder and therefore may have the potential of sufficient iron overload occurring to produce tissue damage. A nearly tenfold difference exists between these prevalence studies, which include the preclinical disorder, and the number of cases diagnosed clinically. Does this mean that we are missing the diagnosis nine times out of ten? There are undoubtedly several reasons for the disparity. Prevalence data are sparse. Much of our information may come from populations of high gene concentration that have evoked a special interest in the disease. Studies using screening tests on "unprejudiced," predominantly white populations are far more limited but suggest a lower prevalence of affected persons, perhaps 1 per 1,000. Another explanation is the discrepancy between the condition and its symptomatic state. We know that the genetic frequency is equal in men and women, yet symptomatic disease in women occurs only about a fifth as frequently as in men. In other words, four of five women do not accrue sufficient iron to be symptomatic. There is also a proportion of men who go through life without symptoms; others have symptoms that are so mild or nonspecific that the disorder is not recognized on clinical grounds. The final possibility is that physicians are not sufficiently astute in making the proper diagnosis. All of these elements undoubtedly explain the apparent discrepancy between reported prevalence and actual diagnosis. Since the number of practicing physicians approximates the number of symptomatic patients with hemochromatosis, the average physician will rarely, if ever, diagnose the condition. Yet even among the well informed, diagnosis is still a chancy matter because of the protean nature of presenting symptoms. At any rate, by the time recognizable symptoms appear, the "horse may be out of the barn." In recent years the public has expressed its displeasure with this state of affairs. Lay societies have been formed whose mission is to disseminate information about the "bronze killer." Participants often are family and relatives of a patient whose unfortunate death was related to a delay or a failure of proper diagnosis. Their members are aware that the disease can be "cured" only if treatment is started before tissue damage occurs or that the disease can be arrested
EDITORIALS
if recognized later on. Their information program has been
so effective that people they reach are sometimes far better
informed than their physicians. How can disease detection be improved? In the silent years of the disorder, there is an accumulation of iron bound to the iron transport protein of the plasma, and hepatic iron stores become excessive. These changes may be detected by laboratory tests that are characteristic of, but not specific for, parenchymal iron overload. The earliest indicator is an elevation of plasma transferrin saturation, at first intermittent and then constant. This merely indicates an imbalance between the iron loading of this iron transport protein and its delivery of iron to transferrin receptors on cell surfaces. Such an elevation does not necessarily mean an increase in iron stores; it may be due to an abnormality in erythropoiesis, for example, caused by chloramphenicol ingestion or other types of marrow damage. It may be due to liver disease, to damage to a ferritin-rich tissue, or simply to an instability in plasma iron in a normal healthy person. Repeated determinations will settle this last point. Plasma ferritin is the other useful screening test; its level will increase progressively in an affected patient in proportion to the increase in storage iron to values of several thousand micrograms per liter. Values of as high as 2,000 jg per liter in the elderly are more frequently due to other forms of liver disease or to chronic inflammation such as rheumatoid arthritis. Values elevated for age and sex, however, when linked to an elevated transferrin saturation, merit more definitive evaluation for iron storage disease. There are two points of attack on hemochromatosis. In the past the approach has been through the acumen of a practicing physician who, when faced with a patient whose symptoms suggest the disease, requests a liver biopsy. Difficulties persist in separating by biopsy the genetic disease from late-stage alcoholic or viral hepatic disease. In such patients the desferrioxamine iron excretion test may be helpful in separating the heavier iron load of idiopathic hemochromatosis; the test is only valid when cirrhosis is present. Quantitating hepatic iron from a liver biopsy specimen would be better, but a reliable iron determination on a fragment of tissue obtained by needle biopsy is not generally available. Results to date indicate the limitations of this clinical approach, especially when the time of diagnosis is considered. The average patient's age at the time of diagnosis is older than 50 in a disorder that is assumed to begin its pathologic iron storage in childhood. Furthermore, after symptoms occur, there is an average lag period of about six years to diagnosis. It is hoped that a greater familiarity with the clinical features of the disease so beautifully presented by Smith in this issue of the journal' would reduce this interval. Because certain cellular damage, particularly that of the myocardium, is completely reversible, prompt institution of phlebotomy can be life-saving. Damage to other tissues may not be reversible, however. While physicians should be prepared to suspect hemochromatosis when appropriate symptoms are present, their "batting average" will continue to be predictably low until the disease is advanced. The attack of the future will be preventing the disease by early detection of the disorder. Already, chance determinations of an elevated transferrin saturation or ferritin level have led to the detection of parenchymal iron loading in younger persons who show no evidence of tissue damage. It is in the preclinical years that a liver biopsy is uniquely diagnostic. There will be a generalized iron loading of parenchymal cells, but Kupffer's cells will be spared, and
THE WESTERN JOURNAL OF MEDICINE
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SEPTEMBER 1990
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o
there will be no evidence of cellular damage. At this stage, the marrow hemosiderin levels will not be increased. It is thought that such persons, once their iron stores are returned to normal and kept there, will have no medical effects of their genetic disorder. A strong case can be made for incorporating measurements of the plasma iron, iron-binding capacity, and ferritin into the routine blood screen. A physician's role then will be to interpret these tests and to determine whether parenchymal iron overload is present. Without such a laboratory survey, there is little hope of recognizing hemochromatosis at the time when treatment has the greatest promise. CLEMENT A. FINCH, MD
Professor of Medicine Emeritus University of Washington School of Medicine
Seattle REFERENCES
1. Smith LH Jr: Overview of hemochromatosis. West J Med 1990 153:296-308
Sep;
Transcatheter Treatment of Congenital Heart Disease Past, Present, and Future SINCE THE 1950s, cardiac catheterization has been an impor-
tant tool in the management of congenital or acquired heart disease. Over this 40-year span, changes have occurred not only in the techniques and equipment used to perform a cardiac catheterization in a child, but also over the past 10 years in the indications for cardiac catheterization. In the past, the primary reason for doing a cardiac catheterization was to make an anatomic or physiologic diagnosis. Although the advent of two-dimensional echocardiography and color-flow Doppler has in part replaced this indication, other new indications for cardiac catheterization in pediatric patients have emerged. Two of the major new indications include the following: electrophysiologic studies and therapeutic catheterization. Therapeutic catheterization can be divided into two major types: catheter-based interventions and pharmacologic intervention. The vast majority of therapeutic catheterizations done in children involve catheter-based interventions. The report by Waldman and Swensson elsewhere in this issue clearly summarizes many of these catheter-based therapeutic procedures. I As the authors note, the birth of therapeutic catheterization can be traced to Dr William Rashkind's development of balloon atrial septostomy in the late 1960s.2 The recent development of interventional pediatric cardiology, however, can be linked to two papers published in the early 1980s. Lock and co-workers reported their results in dilating experimentally created peripheral pulmonary artery stenosis in late 1981,3 and about six months later, Kan and colleagues published their results on balloon valvuloplasty for the treatment of pulmonary stenosis.4 Following these and other reports on the use of balloon angioplasty to treat various types of congenital heart disease, it became apparent that more information was needed regarding the techniques, complications, and safety of these new interventional procedures. Therefore, in 1983, pediatric cardiologists from a number of institutions formed the Valvuloplasty and Angiography of Congenital Anomalies (VACA) Registry.5 More than 20 pediatric cardiology centers from around the world participated in this registry. The results of that registry have recently been published in the American Journal of Cardiology.6-10 Based on that report and a number
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of other publications, including the current report of Waldman and Swensson, it is clear that balloon dilation is an effective, safe form of therapy for children with many forms of congenital heart disease, including valvar pulmonary, tricuspid, mitral, and aortic stenosis; coarctation of the aorta; peripheral pulmonary artery stenosis; and superior vena caval obstruction. There are, however, still a number of areas related to balloon angioplasty that need further evaluation. These include the following: long-term follow-up results, the use of these interventional techniques in infants, the socioeconomic benefits of these interventional techniques, and the combined use of interventional cardiology and cardiac surgery in the treatment of some forms of congenital heart disease. To date, most of the data regarding the efficacy of angioplasty to treat congenital heart disease relate to initial or short-term-less than two years after angioplasty-hemodynamic studies. There have been no long-term studiesmore than five years after intervention-that have documented that these interventional procedures provide long-lasting hemodynamic and angiographic correction of the congenital defect. To establish the efficacy of balloon angioplasty, these long-term studies will need to be done. With regard to the use of these interventional techniques in infants, available data suggest that balloon valvuloplasty is safe and efficacious for the treatment of critical pulmonary stenosis in neonates. The use of balloon valvuloplasty to treat critical aortic stenosis in neonates is less clear, however.11.12 Based on the findings of the VACA registry, valvuloplasty results in the same degree of aortic stenosis gradient reduction in children regardless of whether they are older or younger than 1 year. The incidence of significant complications, however, including death, aortic regurgitation, and femoral artery damage, is inversely related to the age of the child, with valvuloplasty performed during the first month of life having the highest rate of complications.' A major reason why infants and neonates have higher complication rates is thought to relate to the combination of the larger size (10 to 12 French) of the currently available valvuloplasty catheters and the relatively small size of infants' femoral vessels. In the future, with the development of new catheters with a smaller shaft size and lower balloon profile, valvuloplasty for aortic stenosis will be performed safely in most neonates and infants. As well summarized by Waldman and Swensson, there are both major socioeconomic benefits and problems associated with interventional pediatric cardiology. The major benefits include shorter hospital stays, less need for blood transfusion, the lack of a surgical scar and the psychological trauma that entails, and the potential for large financial savings in an already overspent health care market. Major new problems that interventional cardiology has created include obtaining acceptance from third-party payers that these interventional procedures are no longer experimental and are therefore reimbursable; the need to regulate the indications for performing these procedures; the need to develop standards regarding accreditation for training pediatric cardiologists in these interventional procedures; and the need to establish guidelines for regulating which hospitals should be permitted to do these procedures. The final area for which future research is needed relates to the interrelationship between interventional cardiology and cardiac surgery. In the past, before the use of a new interventional procedure was advocated, the catheter intervention was required to be able to replace surgical therapy as the treatment of choice; that is, the results of the intervention had to be as good or better than surgical treatment.
