Clinical Presentation of Hemochromatosis: A Changing Scene PAUL C. ADAMS, M.D., ANN
KERTESZ, R.N., LESLIE S. VALBERG, M.D., Ph.D.,
London, Ontario, Canada
PURPOSE: To investigate the changing modes of clinical presentation and diagnosis in 93 patients with fAmiliAl hemochromatosis and to compare the results with other reports from 1935 to the present. PATIENTS AND METHODS: The presenting features and the frequency of signs and symptoms were analyzed in 93 homozygotes from 56 families. RESULTS: Hemochromatosis was detected by chance in 40% of the 56 probands. AbdominAl pain (16%), joint pAin~ (11%), and weakness (9%) were prominent features that brought the patient to the physician. Although 38% of the male patients had loss of libido and impotence, these were not identified as presenting features. Features of liver disease (84%), arthritis (11%), and diabetes (2 %) led the physician to the diagnosis. Impotence and testicular atrophy were notable, by their absence, in alerting physiciAn q to the presence of hemochromatosis. Screening of family members led to the detection of 37 homozygotes, of whom 46 % were asymptomatic. Among this group, arthropathy and gonadal failure were the most common symptoms. The classic triad of hepatomegaly, diabetes, and pigmentation was present in only 8 % of patients. Clinical features were r a r e in patients with less th~n 5 g of exchangeable body iron and invariably present in those with more than 16 g. CONCLUSION: The presenting clinical features of hemochromatosis have changed since the original description of the disease in 1935. FAmily studies have led to the earlier discovery of more homozygous women and earlier detection with less iron loading and, as a result, fewer signs and symptoms.
From the Department of Medicine, University Hospital, University of Western Ontario, London, Ontario, Canada. Requests for reprints should be addressed to Paul C. Adams, M.D., University Hospital, P.O. Box 5339, London, Ontario, Canada N6A 5A5. Dr. Adams' research was supported by the Medical Research'Council of Canada and a Career Scientist Award of the Ministry of Health of Ontario. Manuscript submitted April 9, 1990, and accepted in revised form November 19, ]990.
emochromatosis is a genetic disease of autosoH "mal recessive inheritance with a prevalence of approximately 1:400 in the white population [1-5]. Increased intestinal absorption of iron leads to the deposition of iron in parenchymal organs, eventually leading to cirrhosis, hepatocellular carcinoma, congestive heart failure, hypogonadism, diabetes, and skin pigmentation. Because early diagnosis of hemochromatosis and venesection therapy can prevent the development of complications and death, we have analyzed the features that brought the patients to the physician, the feature leading the physician to the diagnosis, and the frequency of signs and symptoms at presentation in 93 patients from 56 families with hemochromatosis and compared these features with those from other reports from 1935 to the present.
PATIENTS AND METHODS Patient Population Fifty-six probands were diagnosed at this center and were classified as homozygotes on the basis of marked parenchymal iron loading on microscopic examination of histologic sections of a liver biopsy, chemical hepatic iron determination, and/or exchangeable body iron stores in excess of 5 g. Proband cases were referred to this tertiary care institution with suspected hemochromatosis or more commonly with liver disease of unknown etiology. Other conditions associated with iron overload such as iron-loading anemias, transfusional iron overload, porphyria cutanea tarda, and dietary iron overload were excluded. Supporting data included elevations in the transferrin saturation value, the serum ferritin level, the hepatic iron concentration, and the radioiron absorption value disproportionate to the size of body iron stores. Thirty-seven homozygotes were detected during the screening of the 56 families and had HLA-A and B haplotypes identical to the relevant proband. Signs and symptoms of hemochromatosis were determined from a questionnaire, an interview, and a physical examination of each patient at the time of initial diagnosis. Exchangeable body iron was estimated by assuming that each 500-mL venesection removed 0.25 g of iron. Therapy was considered to be complete when the serum ferritin level was less than 30 #g/L
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SIGNSAND SYMPTOMSOF HEMOCHROMATOSlS/ ADAMSET AL TABLEI Profile of Patientswith Hemochromatosis* Males
Number Mean age (range) Mean serum ferritin (range) (pg/L) Transferrin saturation (%) Mean (range) Hepatic iron concentration (pmol/g) Mean (range) Mean body iron stores(g)
15 63 (48-82) 1,499 (460-3,795)
18 53 (11-79) 466 (17-2,310)
41 54 (19-72) 2,911 (85-12,024)
19 49 (26-72) 1,009 (187-2,706)
293 (73-817) 10
192 (130-355) 2.5
342 (181-609) 13
335 (127-772) 5
Normalrange:serumferritin (15 to 350 pg/L for males. 15to 200pg/L for females),transferrinsaturation20%to 55%,hepaticiron concentrationlessthan40 p mol/g, meanbody iron storeslessthan ! g.
Feature bringing Patient to the Doctor 30
41 Males - 15 Females
1. Incidental 2. Abdominal Pain 3. Joint Pain 4. Health Exam 5. Weakness 6. Diabetes 7. Frequent Infection 8. Confusion 9. Bone Pain 10. Dyspnea 11. Impotence
and/or the patient developed hypochromic microcytic anemia. RESULTS Exchangeable Body Iron Stores On average, the 15 female probands were 9 years older than the 41 male probands (Table I). Mean exchangeable body iron stores in women were 10 g, compared with 13 g in the men. The 18 detected female homozygotes and the 19 detected male homozygotes were 10 years and 5 years younger, respectively, than the probands, and their mean exchangeable body iron stores were less than those of the probands (Table I). Feature Bringing the Patient to the Physician Hemochromatosis was detected in 30% of probands during the management of incidental illnesses and in 10% during periodic health examinations (Figure 1). The most common symptom that brought the other patients to their physicians was abdominal pain in 16%. Impotence was not a presenting feature in any of the male patients. Bone pain was a symptom in women only. Otherwise there were no significant differences between the sexes. 446
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Figure 1. Feature bringing patient to the physician.
Feature Leading the Physician to the Diagnosis Hepatomegaly and/or abnormal liver function tests led the physician to the diagnosis of hemochromatosis in 69% of the probands (Figure 2). Arthritis alerted the physician to the diagnosis in 11%. Impotence and testicular atrophy were notable, by their absence, in alerting the physician to the diagnosis considering their reported prevalence. Interval to Diagnosis The mean interval from the first symptom to the diagnosis of hemochromatosis was 5 years (range: less-than I to 30 years) in women and 8 years (range: less than 1 to 24 years) in men. The symptom of longest duration before the diagnosis was established was joint stiffness and pain. Arthropathy was present for a median time of 10 years (range: 1 to 30 years) prior to the diagnosis of hemochromatosis. In some cases, the delay in diagnosis was due to the failure of the patient to seek medical attention, and in others, it was due to the failure of the physician to recognize the early features of iron loading. Clinical Features at Presentation Twelve percent of the probands were asymptomatic. In those with symptoms or signs, the predomi-
SIGNS AND SYMPTOMS OF HEMOCHROMATOSIS / ADAMS ET AL
Feature leading Doctor to Diagnosis 50
41 Males - 15 Females 1. Hepatomegaly 2. Abnormal LFT 3. Arthritis 4. Hepatic Failure 5. Liver Biopsy 6. CT Scan 7. Diabetes 8. Yersinia 9. Plasma Iron
/ / / / i
/ / / / /
/ / / / /
/ J / / /
/ / / / /111 / / / / / / / /
/ / / /
/ / / / / / / / / / / /
Figure 2. Feature leading physician to diagnosis. LFT = liver function test; CT = computed tomographic.
nant features in order of their frequency were hepatomegaly, arthritis, weakness, pigmentation, gonadal failure, and diabetes (Table II). Hepatoma was present in two male probands. Clinical features were less frequent in the detected homozygotes than in the probands (Table II). Nevertheless, joint pain and stiffness were frequent in both female and male patients, and gonadal failure with impotence, loss of libido, and testicular atrophy were common in males. Thirty-seven percent of the detected males and 55% of the detected females had no signs or symptoms of iron loading. Clinical Features in Relation to Body Iron Stores Thirteen of 53 homozygotes in whom venesection therapy was completed had exchangeable body iron stores of less than 5 g. Only three of these patients were symptomatic; one had impotence, two had joint pain and stiffness, and one had joint pain and weakness. Thirty-seven of the 40 homozygotes with exchangeable body iron stores equal to or greater than 5 g were symptomatic. The three patients without symptoms had iron reserves of 6, 6, and 7 g, respectively. Cirrhosis of the liver was present in all of the patients with exchangeable body iron stores in excess of 16 g.
TABLE II Clinical Features at Presentation In Hemochromatosls (%)
ClinicalFeature None Weakness Abdominalpain Joint pain Pigmentation Hepatomegaly Fibrosis/cirrhosis Hepatoma Diabetes Cardiac disease Gonadalfailure Infection
Females Proband Detected 0 47 13 67 40 73 40 0 27 27 -7
55 11 0 33 6 0 0 0 6 0 -O
Males Proband Detected 12 38 15 42 38 56 51 2 22 0 38 12
37 26 5 47 11 6 5 0 16 5 32 5
difference is explained at least in part by the inclusion in the later series of patients discovered during screening of families and the early detection of iron loading in a relatively large number of probands during the management of incidental illnesses.
COMMENTS In previous reports of hemochromatosis, the symptoms and signs present at the time of diagnosis are described. In this respect, the clinical features Comparison of Clinical Features to Those of Previous observed in the probands in this report resemble those previously reported by Edwards et al . The Reports The frequency of signs and symptoms i~ our pa- prevalence of signs and symptoms at the time of tients resembles the frequency distribution report- diagnosis has changed in recent years due to earlier ed by Edwards et al  in 1980 (Figure 3). The detection of the disease. Consequently, skin pigclinical features of iron loading in these two series mentation, liver disease, diabetes, and heart disease are not nearly as prevalent as in six other large are less prevalent. Only seven of our 93 patients and series of patients reported since 1935 [6-14]. This one of 35 in a recent series  had the classic triad of April 1991 The American Journal of Medicine Volume 90
SIGNS AND SYMPTOMS OF HEMOCHROMATOSIS / ADAMS ET AL
1935 1951 1955 1969 1975 1977 1980a 1980b 1985 1991
1935 1951 1955 1969 1975 1977 1980a 1980b 1985 1991
skin pigmentation, hepatomegaly, and diabetes. Nevertheless, a brown or gray hue to the skin remains a feature of iron loading in 25% to 50% of patients. Atrophy of the skin, ichthyosis, and koilonychia have also been reported as additional cutaneous manifestations of iron overload . Fibrosis and cirrhosis of the liver are also less prevalent in recent reports; however, the frequency of liver disease remains high, indicating that iron loading is still being discovered at an advanced stage in about 35% of patients. This delay in detection is important since cirrhosis is not clearly reversible, although this has been reported [16,17], and hepatocellular carcinoma is a risk. Also, impotence rarely improves with venesection therapy.
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Figure 3. Presenting clinical features of hemochromatosis in major reported s e r i e s - - 1 9 3 5 , 1951 , 1955 , 1969 [I0], 1975 , 1977 . 1980a , 1980b , and 1985  (* not reported).
Both diabetes and heart disease are less frequent now than in the past, presumably due to earlier detection of the disease. Occasionally, when symptoms of iron loading develop early in life, the presenting feature may be fulminant cardiac failure . Arthropathy was not recognized as a feature of hemochromatosis until 1964 . It has been described with increasing frequency since 1975 (Figure 3), and it is now one of the most prevalent features of the disease. Presumably arthropathy was present in early series, but its significance was not appreciated. Manifestations of chondrocalcinosis and degenerative joint disease may be present before other features of hemochromatosis become ap-
SIGNS AND SYMPTOMS OF HEMOCHROMATOSlS / ADAMS ET AL
parent, and their course is independent of the degree of iron loading. Typically, the first and second metacarpal phalangeal joints of the hands are involved, which tends to distinguish this arthritis from other forms of arthropathy . In this series, arthropathy was by far the most common symptom reported prior to the diagnosis of hemochromatosis. A salient feature of this study was an analysis of the clinical features that brought the patient to the physician and the presenting feature that led the physician to the diagnosis. Hemochromatosis is often discovered by chance during the management of incidental illness or periodic health examinations. Symptoms of hemochromatosis that brought our patients to their physicians included abdominal pain, joint pain, weakness, diabetes, and frequent infections. Evidence of liver disease was the predominant feature that led the physician to the diagnosis. This included hepatomegaly, abnormal liver function tests, hepatic failure, excess stainable iron on liver biopsy, and increased hepatic density on abdominal computed tomography-scan. Other important features that led to the diagnosis were chondrocalcinosis, arthritis of the hands, wrists, and knees, and the unexplained development of diabetes. Although impotence and loss of libido were present in 35% of the men, it neither brought the patient to the physician nor did its presence, if known, alert the physician to the diagnosis of hemochromatosis. Surprisingly, an elevated transferrin saturation value rarely alerted the physician to the presence of the disease. The recognition that Yersinia infections may be associated with iron overload led to the diagnosis of hemochromatosis in two patients who have been previously described . Physicians must remain aware that unexplained hepatomegaly, skin pigmentation, loss of libido and impotence, arthropathy, diabetes, or frequent infection may be due to hemochromatosis. The diagnosis remains difficult because many of the signs and symptoms lack sensitivity and specificity for iron overload. An elevated transferrin saturation value is a hallmark of the disease and, when combined with an elevation of the serum ferritin level, provides a good index of homozygous hemochroma-
tosis. Early diagnosis and treatment are of paramount importance if complications and death are to be eliminated.
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