Refer to: Hemochromatosis-Medical Staff Conference, University of California, San Francisco. West J Med 128:133-141, Feb 1978
Medical StaJf Conference
Hemochromatosis These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs. David W. Martin, Jr., Associate Professor of Medicine, and Robert C. Siegel, Associate Professor of Medicine and Orthopaedic Surgery, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, CA 94143.
DR. SMITH: * The topic for discussion at Medical Grand Rounds today will be that of hemochromatosis. The case summary will be given by Dr. Guy Weinberg. DR. WEINBERG:t The patient is a 43-year-old white man who presented in the fall of last year to the Metabolic Clinic with the chief complaint of impotence. Five years ago the patient noted the onset of difficulty of achieving and maintaining an erection, as well as a reduced sex drive. Two years ago his symptoms had continued and his private physician prescribed hormone pills which increased the sex drive, but caused no change in the performance. A year ago the patient noted the onset of pain and stiffness with slight enlargement in all of his proximal interphalangeal joints, as well as the second and third metacarpophalangeal (MCP) joints. There was no heat or redness. The patient was treated at that time with prednisone, the presumptive diagnosis being rheumatoid arthritis. *Lloyd H. of Medicine.
Smith, Jr., MD,
Professor and Chairman, Department
tGuy Weinberg, MD, Medical Resident.
At the time of presentation the patient was completely impotent and had no libido. The rest of the history was noncontributory. Family history indicated that one brother and two sisters had arthritis. On physical examination a II/VI systolic ejection murmur was heard. The patient's testicles were soft and small and there was a female escutcheon and reduced axillary hair. His second and third metacarpophalangeal joints were enlarged but not tender. The initial laboratory studies gave normal findings except for a slightly elevated level of serum glutamic oxaloacetic transaminase (SGOT), a positive rheumatoid factor of 1:320, a serum testosterone value of 101 ng per dl (normal 300 to 1,200), a low serum luteinizing hormone (LH) level of 3 mIU per ml (normal 5 to 25) and a serum iron value of 233 ,Lg per dl (total iron binding capacity, 240 yg per dl). The patient was admitted for evaluation to the Metabolic Service. Results of a liver biopsy showed 4 + iron on a touch preparation and pronounced iron deposition in the parenchyma with focal periportal fibrous tissue. Findings on x-ray films of the hands will be described subseTHE WESTERN JOURNAL OF MEDICINE
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HEMOCHROMATOSIS ABBREVIATIONS USED IN TEXT ACTH = adrenocorticotropic hormone CPPD = calcium pyrophosphate dihydrate FSH = follicle-stimulating hormone LH = luteinizing hormone MCP = metacarpophalangeal SGOT= serum glutamic oxaloacetic transaminase TSH = thyroid-stimulating hormone
quently. Prolactin, thyroid-stimulating hormone (TSH) and cortisol levels were normal. During insulin induced hypoglycemia there were normal responses of hydrocortisone, growth hormone, adrenocorticotropic hormone (ACTH), but a flat curve for both LH and follicle-stimulating hormone (FSH). The patient has been treated by weekly phlebotomy of 500 ml for the past four months. The hematocrit reading has remained stable, but the iron/total iron-binding capacity saturation is now about 85 percent. The patient receives testosterone once or twice a month and has noted a pronounced increase in sexual interest and performance. We have been able to measure iron/total iron-binding capacity in only one sister. Her saturation of iron-binding capacity was about 65 percent. DR. SMITH: Thank you, Dr. Weinberg. The diagnosis of hemochromatosis is obvious as presented now; it certainly was not so at the time the patient was first seen. Dr. Guy Weinberg is to be congratulated in making this diagnosis at a comparatively early stage. In summary, this patient had two main symptoms. The first of these, and the most important from his standpoint, was impotence of five years' duration. The second was an ill-defined type of arthritis diagnosed as rheu-matoid arthritis. He had noted some slight darkening of the skin, but again this was more evident in retrospect. When the diagnosis was suspected, appropriate studies were carried out which clearly showed iron overload by a number of techniques, both direct and indirect. Further studies showed that the areas of injury due to iron overload were confined largely to the endocrine system with pituitary-gonadal insufficiency and to a lesser degree to certain joints. Notably, there was no "bronze diabetes" and no cirrhosis. Fortunately the diagnosis was considered very early despite the atypical presentation of the disease. Appropriate treatment has been instituted and the outcome should be very favorable. 134
FEBRUARY 1978
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128
*
2
Most endocrine and metabolic diseases are disorders of "too much" or "too little." Hemochromatosis is a unique genetic disorder, or possibly a group of disorders, marked by an inappropriate avidity for the absorption of iron. In the normal adult there is approximately 3 to 4 grams of iron. In hemochromatosis this may be increased ten times. The absorption of approximately 1 mg of iron per day maintains normal health. The absorption of only 3 mg per day leads to hemochromatosis. The extra ingredient is time, measured not in days, weeks or months, but in years. It is this phenomenon of continued excessive absorption of a metal with which we shall be concerned during this presentation. There are certain key questions which we would like to be able to answer in a discussion of hemochromatosis: (1) What is the genetic transmission of this disorder, or possibly group of disorders? (2) What is the basic cellular or molecular defect which leads to this continued inappropriate absorption of iron? (3) How does excess iron storage injure tissue? (4) What kinds of disorders result from this tissue injury? (5) When should we suspect the diagnosis and how can it be established? (6) How can this disease be treated and what is the prognosis? Obviously there are many subsidiary questions which flow from those listed, but these are quite sufficient to befuddle us in the time available for discussion today. To understand the abnormalities in iron metabolism in hemochromatosis, we must know something of its normal metabolism. Approximately two thirds of iron is functional. Most of this is in erythrocyte heme, but it is also a constituent of certain enzymes such as catalase, peroxidase and the cytochromes. Another third of iron is in storage form. The major storage form is ferritin, a specialized spherical protein made up of 24 subunits (Figure 1). The apoprotein of ferritin weighs approximately 460,000 daltons. This protein, which may contain up to 23 percent elemental iron in its ferric form, exists as several isoferritins. Another storage form is hemosiderin which probably represents aggregates of partially degraded ferritin, often in an intralysosomal location which is seen as "stainable iron." Approximately 25 to 30 mg of iron per day must be transported through the plasma for the renewal of blood. Transferrin is a specific beta globulin, synthesized largely in the liver for the transport of iron. It carries two ferric ions per molecule
HEMOCHROMATOSIS IRON TURNOVER
Protein subunits 0 0 0 MW= 18,000 Q 0 Q
k
*
*
Apoferritin ~j-4tMW= 460,000
~~0COOH Fe M
MARROW 100mg
RBC
21mg/day
2700mg
~~Fe Fe ~~~~~A
Hemosiderin MW= 106 MW = molecular weight
| AROW|PLASMA
2
2
4mg
T~~AP$
Transferrin Ferritin-Fe (4500 molecules)
MW= 90,000
ATP = adenosine triphosphate
Figure 1.-Iron-binding proteins. Transferrin contains only two molecules of iron, but ferritin may contain up to 4,500 molecules of iron per molecule.
STORAGE 1000mg
GITRACT
Total entering & leaving plasma =
(M
MARROW
on specific binding sites for use in heme synthesis or deposition into a storage form. The 4 mg of iron that circulates saturates about a third of the binding capacity of transferrin (Figure 2A). Trace amounts of ferritin (mostly apoferritin) also circulate, but are not important in iron metabolism. Although 30 mg of iron passes through plasma daily, only 1 mg need be absorbed from dietary sources to maintain balance. The total control of iron metabolism lies in its selective absorption.' This is obviously very anomalous and precarious. There is no physiological mechanism for the control of excretion, such as exists for calcium, sodium or potassium. Normal iron balance is totally dependent upon the adjustment of absorption from the gut. Approximately 15 mg of iron is ingested daily, and about 1 mg of this is absorbed. This is balanced by the 1 mg net loss in man, primarily through the shedding of epithelial cells in the gut and to a much lesser degree from the skin, and possibly through very minor loss of blood in the normal intestine. In women the average daily loss exceeds 1 mg during the normal reproductive period and may average 1.5 to 2 mg because of menstruation. An additional 0.5 grams of iron is lost during pregnancy. This is balanced by slightly higher gut absorption of iron in women. There are a number of variables in absorption, only some of which are now understood. Some intraluminal factors are of importance. Iron is absorbed primarily in its ferrous state. Ascorbic acid may serve to reduce ferric to ferrous iron. Hydrochloric acid may increase the solubility of ingested iron. Certain amino acids enhance absorption of iron. Phytates, phosphate and oxalate may reduce iron absorption. The control of iron absorption largely occurs at the levels of the
34mg/day
HEMOCHROMATOSIS
200mg
21mg/day
RBC
2700mg
~\~ PRIMARY mucosal cell. DietDEFECT HERE? STORA'GE
LiGIIJAC
20,000mg Fe f erriti n
hemosiderin RBC=red blood cells
GI =gastrointestinal
Figure 2.-A, Iron pools and turnover in normal man; B, Iron pools and turnover in hemochromatosis.
mucosal cell. Dietary iron is absorbed in two forms which have independent absorptive mechanisms. The major form is free iron in its ferrous state, but iron is also absorbed while still complexed in heme. Heme is absorbed intact with its iron later released in the mucosal cell catalyzed by the enzyme heme oxidase. There may be some intracellular carrier protein which mediates rapid transport, but its identity has not been established. Transferrin is not necessary for iron absorption, since excess rather than deficient absorption occurs in the rare patients in whom this transport protein is congenitally absent. Apoferritin has been a major candidate for the presumed intracellular signal which controls the rate of absorption of iron by mucosal cells. When iron is deficient, it is postulated that there is reduced synthesis of apoferritin and enhanced absorption of iron in its ferrous state. When iron is normal or increased there is increased synthesis of apoferritin which traps the iron within the mucosal cell, to be later shed in the normal mucosal cell cycle. Unfortunately cellular levels of ferritin or apoferritin have not always correlated with iron THE WESTERN JOURNAL OF MEDICINE
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HEMOCHROMATOSIS +9)
=+F+Lf
FeFe
LIVER
+=FeFe-
TRANSFERRIN|Fr
L
-
-
f
3~ e
Hemosiderin | Frritin
-u7Fe++
RE System
Bone marrow
RE = reticuloendothelial
Figure 3.-Control of iron absorption. Feedback control is exerted from the level of iron stores and from the rate of erythropoiesis. 50- --
O
-
0
o
co -0
-4 '
~~~~~~~~Symptomatic
idiopathic Figure 4.-Regulation of intesti Noa hemochromatosis te 25s Oc Z
10-
Reultio ocusinbtNormal
prosadia
20 2.5 0.5 LIVER IRON CONTENT (g Fe/liver)
_
Figure 4.-Regulation of intestinal iron absorption. Regulation occurs in both normal persons and in patients with hemochromatosis, but the latter require much larger iron stores.
absorption. Other carrier proteins for the transport of iron across the mucosal cell have been reported. The chemistry of the transport process is still unclear. How is iron absorption regulated to insure normal balance (Figure 3)? Two factors at least influence the rate at which the gut absorbs dietary iron: the level of iron stores and the rate of erythropoiesis. These are independent variables. For example, absorption of iron may continue in the face of excess iron stores if there is rapid erythropoiesis. We do not know how these variables create a signal to the mucosal cell to modulate absorption. We do not know whether the primary detection mechanism is in the mucosal cell itself or elsewhere in the body with a secondary signal (chemical ?) transmitted to the gut as the effector organ. Finally, as noted above, we do not know the biochemical response that is elicited in the cell which appropriately regulates the rate of absorption. Since hemochromatosis is probably an inherited disorder of rate control of iron absorption, it seems unlikely that its pathogenesis will be fully elucidated until normal
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FEBRUARY 1978 * 128 * 2
signal-response servomechanisms are better understood. Hemochromatosis represents continued inappropriate iron absorption, a loss of rate control.2'8 The rate of absorption may finally return to normal, but only when storage iron has been increased to injurious levels (Figure 4). The site and the mechanism of this breakdown in rate control are not known. Could there be an intrinsic defect in the mucosal cell or a defective signal from an extramucosal receptor? Hemochromatosis has been reported to show different isozyme patterns for ferritin as a possible mechanism for enhanced iron absorption.4 The significance of these observations is not yet apparent. As noted, iron absorption may be normal (1 mg per day) in the face of severe hemochromatosis. When iron stores are reduced by repeated phlebotomies, however, iron absorption rises again to pathological levels even though overload still exists. In other words the control mechanisms are still intact, but they are insensitive. Much higher levels of storage iron are required to diminish its dietary absorption. In hemochromatosis, the internal economy of iron-that is, its utilization for red cell production and for the synthesis of heme-containing enzymes-is perfectly normal (Figure 2B). More iron circulates in that transferrin is more nearly saturated. The continued absorption of 3 mg, rather than 1 mg, floods the pool since there is no mechanism for increasing excretion. Storage iron may reach 20 to 40 grams, compared with a normal level of 1 gram. A pathological increase in storage iron is deposited to a disproportionate degree in hemosiderin as compared with ferritin. Idiopathic hemochromatosis has been considered to be a genetic disease for more than 50 years, although the mechanism of transmission has been debated. Approximately 25 to 50 percent of first degree relatives of patients with hemochromatosis have been found to have some evidence of enhanced iron absorption or of iron overload. Of particular interest is the new information concerning the linkage of hemochromatosis with certain histocompatability loci (HLA).'5 In one study HLA-A3 occurred in 78.4 percent of patients with hemochromatosis (controls, 27.0 percent) and HLA-B14 occurred in 25.5 percent of patients (controls, 3.4 percent). Other studies have confirmed these observations, which tend to confirm the genetic origin of disease and even suggest that the abnormal gene or genes may be
HEMOCHROMATOSIS
on chromosome 6. New evidence has been obtained that idiopathic hemochromatosis is transmitted as an autosomal dominant disorder, using hepatic stainable iron as the most sensitive marker for the presence of the disease.6 Since the abnormal gene product is not known, it is necessary to use more remote indices, such as the accumulation of iron, for example. The expression of genetic hemochromatosis is notably influenced by age, since time is required for the accumulation of iron, and by sex because of the physiological phlebotomy of menstruation. Alcohol may also influence the expression of the disease by injury to the iron loaded liver and possibly by further enhancing iron absorption. Finally, we must keep in mind that there may be many different subtypes of hemochromatosis, comparable to abnormal hemoglobins, with heterogeneity in severity and type of phenotypic expression. Hemochromatosis is a rare disorder, accounting for approximately one of every 7,000 hospital deaths. In its clinical expression it is largely a disease of men (90 percent) because of the normal iron loss in women due to menstruation and pregnancy. In fact, according to current evidence, the genetic defect as opposed to the clinical disorder should be equally as frequent in men and women. Clinical hemochromatosis usually appears late, age 40 to 50, despite the fact that it is a genetic disorder. We assume that the genetic defect itself is not directly injurious. It only alters the ability of the host to cope with dietary iron. Iron overload is a secondary phenomenon which requires many years for its manifestation. When clinically manifest, hemochromatosis may present with signs or symptoms relating to involvement of the skin, liver, pancreas, heart, endocrine system and joints. Our patient had primarily endocrine and articular symptoms, and we shall begin by discussing these. Increased pigmentation of the skin occurs very frequently in hemochromatosis. This so-called bronzing (actually more slate gray coloring) represents a combination of melanin and iron deposition. Why are the melanocytes stimulated by iron overload? I do not know, and have not seen studies -concerning levels of melanocyte stimulating hormone. Diabetes mellitus will be discussed later. Injury to the anterior lobe of the pituitary gland is perhaps the most frequent endocrine abnormality in hemochromatosis,6 other than its complex relationship with diabetes mellitus. The deposition of hemo-
siderin in the pituitary results in cell necrosis and fibrosis with no return of function following iron removal. The first clinical manifestation of the pituitary injury is usually of hypogonadism-impotence in the male or menstrual disorders in the female. Laboratory studies show reduced levels of gonadotropins with little or no response to clomiphene or LH releasing factor. The case discussed here illustrates that complication. The secretion of growth hormone may also be reduced. Panhypopituitarism is much rarer. A few cases of hypoparathyroidism and one case of selective hypoaldosteronism have been described and attributed to iron injury. The arthropathy of hemochromatosis was described comparatively recently (1964) 78 despite the fact that it occurs in fully 50 percent of patients with hemochromatosis. It may be the first manifestation of the disease, and as noted it occurred early in the course of our patient. Chondrocalcinosis shown by radiologic studies occurs in approximately 50 percent of cases and hemosiderin is deposited in synovial lining cells and in cartilage. The clinical features are rather nonspecific, which accounts for the usual delay in diagnosis. Pseudogout may occur with calcium pyrophosphate dihydrate crystals associated with chondrocalcinosis. More commonly there is chronic arthritis of the metacarpophalangeal and proximal interphalangeal joints which may superficially resemble rheumatoid arthritis. Some patients have more generalized arthralgias and even polyarthritis. There are interesting and highly suggestive radiographic findings in hemochromatotic arthritis. I have asked Dr. Harry Genant from the Radiology Department, who has been very interested in this topic, to show the x-ray films in this case and to comment at greater length about the radiographic findings in patients with the arthropathy of hemochromatosis. DR. GENANT: * Arthropathy, as has been indicated, will affect approximately 50 percent of patients with hemochromatosis and will result in an interesting radiographic appearance. In most cases these features are indistinguishable from idiopathic pseudogout or calcium pyrophosphate dihydrate (CPPD) crystal deposition disease. There are, however, some features that occasionally will distinguish the secondary hemochromatotic arthropathy from primary pseudogout. I shall first discuss the radiographic appearance *Harry Genant, MD, Radiology Department, University of California, San Francisco.
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HEMOCHROMATOSIS
in the patient presented, and subsequently shall discuss several cases with more advanced disease. The radiographs in this patient are of interest only with respect to the hands. The findings consist of mild periarticular soft tissue swelling involving the proximal interphalangeal and metacarpophalangeal articulations. Mild generalized osteopenia is evidenced by slight thinning of the cortices, particularly in the metacarpals. In addition, a degenerative-like arthropathy with bone proliferation at the metacarpophalangeal and proximal interphalangeal articulations can be seen. These changes are rather subtle and are not those of advanced arthropathy. A close-up view demonstrates slight bone proliferation or overgrowth at several sites and subtle, but definite, cystic changes. This type of involvement of the MCP joints is fairly characteristic of hemo-chromatosis, although this is early disease. A close-up view of the wrist shows cartilage narrowing associated with the subchondral cyst formation which is fairly characteristic. We do not see
the pattern of chondrocalcinosis, or articular calcification, which occurs in about 50 percent of patients with hemochromatosis and arthropathy. I would like to go on to show more advanced changes in several other cases. In Figure 5 we can see generalized osteopenia that is more severe than in the previous case; the cortices are quite thin. We can see that the metacarpophalangeal articulations are quite abnormal. There is cartilage loss, cyst formation in the metacarpal heads and bone overgrowth. At the wrist we can see articular calcification which represents CPPD crystal deposition in the triangular cartilage which is the usual location. Additionally, we can see mild sclerosis and cartilage loss. A close-up view of
Figure 6.-Close view of the metacarpophalangeal joints showing joint narrowing subchondral collapse and striking proliferation of bone, producing a "squared off" appearance.
Figure 5.-Roentgenogram of the hand of patient with hemochromatosis. Diffuse osteopenia and calcification of the articular disk of the wrist, associated with arthropathy of the radiocarpal joint.
138
FEBRUARY 1978 * 128 * 2
Figure 7. Distinct linear and punctate calcification of the fibrocartilage of the lateral meniscus is clearly shown in this magnified view. An associated marginal osteophyte is visible.
HEMOCHROMATOSIS
the metacarpal heads (Figure 6) shows this fairly characteristic squaring off and teardrop formation. This is probably the most characteristic feature of the hemochromatotic arthropathy. Small cysts can be seen as well. In idiopathic pseudogout, patients generally present with symptoms in the knees, whereas in hemochromatosis it is more likely that patients will present with symptoms in the hands. In any
Figure 8.-Anteroposterior roentgenogram of the left knee showing calcification of the medial and lateral menisci, and advanced degenerative changes with marginal osteophytosis, subchondral sclerosis and joint narrowing.
.
event, the knees will generally be involved at some point, and what we will see is chondrocalcinosis, fine linear and punctate calcifications, in the fibrocartilage of the meniscus and also in the hyaline cartilage which parallels the articular surfaces (Figure 7). Additionally, we may see arthropathy in the knee-that is, degenerativelike arthropathy consisting of osteophyte formation and subchondral sclerosis (Figure 8). The hips are involved less frequently than the knees and the hands, but may show evidence of articular calcification and also the symphysis may show this dense calcification (Figure 9). Finally, the spine may be involved in hemochromatosis, although it generally does not produce symptoms. We may see fine linear calcifications in the outer fibers of the annulus fibrosis (Figure 10). This again is CPPD crystal deposition, and this appearance simulates syndesmophytosis encountered in ankylosing spondylitis. In summary, the arthropathy of hemochromatosis is quite similar to that of primary pseudogout, and is characterized by articular degeneration and chondrocalcinosis.
F-~~~~~~~~~~~~~w
Figure 9.-Striking articular and extra-articular calcification involving the symphysis pubis, hyaline cartilage and labrum of the hip, and the adductor insertions at the ischium.
Figure 10.-Subtle
can be seen in the
calcification of the annulus fibrosus
anteroposterior projection.
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HEMOCHROMATOSIS
DR. SMITH: Thank you, Dr. Genant. Unfortunately, as in the case of endocrine disturbances, the arthritis of hemochromatosis is not improved by removal of iron. The liver is the major site for iron storage in health. It also receives a disproportionate amount of the iron overload of hemochromatosis.9 Injury to the liver is frequent and often severe. In the case discussed today this particular complication was not seen. Our discussion of iron metabolism and liver disease will therefore be brief. Characteristically there is slow, chronic progression of liver injury with resulting fibrosis. In comparison with alcoholic cirrhosis, portal hypertension and ascites are less frequent. Hepatoma on the other hand has been reported as occurring in as many as 24 percent of patients with hemochromatosis in whom cirrhosis develops. Liver function may respond to a remarkable degree to iron depletion. Many investigators, particularly in France and in the United States, have noted a strong association between alcohol abuse and the cirrhosis of hemochromatosis. The interplay between alcohol and iron in the genesis of liver disease is still unclear and controversial. There is some evidence that alcohol increases iron absorption and therefore may be additive to the gut defect of hemochromatosis. Possibly iron increases the susceptibility of the liver to injury by alcohol. On the other hand, severe hemochromatotic liver disease has developed in many patients in the absence of any ingestion of alcohol or other known hepatotoxin. One must conclude that iron overload alone is sufficient to produce cirrhosis. The heart may be involved in hemochromatosis both histologically and clinically.'0 Heart disease has been reported as the cause of death in as many as 30 percent of cases in the older series, but this may no longer be true with more intensive treatment. Deposition of hemosiderin in the heart results in necrosis and fibrosis as in other tissues. There is a greater tendency for ventricular rather than atrial involvement, and for myocardial rather than conducting tissue involvement. The clinical picture may resemble that of a diffuse cardiomyopathy with a large dilated heart. Occasionally there is "restrictive" cardiomyopathy resembling constrictive pericarditis. More rarely tachyarrhythmias and heart block have been described. The iron heart is not a i strong heart, but a weak one. Diabetes mellitus is one of the cardinal manifestations of hemochromatosis. The association
140
FEBRUARY 1978 * 128 * 2
is a confusing one, however. Our patient did not have diabetes, so our summary today about this association will be brief and somewhat didactic. Clinical diabetes occurs in the majority of patients with hemochromatosis (65 to 80 percent), but there are some hemochromatotic families without diabetes. Diabetic complications may be frequent with microaneurysms, nephropathy and neuropathy. In studies carried out by Dr. Marvin H. Siperstein, seven of seven patients with hemochromatosis and diabetes had thickening of the capillary basement membrane. An additional patient who did not have diabetes had normal membrane thickness. Some studies have found a high incidence of diabetes mellitus in the relatives of patients who exhibit diabetes in association with their hemochromatosis. As an example, Domack and associates'" studied the families of patients with hemochromatosis and diabetes and found that 25 percent had diabetes mellitus. In the families of patients with hemochromatosis without diabetes, only 4 percent of the relatives had diabetes. The pathogenesis of carbohydrate intolerance in hemochromatosis is therefore complex.12 It may represent several things: the carbohydrate intolerance of cirrhosis itself, injury to the pancreatic islets by iron deposition with resultant insulin deficiency, and a genetic cross linkage with diabetes mellitus. Until better markers are found for both diabetes mellitus and for hemochromatosis, their interrelationship will remain obscure. How can one establish the diagnosis of hemochromatosis? First, the diagnosis should be entertained during the earlier clinical manifestations, as was true in the case discussed today. In addition, family studies should be carried out to detect patients before irreversible injury occurs. All of the laboratory aids for diagnosis are directed toward documenting iron overload. These tests differ in their respective sensitivities. The most sensitive test is directly showing increased hepatic parenchymal iron by liver biopsy, with an increase of stainable iron or an increase on direct chemical analysis.'3 Obviously such a study is rarely done unless one finds other evidence of iron overload, particularly in the serum. In hemochromatosis, serum iron is usually greater than 170 ,ug per dl and the saturation of transferrin greater than 50 percent. An indirect index of iron overload can be obtained by measuring its urinary excretion after the administration of a standard dose of chelator desferrioxamine
HEMOCHROMATOSIS 47yr male 50
HEMATOCRIT
40-
-"*N 30O
30J 300-
i20
SERUM IRON
200
149%
100
i
g Fe REMOVED
-10
0 100
300
500 DAYS
700
900
Figure 11.-Response to weekly phlebotomy therapy in hemochromatosis. The shaded area depicts the cumulative iron removed in grams. Note that two years were required to deplete the pathologically elevated iron stores.
(patients with hemochromatosis excrete more than 2.2 mg of iron in the subsequent 24 hours). Serum ferritin may be increased in hemochromatosis, but newer studies show that this does not occur early enough to be a sensitive aid in diagnosis. In summary, increased saturation of plasma transferrin and the direct demonstration of increased hepatic iron by biopsy are the most sensitive indices of the iron overload of hemochromatosis. How does one treat a patient with hemochromatosis? Fortunately treatment is usually simple and satisfactory. One phlebotomy of 500 ml of blood removes approximately 250 mg of iron. Phlebotomy is repeated once or sometimes even twice a week until the iron stores are depleted, which may require one or two years (Figure 11 ). Maintenance phlebotomy is then required to balance continued excessive iron absorption. Since this is a genetic disease it is imperative to study patients' relatives in order to find early cases. Iron depletion by phlebotomy clearly prolongs survival.'4 Hemochromatotic liver disease, heart disease and possibly diabetes are improved; endocrine deficiencies and arthritis usually are not. What are the causes of death in those who do die with hemochromatosis? Hepatoma is relatively frequent and unfortunately patients who have hemochromatotic cirrhosis continue to be at risk for hepatoma despite the removal of iron. Recent studies indicate a puzzlingly high association of other neoplasias with hemochromatosis. The reason for this association of iron overload and neoplasia is not clear. Deaths also con-
TABLE 1.-Unanswered Questions in Hemochromatosis * Is the gut mucosal abnormality that enhances Fe absorption primary or secondary to an abnormal signal? * What is the genetic transmission of the defect or group of defects? * What is the role of alcohol in the expression of hemochromatosis? * What is the relationship of the glucose intolerance of hemochromatosis to diabetes mellitus? * What is the mechanism by which storage iron injures tissue?
tinue to occur from hepatic failure, variceal bleeding and the vascular complications of diabetes, but such deaths are much fewer in treated as compared with untreated patients. In summary, hemochromatosis is a rare genetic disease of the rate control of iron absorption. There are still many unanswered questions concerning it (Table 1). The excessive iron absorption can be suppressed, but only at the cost of a massive overload of iron sufficient to cause tissue injury. Fortunately, if the disease is diagnosed early, as it was in our patient today, it can be adequately treated by phelebotomy and endocrine replacement therapy. A final elucidation of the pathogenesis of hemochromatosis will require new data concerning the mechanisms by which the absorption of iron is normally controlled. REFERENCES 1. Forth W, Rummel W: Iron absorption. Physiol Rev 53:724792, Jul 1973 2. Pollycove M: Hemochromatosis, In Stanbury JB, Wyngaarden JB, Fredrickson DS (Eds): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill Co, 1978 (in press) 3. Sherlock S: Hemochromatosis: Course and treatment. Ann Rev Med 27:143-149, 1976 4. Powell LW, Alpert E, Isselbacher KJ, et al: Abnormality in tissue isoferritin distribution in idiopathic hemochromatosis. Nature 250:333-335, Jul 1974 5. Simon M: Heredity of idiopathic hemochromatosis: A study of 106 families. Clin Genetics 11:327, May 1977 6. Walsh CH, Wright AD, Williams JW, et al: A study of pituitary function in patients with idiopathic hemochromatosis. J Clin Endocrinol Metab 43:866-872, Oct 1976 7. Schumacher HR Jr: Hemochromatosis and arthritis. Arthritis Rheum 7:41-50, Feb 1964 8. Hirsch JH, Killien FC, Troupin RH: The arthropathy of hemochromatosis. Radiology 118:591-596, Mar 1976 9. Grace ND, Powell LW: Iron storage disorders of the liver. Gastroenterology 67:1257-1283, Dec 1974 10. Buja LM, Roberts WC: Iron in the heart-Etiology and clinical significance. Am J Med 51:209-221, Aug 1971 11. Dymock IW, Cassar J, Pyke DA, et al: Observations on the pathogenesis, complications and treatment of diabetes in 115 cases of haemochromatosis. Am J Med 52:203-210, Feb 1972 12. Stocks AE, Powell LW: Carbohydrate intolerance in idiopathic hemochromatosis and cirrhosis of the liver. Quart J Med 42:733-749, Oct 1973 13. Edwards CQ, Carroll M, Bray P, et al: Hereditary hemochromatosis: Diagnosis in siblings and children. N Engl J Med 297:7-13, Jul 7, 1977
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Medical StaJf Conference
Hemochromatosis These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs. David W. Martin, Jr., Associate Professor of Medicine, and Robert C. Siegel, Associate Professor of Medicine and Orthopaedic Surgery, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, CA 94143.
DR. SMITH: * The topic for discussion at Medical Grand Rounds today will be that of hemochromatosis. The case summary will be given by Dr. Guy Weinberg. DR. WEINBERG:t The patient is a 43-year-old white man who presented in the fall of last year to the Metabolic Clinic with the chief complaint of impotence. Five years ago the patient noted the onset of difficulty of achieving and maintaining an erection, as well as a reduced sex drive. Two years ago his symptoms had continued and his private physician prescribed hormone pills which increased the sex drive, but caused no change in the performance. A year ago the patient noted the onset of pain and stiffness with slight enlargement in all of his proximal interphalangeal joints, as well as the second and third metacarpophalangeal (MCP) joints. There was no heat or redness. The patient was treated at that time with prednisone, the presumptive diagnosis being rheumatoid arthritis. *Lloyd H. of Medicine.
Smith, Jr., MD,
Professor and Chairman, Department
tGuy Weinberg, MD, Medical Resident.
At the time of presentation the patient was completely impotent and had no libido. The rest of the history was noncontributory. Family history indicated that one brother and two sisters had arthritis. On physical examination a II/VI systolic ejection murmur was heard. The patient's testicles were soft and small and there was a female escutcheon and reduced axillary hair. His second and third metacarpophalangeal joints were enlarged but not tender. The initial laboratory studies gave normal findings except for a slightly elevated level of serum glutamic oxaloacetic transaminase (SGOT), a positive rheumatoid factor of 1:320, a serum testosterone value of 101 ng per dl (normal 300 to 1,200), a low serum luteinizing hormone (LH) level of 3 mIU per ml (normal 5 to 25) and a serum iron value of 233 ,Lg per dl (total iron binding capacity, 240 yg per dl). The patient was admitted for evaluation to the Metabolic Service. Results of a liver biopsy showed 4 + iron on a touch preparation and pronounced iron deposition in the parenchyma with focal periportal fibrous tissue. Findings on x-ray films of the hands will be described subseTHE WESTERN JOURNAL OF MEDICINE
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HEMOCHROMATOSIS ABBREVIATIONS USED IN TEXT ACTH = adrenocorticotropic hormone CPPD = calcium pyrophosphate dihydrate FSH = follicle-stimulating hormone LH = luteinizing hormone MCP = metacarpophalangeal SGOT= serum glutamic oxaloacetic transaminase TSH = thyroid-stimulating hormone
quently. Prolactin, thyroid-stimulating hormone (TSH) and cortisol levels were normal. During insulin induced hypoglycemia there were normal responses of hydrocortisone, growth hormone, adrenocorticotropic hormone (ACTH), but a flat curve for both LH and follicle-stimulating hormone (FSH). The patient has been treated by weekly phlebotomy of 500 ml for the past four months. The hematocrit reading has remained stable, but the iron/total iron-binding capacity saturation is now about 85 percent. The patient receives testosterone once or twice a month and has noted a pronounced increase in sexual interest and performance. We have been able to measure iron/total iron-binding capacity in only one sister. Her saturation of iron-binding capacity was about 65 percent. DR. SMITH: Thank you, Dr. Weinberg. The diagnosis of hemochromatosis is obvious as presented now; it certainly was not so at the time the patient was first seen. Dr. Guy Weinberg is to be congratulated in making this diagnosis at a comparatively early stage. In summary, this patient had two main symptoms. The first of these, and the most important from his standpoint, was impotence of five years' duration. The second was an ill-defined type of arthritis diagnosed as rheu-matoid arthritis. He had noted some slight darkening of the skin, but again this was more evident in retrospect. When the diagnosis was suspected, appropriate studies were carried out which clearly showed iron overload by a number of techniques, both direct and indirect. Further studies showed that the areas of injury due to iron overload were confined largely to the endocrine system with pituitary-gonadal insufficiency and to a lesser degree to certain joints. Notably, there was no "bronze diabetes" and no cirrhosis. Fortunately the diagnosis was considered very early despite the atypical presentation of the disease. Appropriate treatment has been instituted and the outcome should be very favorable. 134
FEBRUARY 1978
*
128
*
2
Most endocrine and metabolic diseases are disorders of "too much" or "too little." Hemochromatosis is a unique genetic disorder, or possibly a group of disorders, marked by an inappropriate avidity for the absorption of iron. In the normal adult there is approximately 3 to 4 grams of iron. In hemochromatosis this may be increased ten times. The absorption of approximately 1 mg of iron per day maintains normal health. The absorption of only 3 mg per day leads to hemochromatosis. The extra ingredient is time, measured not in days, weeks or months, but in years. It is this phenomenon of continued excessive absorption of a metal with which we shall be concerned during this presentation. There are certain key questions which we would like to be able to answer in a discussion of hemochromatosis: (1) What is the genetic transmission of this disorder, or possibly group of disorders? (2) What is the basic cellular or molecular defect which leads to this continued inappropriate absorption of iron? (3) How does excess iron storage injure tissue? (4) What kinds of disorders result from this tissue injury? (5) When should we suspect the diagnosis and how can it be established? (6) How can this disease be treated and what is the prognosis? Obviously there are many subsidiary questions which flow from those listed, but these are quite sufficient to befuddle us in the time available for discussion today. To understand the abnormalities in iron metabolism in hemochromatosis, we must know something of its normal metabolism. Approximately two thirds of iron is functional. Most of this is in erythrocyte heme, but it is also a constituent of certain enzymes such as catalase, peroxidase and the cytochromes. Another third of iron is in storage form. The major storage form is ferritin, a specialized spherical protein made up of 24 subunits (Figure 1). The apoprotein of ferritin weighs approximately 460,000 daltons. This protein, which may contain up to 23 percent elemental iron in its ferric form, exists as several isoferritins. Another storage form is hemosiderin which probably represents aggregates of partially degraded ferritin, often in an intralysosomal location which is seen as "stainable iron." Approximately 25 to 30 mg of iron per day must be transported through the plasma for the renewal of blood. Transferrin is a specific beta globulin, synthesized largely in the liver for the transport of iron. It carries two ferric ions per molecule
HEMOCHROMATOSIS IRON TURNOVER
Protein subunits 0 0 0 MW= 18,000 Q 0 Q
k
*
*
Apoferritin ~j-4tMW= 460,000
~~0COOH Fe M
MARROW 100mg
RBC
21mg/day
2700mg
~~Fe Fe ~~~~~A
Hemosiderin MW= 106 MW = molecular weight
| AROW|PLASMA
2
2
4mg
T~~AP$
Transferrin Ferritin-Fe (4500 molecules)
MW= 90,000
ATP = adenosine triphosphate
Figure 1.-Iron-binding proteins. Transferrin contains only two molecules of iron, but ferritin may contain up to 4,500 molecules of iron per molecule.
STORAGE 1000mg
GITRACT
Total entering & leaving plasma =
(M
MARROW
on specific binding sites for use in heme synthesis or deposition into a storage form. The 4 mg of iron that circulates saturates about a third of the binding capacity of transferrin (Figure 2A). Trace amounts of ferritin (mostly apoferritin) also circulate, but are not important in iron metabolism. Although 30 mg of iron passes through plasma daily, only 1 mg need be absorbed from dietary sources to maintain balance. The total control of iron metabolism lies in its selective absorption.' This is obviously very anomalous and precarious. There is no physiological mechanism for the control of excretion, such as exists for calcium, sodium or potassium. Normal iron balance is totally dependent upon the adjustment of absorption from the gut. Approximately 15 mg of iron is ingested daily, and about 1 mg of this is absorbed. This is balanced by the 1 mg net loss in man, primarily through the shedding of epithelial cells in the gut and to a much lesser degree from the skin, and possibly through very minor loss of blood in the normal intestine. In women the average daily loss exceeds 1 mg during the normal reproductive period and may average 1.5 to 2 mg because of menstruation. An additional 0.5 grams of iron is lost during pregnancy. This is balanced by slightly higher gut absorption of iron in women. There are a number of variables in absorption, only some of which are now understood. Some intraluminal factors are of importance. Iron is absorbed primarily in its ferrous state. Ascorbic acid may serve to reduce ferric to ferrous iron. Hydrochloric acid may increase the solubility of ingested iron. Certain amino acids enhance absorption of iron. Phytates, phosphate and oxalate may reduce iron absorption. The control of iron absorption largely occurs at the levels of the
34mg/day
HEMOCHROMATOSIS
200mg
21mg/day
RBC
2700mg
~\~ PRIMARY mucosal cell. DietDEFECT HERE? STORA'GE
LiGIIJAC
20,000mg Fe f erriti n
hemosiderin RBC=red blood cells
GI =gastrointestinal
Figure 2.-A, Iron pools and turnover in normal man; B, Iron pools and turnover in hemochromatosis.
mucosal cell. Dietary iron is absorbed in two forms which have independent absorptive mechanisms. The major form is free iron in its ferrous state, but iron is also absorbed while still complexed in heme. Heme is absorbed intact with its iron later released in the mucosal cell catalyzed by the enzyme heme oxidase. There may be some intracellular carrier protein which mediates rapid transport, but its identity has not been established. Transferrin is not necessary for iron absorption, since excess rather than deficient absorption occurs in the rare patients in whom this transport protein is congenitally absent. Apoferritin has been a major candidate for the presumed intracellular signal which controls the rate of absorption of iron by mucosal cells. When iron is deficient, it is postulated that there is reduced synthesis of apoferritin and enhanced absorption of iron in its ferrous state. When iron is normal or increased there is increased synthesis of apoferritin which traps the iron within the mucosal cell, to be later shed in the normal mucosal cell cycle. Unfortunately cellular levels of ferritin or apoferritin have not always correlated with iron THE WESTERN JOURNAL OF MEDICINE
135
HEMOCHROMATOSIS +9)
=+F+Lf
FeFe
LIVER
+=FeFe-
TRANSFERRIN|Fr
L
-
-
f
3~ e
Hemosiderin | Frritin
-u7Fe++
RE System
Bone marrow
RE = reticuloendothelial
Figure 3.-Control of iron absorption. Feedback control is exerted from the level of iron stores and from the rate of erythropoiesis. 50- --
O
-
0
o
co -0
-4 '
~~~~~~~~Symptomatic
idiopathic Figure 4.-Regulation of intesti Noa hemochromatosis te 25s Oc Z
10-
Reultio ocusinbtNormal
prosadia
20 2.5 0.5 LIVER IRON CONTENT (g Fe/liver)
_
Figure 4.-Regulation of intestinal iron absorption. Regulation occurs in both normal persons and in patients with hemochromatosis, but the latter require much larger iron stores.
absorption. Other carrier proteins for the transport of iron across the mucosal cell have been reported. The chemistry of the transport process is still unclear. How is iron absorption regulated to insure normal balance (Figure 3)? Two factors at least influence the rate at which the gut absorbs dietary iron: the level of iron stores and the rate of erythropoiesis. These are independent variables. For example, absorption of iron may continue in the face of excess iron stores if there is rapid erythropoiesis. We do not know how these variables create a signal to the mucosal cell to modulate absorption. We do not know whether the primary detection mechanism is in the mucosal cell itself or elsewhere in the body with a secondary signal (chemical ?) transmitted to the gut as the effector organ. Finally, as noted above, we do not know the biochemical response that is elicited in the cell which appropriately regulates the rate of absorption. Since hemochromatosis is probably an inherited disorder of rate control of iron absorption, it seems unlikely that its pathogenesis will be fully elucidated until normal
136
FEBRUARY 1978 * 128 * 2
signal-response servomechanisms are better understood. Hemochromatosis represents continued inappropriate iron absorption, a loss of rate control.2'8 The rate of absorption may finally return to normal, but only when storage iron has been increased to injurious levels (Figure 4). The site and the mechanism of this breakdown in rate control are not known. Could there be an intrinsic defect in the mucosal cell or a defective signal from an extramucosal receptor? Hemochromatosis has been reported to show different isozyme patterns for ferritin as a possible mechanism for enhanced iron absorption.4 The significance of these observations is not yet apparent. As noted, iron absorption may be normal (1 mg per day) in the face of severe hemochromatosis. When iron stores are reduced by repeated phlebotomies, however, iron absorption rises again to pathological levels even though overload still exists. In other words the control mechanisms are still intact, but they are insensitive. Much higher levels of storage iron are required to diminish its dietary absorption. In hemochromatosis, the internal economy of iron-that is, its utilization for red cell production and for the synthesis of heme-containing enzymes-is perfectly normal (Figure 2B). More iron circulates in that transferrin is more nearly saturated. The continued absorption of 3 mg, rather than 1 mg, floods the pool since there is no mechanism for increasing excretion. Storage iron may reach 20 to 40 grams, compared with a normal level of 1 gram. A pathological increase in storage iron is deposited to a disproportionate degree in hemosiderin as compared with ferritin. Idiopathic hemochromatosis has been considered to be a genetic disease for more than 50 years, although the mechanism of transmission has been debated. Approximately 25 to 50 percent of first degree relatives of patients with hemochromatosis have been found to have some evidence of enhanced iron absorption or of iron overload. Of particular interest is the new information concerning the linkage of hemochromatosis with certain histocompatability loci (HLA).'5 In one study HLA-A3 occurred in 78.4 percent of patients with hemochromatosis (controls, 27.0 percent) and HLA-B14 occurred in 25.5 percent of patients (controls, 3.4 percent). Other studies have confirmed these observations, which tend to confirm the genetic origin of disease and even suggest that the abnormal gene or genes may be
HEMOCHROMATOSIS
on chromosome 6. New evidence has been obtained that idiopathic hemochromatosis is transmitted as an autosomal dominant disorder, using hepatic stainable iron as the most sensitive marker for the presence of the disease.6 Since the abnormal gene product is not known, it is necessary to use more remote indices, such as the accumulation of iron, for example. The expression of genetic hemochromatosis is notably influenced by age, since time is required for the accumulation of iron, and by sex because of the physiological phlebotomy of menstruation. Alcohol may also influence the expression of the disease by injury to the iron loaded liver and possibly by further enhancing iron absorption. Finally, we must keep in mind that there may be many different subtypes of hemochromatosis, comparable to abnormal hemoglobins, with heterogeneity in severity and type of phenotypic expression. Hemochromatosis is a rare disorder, accounting for approximately one of every 7,000 hospital deaths. In its clinical expression it is largely a disease of men (90 percent) because of the normal iron loss in women due to menstruation and pregnancy. In fact, according to current evidence, the genetic defect as opposed to the clinical disorder should be equally as frequent in men and women. Clinical hemochromatosis usually appears late, age 40 to 50, despite the fact that it is a genetic disorder. We assume that the genetic defect itself is not directly injurious. It only alters the ability of the host to cope with dietary iron. Iron overload is a secondary phenomenon which requires many years for its manifestation. When clinically manifest, hemochromatosis may present with signs or symptoms relating to involvement of the skin, liver, pancreas, heart, endocrine system and joints. Our patient had primarily endocrine and articular symptoms, and we shall begin by discussing these. Increased pigmentation of the skin occurs very frequently in hemochromatosis. This so-called bronzing (actually more slate gray coloring) represents a combination of melanin and iron deposition. Why are the melanocytes stimulated by iron overload? I do not know, and have not seen studies -concerning levels of melanocyte stimulating hormone. Diabetes mellitus will be discussed later. Injury to the anterior lobe of the pituitary gland is perhaps the most frequent endocrine abnormality in hemochromatosis,6 other than its complex relationship with diabetes mellitus. The deposition of hemo-
siderin in the pituitary results in cell necrosis and fibrosis with no return of function following iron removal. The first clinical manifestation of the pituitary injury is usually of hypogonadism-impotence in the male or menstrual disorders in the female. Laboratory studies show reduced levels of gonadotropins with little or no response to clomiphene or LH releasing factor. The case discussed here illustrates that complication. The secretion of growth hormone may also be reduced. Panhypopituitarism is much rarer. A few cases of hypoparathyroidism and one case of selective hypoaldosteronism have been described and attributed to iron injury. The arthropathy of hemochromatosis was described comparatively recently (1964) 78 despite the fact that it occurs in fully 50 percent of patients with hemochromatosis. It may be the first manifestation of the disease, and as noted it occurred early in the course of our patient. Chondrocalcinosis shown by radiologic studies occurs in approximately 50 percent of cases and hemosiderin is deposited in synovial lining cells and in cartilage. The clinical features are rather nonspecific, which accounts for the usual delay in diagnosis. Pseudogout may occur with calcium pyrophosphate dihydrate crystals associated with chondrocalcinosis. More commonly there is chronic arthritis of the metacarpophalangeal and proximal interphalangeal joints which may superficially resemble rheumatoid arthritis. Some patients have more generalized arthralgias and even polyarthritis. There are interesting and highly suggestive radiographic findings in hemochromatotic arthritis. I have asked Dr. Harry Genant from the Radiology Department, who has been very interested in this topic, to show the x-ray films in this case and to comment at greater length about the radiographic findings in patients with the arthropathy of hemochromatosis. DR. GENANT: * Arthropathy, as has been indicated, will affect approximately 50 percent of patients with hemochromatosis and will result in an interesting radiographic appearance. In most cases these features are indistinguishable from idiopathic pseudogout or calcium pyrophosphate dihydrate (CPPD) crystal deposition disease. There are, however, some features that occasionally will distinguish the secondary hemochromatotic arthropathy from primary pseudogout. I shall first discuss the radiographic appearance *Harry Genant, MD, Radiology Department, University of California, San Francisco.
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HEMOCHROMATOSIS
in the patient presented, and subsequently shall discuss several cases with more advanced disease. The radiographs in this patient are of interest only with respect to the hands. The findings consist of mild periarticular soft tissue swelling involving the proximal interphalangeal and metacarpophalangeal articulations. Mild generalized osteopenia is evidenced by slight thinning of the cortices, particularly in the metacarpals. In addition, a degenerative-like arthropathy with bone proliferation at the metacarpophalangeal and proximal interphalangeal articulations can be seen. These changes are rather subtle and are not those of advanced arthropathy. A close-up view demonstrates slight bone proliferation or overgrowth at several sites and subtle, but definite, cystic changes. This type of involvement of the MCP joints is fairly characteristic of hemo-chromatosis, although this is early disease. A close-up view of the wrist shows cartilage narrowing associated with the subchondral cyst formation which is fairly characteristic. We do not see
the pattern of chondrocalcinosis, or articular calcification, which occurs in about 50 percent of patients with hemochromatosis and arthropathy. I would like to go on to show more advanced changes in several other cases. In Figure 5 we can see generalized osteopenia that is more severe than in the previous case; the cortices are quite thin. We can see that the metacarpophalangeal articulations are quite abnormal. There is cartilage loss, cyst formation in the metacarpal heads and bone overgrowth. At the wrist we can see articular calcification which represents CPPD crystal deposition in the triangular cartilage which is the usual location. Additionally, we can see mild sclerosis and cartilage loss. A close-up view of
Figure 6.-Close view of the metacarpophalangeal joints showing joint narrowing subchondral collapse and striking proliferation of bone, producing a "squared off" appearance.
Figure 5.-Roentgenogram of the hand of patient with hemochromatosis. Diffuse osteopenia and calcification of the articular disk of the wrist, associated with arthropathy of the radiocarpal joint.
138
FEBRUARY 1978 * 128 * 2
Figure 7. Distinct linear and punctate calcification of the fibrocartilage of the lateral meniscus is clearly shown in this magnified view. An associated marginal osteophyte is visible.
HEMOCHROMATOSIS
the metacarpal heads (Figure 6) shows this fairly characteristic squaring off and teardrop formation. This is probably the most characteristic feature of the hemochromatotic arthropathy. Small cysts can be seen as well. In idiopathic pseudogout, patients generally present with symptoms in the knees, whereas in hemochromatosis it is more likely that patients will present with symptoms in the hands. In any
Figure 8.-Anteroposterior roentgenogram of the left knee showing calcification of the medial and lateral menisci, and advanced degenerative changes with marginal osteophytosis, subchondral sclerosis and joint narrowing.
.
event, the knees will generally be involved at some point, and what we will see is chondrocalcinosis, fine linear and punctate calcifications, in the fibrocartilage of the meniscus and also in the hyaline cartilage which parallels the articular surfaces (Figure 7). Additionally, we may see arthropathy in the knee-that is, degenerativelike arthropathy consisting of osteophyte formation and subchondral sclerosis (Figure 8). The hips are involved less frequently than the knees and the hands, but may show evidence of articular calcification and also the symphysis may show this dense calcification (Figure 9). Finally, the spine may be involved in hemochromatosis, although it generally does not produce symptoms. We may see fine linear calcifications in the outer fibers of the annulus fibrosis (Figure 10). This again is CPPD crystal deposition, and this appearance simulates syndesmophytosis encountered in ankylosing spondylitis. In summary, the arthropathy of hemochromatosis is quite similar to that of primary pseudogout, and is characterized by articular degeneration and chondrocalcinosis.
F-~~~~~~~~~~~~~w
Figure 9.-Striking articular and extra-articular calcification involving the symphysis pubis, hyaline cartilage and labrum of the hip, and the adductor insertions at the ischium.
Figure 10.-Subtle
can be seen in the
calcification of the annulus fibrosus
anteroposterior projection.
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HEMOCHROMATOSIS
DR. SMITH: Thank you, Dr. Genant. Unfortunately, as in the case of endocrine disturbances, the arthritis of hemochromatosis is not improved by removal of iron. The liver is the major site for iron storage in health. It also receives a disproportionate amount of the iron overload of hemochromatosis.9 Injury to the liver is frequent and often severe. In the case discussed today this particular complication was not seen. Our discussion of iron metabolism and liver disease will therefore be brief. Characteristically there is slow, chronic progression of liver injury with resulting fibrosis. In comparison with alcoholic cirrhosis, portal hypertension and ascites are less frequent. Hepatoma on the other hand has been reported as occurring in as many as 24 percent of patients with hemochromatosis in whom cirrhosis develops. Liver function may respond to a remarkable degree to iron depletion. Many investigators, particularly in France and in the United States, have noted a strong association between alcohol abuse and the cirrhosis of hemochromatosis. The interplay between alcohol and iron in the genesis of liver disease is still unclear and controversial. There is some evidence that alcohol increases iron absorption and therefore may be additive to the gut defect of hemochromatosis. Possibly iron increases the susceptibility of the liver to injury by alcohol. On the other hand, severe hemochromatotic liver disease has developed in many patients in the absence of any ingestion of alcohol or other known hepatotoxin. One must conclude that iron overload alone is sufficient to produce cirrhosis. The heart may be involved in hemochromatosis both histologically and clinically.'0 Heart disease has been reported as the cause of death in as many as 30 percent of cases in the older series, but this may no longer be true with more intensive treatment. Deposition of hemosiderin in the heart results in necrosis and fibrosis as in other tissues. There is a greater tendency for ventricular rather than atrial involvement, and for myocardial rather than conducting tissue involvement. The clinical picture may resemble that of a diffuse cardiomyopathy with a large dilated heart. Occasionally there is "restrictive" cardiomyopathy resembling constrictive pericarditis. More rarely tachyarrhythmias and heart block have been described. The iron heart is not a i strong heart, but a weak one. Diabetes mellitus is one of the cardinal manifestations of hemochromatosis. The association
140
FEBRUARY 1978 * 128 * 2
is a confusing one, however. Our patient did not have diabetes, so our summary today about this association will be brief and somewhat didactic. Clinical diabetes occurs in the majority of patients with hemochromatosis (65 to 80 percent), but there are some hemochromatotic families without diabetes. Diabetic complications may be frequent with microaneurysms, nephropathy and neuropathy. In studies carried out by Dr. Marvin H. Siperstein, seven of seven patients with hemochromatosis and diabetes had thickening of the capillary basement membrane. An additional patient who did not have diabetes had normal membrane thickness. Some studies have found a high incidence of diabetes mellitus in the relatives of patients who exhibit diabetes in association with their hemochromatosis. As an example, Domack and associates'" studied the families of patients with hemochromatosis and diabetes and found that 25 percent had diabetes mellitus. In the families of patients with hemochromatosis without diabetes, only 4 percent of the relatives had diabetes. The pathogenesis of carbohydrate intolerance in hemochromatosis is therefore complex.12 It may represent several things: the carbohydrate intolerance of cirrhosis itself, injury to the pancreatic islets by iron deposition with resultant insulin deficiency, and a genetic cross linkage with diabetes mellitus. Until better markers are found for both diabetes mellitus and for hemochromatosis, their interrelationship will remain obscure. How can one establish the diagnosis of hemochromatosis? First, the diagnosis should be entertained during the earlier clinical manifestations, as was true in the case discussed today. In addition, family studies should be carried out to detect patients before irreversible injury occurs. All of the laboratory aids for diagnosis are directed toward documenting iron overload. These tests differ in their respective sensitivities. The most sensitive test is directly showing increased hepatic parenchymal iron by liver biopsy, with an increase of stainable iron or an increase on direct chemical analysis.'3 Obviously such a study is rarely done unless one finds other evidence of iron overload, particularly in the serum. In hemochromatosis, serum iron is usually greater than 170 ,ug per dl and the saturation of transferrin greater than 50 percent. An indirect index of iron overload can be obtained by measuring its urinary excretion after the administration of a standard dose of chelator desferrioxamine
HEMOCHROMATOSIS 47yr male 50
HEMATOCRIT
40-
-"*N 30O
30J 300-
i20
SERUM IRON
200
149%
100
i
g Fe REMOVED
-10
0 100
300
500 DAYS
700
900
Figure 11.-Response to weekly phlebotomy therapy in hemochromatosis. The shaded area depicts the cumulative iron removed in grams. Note that two years were required to deplete the pathologically elevated iron stores.
(patients with hemochromatosis excrete more than 2.2 mg of iron in the subsequent 24 hours). Serum ferritin may be increased in hemochromatosis, but newer studies show that this does not occur early enough to be a sensitive aid in diagnosis. In summary, increased saturation of plasma transferrin and the direct demonstration of increased hepatic iron by biopsy are the most sensitive indices of the iron overload of hemochromatosis. How does one treat a patient with hemochromatosis? Fortunately treatment is usually simple and satisfactory. One phlebotomy of 500 ml of blood removes approximately 250 mg of iron. Phlebotomy is repeated once or sometimes even twice a week until the iron stores are depleted, which may require one or two years (Figure 11 ). Maintenance phlebotomy is then required to balance continued excessive iron absorption. Since this is a genetic disease it is imperative to study patients' relatives in order to find early cases. Iron depletion by phlebotomy clearly prolongs survival.'4 Hemochromatotic liver disease, heart disease and possibly diabetes are improved; endocrine deficiencies and arthritis usually are not. What are the causes of death in those who do die with hemochromatosis? Hepatoma is relatively frequent and unfortunately patients who have hemochromatotic cirrhosis continue to be at risk for hepatoma despite the removal of iron. Recent studies indicate a puzzlingly high association of other neoplasias with hemochromatosis. The reason for this association of iron overload and neoplasia is not clear. Deaths also con-
TABLE 1.-Unanswered Questions in Hemochromatosis * Is the gut mucosal abnormality that enhances Fe absorption primary or secondary to an abnormal signal? * What is the genetic transmission of the defect or group of defects? * What is the role of alcohol in the expression of hemochromatosis? * What is the relationship of the glucose intolerance of hemochromatosis to diabetes mellitus? * What is the mechanism by which storage iron injures tissue?
tinue to occur from hepatic failure, variceal bleeding and the vascular complications of diabetes, but such deaths are much fewer in treated as compared with untreated patients. In summary, hemochromatosis is a rare genetic disease of the rate control of iron absorption. There are still many unanswered questions concerning it (Table 1). The excessive iron absorption can be suppressed, but only at the cost of a massive overload of iron sufficient to cause tissue injury. Fortunately, if the disease is diagnosed early, as it was in our patient today, it can be adequately treated by phelebotomy and endocrine replacement therapy. A final elucidation of the pathogenesis of hemochromatosis will require new data concerning the mechanisms by which the absorption of iron is normally controlled. REFERENCES 1. Forth W, Rummel W: Iron absorption. Physiol Rev 53:724792, Jul 1973 2. Pollycove M: Hemochromatosis, In Stanbury JB, Wyngaarden JB, Fredrickson DS (Eds): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill Co, 1978 (in press) 3. Sherlock S: Hemochromatosis: Course and treatment. Ann Rev Med 27:143-149, 1976 4. Powell LW, Alpert E, Isselbacher KJ, et al: Abnormality in tissue isoferritin distribution in idiopathic hemochromatosis. Nature 250:333-335, Jul 1974 5. Simon M: Heredity of idiopathic hemochromatosis: A study of 106 families. Clin Genetics 11:327, May 1977 6. Walsh CH, Wright AD, Williams JW, et al: A study of pituitary function in patients with idiopathic hemochromatosis. J Clin Endocrinol Metab 43:866-872, Oct 1976 7. Schumacher HR Jr: Hemochromatosis and arthritis. Arthritis Rheum 7:41-50, Feb 1964 8. Hirsch JH, Killien FC, Troupin RH: The arthropathy of hemochromatosis. Radiology 118:591-596, Mar 1976 9. Grace ND, Powell LW: Iron storage disorders of the liver. Gastroenterology 67:1257-1283, Dec 1974 10. Buja LM, Roberts WC: Iron in the heart-Etiology and clinical significance. Am J Med 51:209-221, Aug 1971 11. Dymock IW, Cassar J, Pyke DA, et al: Observations on the pathogenesis, complications and treatment of diabetes in 115 cases of haemochromatosis. Am J Med 52:203-210, Feb 1972 12. Stocks AE, Powell LW: Carbohydrate intolerance in idiopathic hemochromatosis and cirrhosis of the liver. Quart J Med 42:733-749, Oct 1973 13. Edwards CQ, Carroll M, Bray P, et al: Hereditary hemochromatosis: Diagnosis in siblings and children. N Engl J Med 297:7-13, Jul 7, 1977
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