LETTERS
Letters that report new clinical or laboratory observations, cases of unusual importance, and new developments in medical care will be considered for publication in this section. Manuscripts must be typed double-spaced. Text length must not exceed 750 words; no more than five references and one figure or table can be used. See "Information for Authors" on page 1-6 for form of references. Manuscripts should include an abstract of length not exceeding 100 words. Letters will be reviewed by consultants when, in the opinion of the editors, such review is needed. The Editor reserves the right to shorten letters and to make changes that accord with our style. Familial Hyperparathyroidism
of cases of primary hyperparathyroidism has been reported, but the prevalence of such cases has not been established. Jackson and Boonstra (1) recorded the prevalence of involvement of other members of families of propositi with primary hyperparathyroidism to be 0.14 per thousand. An opportunity to study the prevalence of familial primary hyperparathyroidism arose through a health check-up in the Stockholm area in Sweden. Between 1971 FAMILIAL OCCURRENCE
Figure 1. O = female, # = female with primary hyperparathyroidism, 0 = female with primary hyperparathyroidism taking part in the original health screening, • = male, • = male with primary hyperparathyroidism.
Age (years) are indicated above the symbol and mean value of repeated recordings of serum calcium (mmol/litre) below. 614
and 1973, 15 903 persons aged 20 to 63 years took part in a medical screening. Ninety-five (0.6%) of them (80 women, 15 men) were found to have verified hypercalcaemia (defined as at least two out of three consecutive recordings — 2.64 mmol/litre, using atomic absorption spectrophotometry). Further details of this study have been described by Christensson and associates. (2). In 82 of the 95 patients, causes of hypercalcaemic disorders other than primary hyperparathyroidism were ruled out. So far, 60 of these patients have been operated on, and parathyroid adenomata have been found in all but two. The diagnosis in the remaining 22 patients is probably primary hyperparathyroidism. Parents, siblings, and children of each of the 82 patients were invited to participate in further studies, including repeated serum calcium tests. Ninety parents were alive and 86 of them took part in a follow-up study from 1973 to 1976. In the same period, 150 out of 162 siblings participated and so did 148 out of 156 children of the subjects with verified hypercalcaemia. All the subjects were checked with repeated serum calcium determinations and with recordings of serum phosphate, serum albumin, serum magnesium, and creatinine clearance. Other cases of primary hyperparathyroidism were found in members of only two of the investigated families. These are presented as pedigrees in Figure 1. In family one, two cases were found, whereas family two had eight cases, covering three generations. All the information in Figure 1 is from the same year. No other endocrine disorders were detected in the family members, neither were there any laboratory manifestations except for the repeatedly confirmed elevation of serum calcium. As pointed out above, the prevalence of familial primary hyperparathyroidism is unknown. The prevalence in our study is 0.13 per thousand; it does not differ significantly from the finding of 0.14 per thousand by Jackson and Boonstra (1). In most cases (up to 85%) hyperparathyroidism is nonfamilial (3). The prevalence of primary hyperparathyroidism of 0.52% in the present study exceeds that of several other studies: 0.1% found by Boonstra and Jackson (4) and 0.15% seen by Keating and associates (5). The subjects were studied with repeated determinations during various periods and under standardized conditions. The high prevalence of primary hyperparathyroidism in a Swedish population, compared to elsewhere, can not be explained by any specific factor. The prevalence of 0.52% was found in subjects taking part in a health screening, and the frequency is not obtained from selected hospitalized patients as is common elsewhere. It is possible, however, that high figures will be found in other countries, where extensive health controls are part of the medical attendance. Naturally, cases of hypocalcaemic (secondary) and normocalcaemic hyperparathyroidism will not be detected by routine screenings such as the one in this study. In conclusion, the prevalence of primary hyperparathyroidism is higher in a health-screened Swedish population
November 1976 • Annals of Internal Medicine • Volume 85 • Number 5
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(0.52%), compared to corresponding figures from American studies. However, the frequency of familial primary hyperparathyroidism in this Swedish population (0.13 per thousand) did not differ from corresponding data in American surveys. This study was supported by grants from Clas Groschinsky's Minnesfond, Stockholm and the Funds of Svenska Lakaresallskapet (Stockholm) and of Svenska sallskapet for medicinsk forskning (Stockholm). TONY CHRISTENSSON M.D.
Department of Medicine Serafimerlasarettet S-112 83 Stockholm, Sweden Received 21 May 1976. References
1. JACKSON CE, BOONSTRA CE: The relationship of hereditary
hyperparathyroidism to endocrine adenomatosis. Am J Med 43:727-734, 1967 2. CHRISTENSSON T, HELLSTROM K, WENGLE B, et al: Prevalence of
hypercalcaemia in a health check of 15,903 employees of the Stockholm City and County Council. Acta Med Scand. In press, 1975 3. BLONDE L, BERNENE JL, GOODMAN AD: Familial hypertension.
J. La State Med Soc 127:349-353, 1975 4. BOONSTRA CE, JACKSON CE: Serum calcium survey for hyperparathyroidism: results in 50,000 clinic patients. Am J Clin Pathol 55:523-526, 1971 5. KEATING FR JR, JONES JD, ELVEBACK LR: Distribution of serum
calcium and phosphorus values in unselected ambulatory patients. J Lab Clin Med 74:507-514, 1969
D-Penicillamine-lnduced Polymyositis in Rheumatoid Arthritis D-PENICILLAMINE is an effective treatment for active rheumatoid arthritis ( 1 ) . As more experience is gained with this drug, the more apparent becomes its spectrum of toxicity. A lupus-like syndrome (2) and polymyositis (3) have been reported as complications of D-penicillamine therapy. This report describes a patient who, 1 month after beginning therapy for rheumatoid arthritis, manifested signs and symptoms of polymyositis associated with myocarditis, proteinuria, and hypocomplementemia. A 58-year-old woman was admitted to Columbia Hospital in Milwaukee, Wisconsin, 12 May 1975, for weakness. She had been in good health until 2Vi years before admission when she was diagnosed as having rheumatoid arthritis. Prior to April 1975, she had been treated with 900 mg of parenteral gold and low dose corticosteroids. In April she was admitted and a diagnosis of Sjogren's syndrome was also established. She was treated with ibuprofen and prednisone, 5 mg. Dpenicillamine, 250 mg three times a day, was started 15 April 1975, because of progressive disability. Two weeks before admission, the patient developed a nonproductive cough without documented fever. About 1 week before admission, she began experiencing palpitation about twice daily. Three days before admission, she had become so weak that she could not get out of bed and, by admission, she was unable to feed herself. When fed, she was unable to swallow solids. She denied myalgias or arthralgias. She also denied regular ingestion of alcohol. On examination, the patient appeared chronically ill. There were bilateral pea-sized anterior and posterior cervical lymph nodes. Similar-sized nodes were noted in the supraclavicular, axillary, and inguinal regions. There was a grade TT/VI systolic murmur and an S4. The patient had muscle weakness, proximal greater than distal, such that she was unable to lift
her head, arms, or legs off the bed. No evidence of peripheral or cranial neuropathy was noted. There was mild synovitis present at the metacarpophalangeal joints and ulnar deviation. No skin lesions were observed. Hemoglobin was 10.3 g, leukocyte count, 7200/mm3; erythrocyte sedimentation rate, 40. The urine was brown, protein 1 + , hemoglobin 4+ (Multistix*), and there were 10 to 15 leukocytes, and 0 to 2 erythrocytes per high-powered field. There were numerous hyaline and granular casts. The urine was negative for myoglobin and hemoglobin by the ammonium sulfate precipitation technique. Serum glutamic-oxalacetic transaminase was 647 IU/litre; lactic dehydrogenase, 575 IU/litre; creatinine phosphokinase, 7000 IU/litre; and hydroxybutyric dehydrogenase, 1256 IU/litre; Ca, 41 units, (normal 55 to 120); C4 10 units (normal 20 to 50); 24-h urine for protein, 1.47 g/litre. Antinuclear antibody, 1:4096; anti-DNA, 18.6% (normal, 1 to 14), rheumatoid factor, 1:512. Viral titers when the patient was acutely ill, and convalescent, showed no infection. Electrocardiogram on admission demonstrated a complete right bundle branch block with inverted T waves in V2 and V3. Electromyogram demonstrated increased insertional activity with positive waves and fibrillations. There were many brief, short polyphasic potentials. Muscle biopsy from the left deltoid showed acute and severe inflammatory myopathy (Figure 1). All medications were stopped, and the patient was begun on high-dose prednisone. Her course was complicated by transient dysrhythmias that responded to digoxin. Within 1 month, the patient was able to ambulate without assistance. Steroids were subsequently withdrawn and all values, with the exception of the antinuclear antibody and rheumatoid factor, have remained normal for the 6 months her course has been followed. Although this patient fulfills all the criteria proposed by Bohan and Peter (4) for the diagnosis of polymyositis, the association of myocarditis, proteinuria, and hypocomplementemia is not typical of polymyositis. This particular constellation has not been reported in previous D-penicillamine-induced polymyositis (3) or lupus-like syndromes (2). Because of the temporal relationships involved and the response to therapy, we believe that this case represents an immune complex disorder secondary to D-penicillamine treatment. The pathophysiology is still unclear. In view of this report and the established toxicity of this drug, caution is warranted in further trials with D-penicilla* Ames Co., Elkhart, Indiana
Figure. 1 . Biopsy of left deltoid muscle, demonstrating mononuclear inflammatory cell infiltrate and muscle necrosis with associated sarcolemmal proliferation. (Hematoxylin and eosin; original magnification, X 110). Letters
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615
mine in patients with rheumatoid arthritis, a disease that is rarely life threatening. BOBB G. CUCHER, M.D. A. L. GOLDMAN, M.D.
Department of Medicine Columbia Hospital; and The Medical College of Wisconsin Milwaukee, WI 53226 Received 13 February 1976. References 1. MULTICENTRE TRIAL GROUP: Controlled trial of D-penicillamine
in severe rheumatoid arthritis. Lancet 1:275-280, 1973 2. HARPEY JP, CAILLE B, MOULIAS P, et al: Lupus-like syndrome
induced by D-penicillamine in Wilson's disease. Lancet 1:292, 1971 3. SCHRAEDER PL, PETERS HA, DAHL DS: Polymyositis and peni-
cillamine. Arch Neurol 27:456-457, 1972 4. BOHAN A, PETER JB: Polymyositis and dermatomyositis. N Engl
J Med 292:344-347, 403-407, 1975
Diffuse Intervertebral Disk Calcification in Primary Amyloidosis DIFFUSE CALCIFICATION of many lumbar and thoracic in-
tervertebral disks has been thought to be highly suggestive, if not pathognomonic, of ochronosis. A patient with widespread intervertebral disk calcification that was unexplained during life, was found at autopsy to have primary amyloidosis with infiltration of the intervertebral disks by both amyloid deposits and calcification. This association has not been noted previously. Amyloidosis may be responsible for diffuse intervertebral disk calcification. In December 1962, a 63-year-old Puerto Rican musician was noted to have calcification of several thoracic intervertebral disks on routine chest Xray. In 1965 an upper gastrointestinal contrast X-ray examination, performed because of dyspepsia, showed benign antral gastritis and a duodenal diverticulum. In addition, diffuse calcification of the thoracic and lumbar intervertebral disks was noted (Figure 1A and IB). A urine specimen was tested at this time for the presence of homogentisic acid using 10% NaOH and Benedict's solution; no color change was noted. There was no evidence of parathyroid abnormalities, renal disease, or calcification of peripheral joints. A chest Xray in 1968 demonstrated mild cardiomegaly for the first time. There was no hypertension or evidence of valvular disease. In December 1971 he was found to be in mild congestive heart failure; treatment with digoxin and diuretics
was initiated, but symptoms of congestive heart failure persisted. There was no proteinuria. In February 1973 he developed atrial fibrillation. Three weeks later he was hospitalized because of sudden onset of right-side weakness. Initial physical examination revealed flaccid right hemiparesis and congestive heart failure. Electrocardiogram showed atrial fibrillation; chest Xray demonstrated marked cardiomegaly; urinalysis, complete blood count, and values for blood chemistry were within normal limits. Serum albumin was 4/dl and globulin, 3/dl. He was treated for congestive heart failure and discharged with moderate improvement of his hemiparesis. Continued follow-up showed persistence of mild congestive heart failure. Repeated examinations of the urine showed no color change either on prolonged standing or on alkalinization of urine. In October 1973 he was readmitted with a 2-day history of vomiting. Shortly after admission he complained of chest pain and shortness of breath. Electrocardiograms and serum enzymes showed an acute inferior wall myocardial infarction. Soon thereafter he developed cardiogenic shock; he died 3 days later. Gross examination showed biventricular myocardial hypertrophy; the myocardium itself was slightly pale. The coronary arteries were relatively free of atherosclerosis. There was a 2-cm pyloric ulcer in the stomach, and a large diverticulum was evident in the second portion of the duodenum. The rest of the findings at gross examination were unremarkable. Microscopic examination showed generalized amyloidosis, most marked in the heart, and also involving the lungs, liver, gastrointestinal tract, spleen, kidneys, pancreas, testes, and adrenals. The intervertebral disks showed destruction with calcification and widespread amyloid deposits. No evidence of ochronotic pigment was found. Recent reviews (1, 2) have emphasized the variable presentation and protean clinical manifestations of systemic amyloidosis. Although involvement of joints and periarticular structures has been noted in some patients with this condition ( 3 ) , amyloidosis of the intervertebral disks has not been reported. It seems likely that diffuse intervertebral disk calcification in this patient occurred consequent to local amyloid deposition. It is recognized that local amyloid deposits can precede the clinical recognition of systemic disease by many years, and calcification of such deposits has been noted by several authors in sites such as lung and endocardium (4, 5 ) . Furthermore, other explanations of intervertebral disk calcification are not consistent with the findings in this patient. Calcification due to degenerative
Figure 1A and IB. Lateral and anteroposterior views of thoracic and lumbar spine of the patient in the present report. C. Anteroposterior view of thoracic and lumbar spine of a patient with documented ochronosis. 616
November 1976 • Annals of Internal Medicine • Volume 85 • Numbers
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disk disease is usually discrete and localized to the lumbar spine, where degenerative disk disease is most frequent. Diffuse, widespread calcification of the intervertebral disks, as seen in this patient, is not characteristic of degenerative disk disease. Similarly, there was no evidence either when the patient was alive or at autopsy for the diagnosis of ochronosis. Localized calcification in ochronosis is felt to occur secondary to destruction of disks by infiltration with homogentistic acid. The current report demonstrates that amyloid infiltration can similarly lead to destruction and secondary calcification of intervertebral disks. The radiographic appearance and distribution of disk calcification seen in ochronosis does not differ significantly from that seen in the patient reported here (Figure 1C). These findings add amyloidosis to ochronosis as a recognized cause of diffuse calcification of intervertebral discs and suggest that other infiltrative processes may similarly lead to calcification at these sites. STANLEY P. BALLOU, M.D. MUHAMMAD ASIM KHAN, M.D., M.R.C.P. IRVING KUSHNER, M.D., F.A.C.P.
Department of Medicine Case Western Reserve University School of Medicine at Cleveland Metropolitan General Hospital Cleveland OH 44109 REFERENCES
1. KYLE RA, BAYRD ED: Amyloidosis: review of 236 cases. Medicine (Baltimore) 54:271-299, 1975 2. BRANDT K, CATHCART ES, COHEN AS: A clinical analysis of the
course and prognosis of forty-two patients with amyloidosis. Am J Med 44:955-969, 1968 3. WIERNIK PH: Amyloid joint disease. Medicine (Baltimore) 51: 465-479, 1972 4. WEISS L: Isolated multiple nodular pulmonary amyloidosis. Am J Clin Pathol 33:318-329, 1960 5. KOLETSKY S, STECHER RM: Primary systemic amyloidosis: involvement of cardiac valves, joints and bones, with pathologic fracture of the femur. Arch Path 27:267-288, 1939
women. (The slope for men was 0.0094 mg/day • ml and women, 0.0072, and the average slope was 0.0084 mg/ day • ml.) The regression line for men was significantly higher (F < 0.05) but parallel to that of women. As a result of these findings, the upper limit of normal range of 24-h urine oxalic acid will vary according to urine volume, in men being approximately 46, 55, and 63 mg/ day for urine volumes 1000, 2000 and 3000 ml/day, respectively, while in women the corresponding values are slightly lower at approximately 42, 50, and 58 mg/day. A similar positive correlation was found when the urine oxalic acid/g of creatinine was plotted against 24-h volume (Figure 1); this suggests that the observed correlation was not due to incomplete urine collection. It is interesting to note that in this correlation the regression line for men still was parallel but was significantly lower than that for women. After this observation, we studied the correlation between 24-h urine oxalic acid and 24-h urine volume in a group of 20 patients with recurrent calcium containing kidney stones who had two or more 24-h urine collections. Again we showed that even in the same person this correlation between 24-h urine volume and 24-h urine oxalic acid exists (P < 0.001). The average slope for these 20 patients was 0.020 mg/day • ml. Our findings agree with those of Pinto and colleagues (4), who observed an increase in the clearance of oxalic acid parallel to urine flow rate up to 3.2 ml/min. We conclude that reliable comparisons between normal subjects and those who form stones cannot be made on the absolute amount of urinary oxalic acid excreted in 24 h, unless the 24-h urine volume also is taken into consideration. Of course, an alternative method would be to
Urine Oxalic Acid: Relation to Urine Flow FINLAYSON (1) has emphasized that merely measuring the 24-h excretion rates of different urinary constituents will be of little value in the study of patients with kidney stones or in determining the effectiveness of different therapeutic regimens, since the formation of kidney stones depends mainly on the concentration of urinary salts. This fundamental point has not been sufficiently emphasized in most papers on renal stones. Comparisons of patients with kidney stones and normal control subjects based on 24-h urine excretion rates are also unreliable because the excretion rates of some constituents are dependent on the rate of urine flow (24-h urine volumes) (2). We recently showed this relation between the amount of oxalic acid excreted in 24 h and the 24-h urine volume. Urine anhydrous oxalic acid was measured by a modification of the method of Hodgkinson and Williams (3). The mean value for a group of 42 men and women was 32.9 mg/day with a range between 21.9 and 49.2 mg/day, similar to the normal ranges observed by Hodgkinson and Williams (3). However, there was a significant positive correlation (P < 0.05) between the 24-h urine excretion of oxalic acid and the 24-h volume in both men and
Figure 1. Correlation between urine anhydrous oxalic acid and 24-h urine volume in a group of normal subjects. Letters
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determine the actual concentration calcium oxalate ( 5 ) .
(activity products) of
D. G. OREOPOULOS, M.D.
H. HUSDAN, PH.D. M. LEUNG, B.SC. D . B. W. REID, M.SC. A. RAPOPORT, M.D.
Metabolic-Renal Unit, The Toronto Western Hospital and the Departments of Medicine, Clinical Biochemistry and Preventive Medicine and Biostatistics, University of Toronto, Toronto, Ontario, Canada. The Toronto Western Hospital and Departments of Medicine, Clinical Biochemistry and Preventive Medicine and Biostatistics University of Toronto
Toronto, ONT, Canada Received 16 April 1976. REFERENCES
1. FINLAYSON B: Renal lithiasis in review. Urol Clin North Am 1:181-212, 1974 2. OREOPOULOS DG, WALKER D, AKRIOTIS DJ, et al: Excretion of
inhibitors of calcification in urine. Part I: Findings in control subjects and patients with renal stones. Can Med Assoc J 112:827-831, 1975 3. HODGKINSON A, WILLIAMS A: An improved colorimetric procedure
for urine oxalate. Clin Chim Acta 36:127-132, 1972 4. PINTO B, CRESPI G, SOLE-BALCELLS F, et al: Patterns of oxalate
metabolism in recurrent oxalate stone formers. Kidney Int 5:285291, 1974 5. ROBERTSON WG, PEACOCK M, NORDIN BEC: Activity products in
stone forming and non stone forming urine. Clin Sci 34:579-594, 1968
The World, 1976, Through the Eyes of the Chinese Medical Journal The current international situation is excellent, there is great disorder under heaven. All the basic contradictions in the world are daily sharpening. The factors for both revolution and war are visibly increasing. Phoney "goulash" communism has gone bankrupt. The Marxist-Leninist Parties and organizations in various countries are growing stronger in the struggle against modern revisionism. The countries and people of the third world have been playing their role as the main force in the struggle against imperialism, colonialism and great-power hegemonism. The contention between the two hegemonic powers, the Soviet Union and the United States, is intensifying; strategically Europe is the focus of their contention. Soviet social-imperialism, which is "making a feint to the east while attacking in the west" and most energetically playing the fraudulent game of "detente," is precisely the most dangerous source of war today. We must heighten our vigilance and be prepared against war. We must continue to carry out the strategic principles advanced by Chairman Mao: "Dig tunnels deep, store grain everywhere, and never seek hegemony"; "Be prepared against war, be prepared against natural disasters, and do everything for the people." The People's Liberation Army and the masses of militiamen should carry forward their glorious revolutionary traditions, strengthen preparedness against war, train hard, be strict with themselves and always be ready to wipe out any invading enemy. We are determined to liberate Taiwan Province, our sacred territory. Nothing Is Hard in This World If You Dare to Scale the Heights. 1976 New Year's Day editorial. By "Renmin Ribao," "Hongqi," and "Jiefangjun Bao" Chinese Medical Journal 2 (new series) (1, special supplement): 3-8, 1976.
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Letters that report new clinical or laboratory observations, cases of unusual importance, and new developments in medical care will be considered for publication in this section. Manuscripts must be typed double-spaced. Text length must not exceed 750 words; no more than five references and one figure or table can be used. See "Information for Authors" on page 1-6 for form of references. Manuscripts should include an abstract of length not exceeding 100 words. Letters will be reviewed by consultants when, in the opinion of the editors, such review is needed. The Editor reserves the right to shorten letters and to make changes that accord with our style. Familial Hyperparathyroidism
of cases of primary hyperparathyroidism has been reported, but the prevalence of such cases has not been established. Jackson and Boonstra (1) recorded the prevalence of involvement of other members of families of propositi with primary hyperparathyroidism to be 0.14 per thousand. An opportunity to study the prevalence of familial primary hyperparathyroidism arose through a health check-up in the Stockholm area in Sweden. Between 1971 FAMILIAL OCCURRENCE
Figure 1. O = female, # = female with primary hyperparathyroidism, 0 = female with primary hyperparathyroidism taking part in the original health screening, • = male, • = male with primary hyperparathyroidism.
Age (years) are indicated above the symbol and mean value of repeated recordings of serum calcium (mmol/litre) below. 614
and 1973, 15 903 persons aged 20 to 63 years took part in a medical screening. Ninety-five (0.6%) of them (80 women, 15 men) were found to have verified hypercalcaemia (defined as at least two out of three consecutive recordings — 2.64 mmol/litre, using atomic absorption spectrophotometry). Further details of this study have been described by Christensson and associates. (2). In 82 of the 95 patients, causes of hypercalcaemic disorders other than primary hyperparathyroidism were ruled out. So far, 60 of these patients have been operated on, and parathyroid adenomata have been found in all but two. The diagnosis in the remaining 22 patients is probably primary hyperparathyroidism. Parents, siblings, and children of each of the 82 patients were invited to participate in further studies, including repeated serum calcium tests. Ninety parents were alive and 86 of them took part in a follow-up study from 1973 to 1976. In the same period, 150 out of 162 siblings participated and so did 148 out of 156 children of the subjects with verified hypercalcaemia. All the subjects were checked with repeated serum calcium determinations and with recordings of serum phosphate, serum albumin, serum magnesium, and creatinine clearance. Other cases of primary hyperparathyroidism were found in members of only two of the investigated families. These are presented as pedigrees in Figure 1. In family one, two cases were found, whereas family two had eight cases, covering three generations. All the information in Figure 1 is from the same year. No other endocrine disorders were detected in the family members, neither were there any laboratory manifestations except for the repeatedly confirmed elevation of serum calcium. As pointed out above, the prevalence of familial primary hyperparathyroidism is unknown. The prevalence in our study is 0.13 per thousand; it does not differ significantly from the finding of 0.14 per thousand by Jackson and Boonstra (1). In most cases (up to 85%) hyperparathyroidism is nonfamilial (3). The prevalence of primary hyperparathyroidism of 0.52% in the present study exceeds that of several other studies: 0.1% found by Boonstra and Jackson (4) and 0.15% seen by Keating and associates (5). The subjects were studied with repeated determinations during various periods and under standardized conditions. The high prevalence of primary hyperparathyroidism in a Swedish population, compared to elsewhere, can not be explained by any specific factor. The prevalence of 0.52% was found in subjects taking part in a health screening, and the frequency is not obtained from selected hospitalized patients as is common elsewhere. It is possible, however, that high figures will be found in other countries, where extensive health controls are part of the medical attendance. Naturally, cases of hypocalcaemic (secondary) and normocalcaemic hyperparathyroidism will not be detected by routine screenings such as the one in this study. In conclusion, the prevalence of primary hyperparathyroidism is higher in a health-screened Swedish population
November 1976 • Annals of Internal Medicine • Volume 85 • Number 5
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(0.52%), compared to corresponding figures from American studies. However, the frequency of familial primary hyperparathyroidism in this Swedish population (0.13 per thousand) did not differ from corresponding data in American surveys. This study was supported by grants from Clas Groschinsky's Minnesfond, Stockholm and the Funds of Svenska Lakaresallskapet (Stockholm) and of Svenska sallskapet for medicinsk forskning (Stockholm). TONY CHRISTENSSON M.D.
Department of Medicine Serafimerlasarettet S-112 83 Stockholm, Sweden Received 21 May 1976. References
1. JACKSON CE, BOONSTRA CE: The relationship of hereditary
hyperparathyroidism to endocrine adenomatosis. Am J Med 43:727-734, 1967 2. CHRISTENSSON T, HELLSTROM K, WENGLE B, et al: Prevalence of
hypercalcaemia in a health check of 15,903 employees of the Stockholm City and County Council. Acta Med Scand. In press, 1975 3. BLONDE L, BERNENE JL, GOODMAN AD: Familial hypertension.
J. La State Med Soc 127:349-353, 1975 4. BOONSTRA CE, JACKSON CE: Serum calcium survey for hyperparathyroidism: results in 50,000 clinic patients. Am J Clin Pathol 55:523-526, 1971 5. KEATING FR JR, JONES JD, ELVEBACK LR: Distribution of serum
calcium and phosphorus values in unselected ambulatory patients. J Lab Clin Med 74:507-514, 1969
D-Penicillamine-lnduced Polymyositis in Rheumatoid Arthritis D-PENICILLAMINE is an effective treatment for active rheumatoid arthritis ( 1 ) . As more experience is gained with this drug, the more apparent becomes its spectrum of toxicity. A lupus-like syndrome (2) and polymyositis (3) have been reported as complications of D-penicillamine therapy. This report describes a patient who, 1 month after beginning therapy for rheumatoid arthritis, manifested signs and symptoms of polymyositis associated with myocarditis, proteinuria, and hypocomplementemia. A 58-year-old woman was admitted to Columbia Hospital in Milwaukee, Wisconsin, 12 May 1975, for weakness. She had been in good health until 2Vi years before admission when she was diagnosed as having rheumatoid arthritis. Prior to April 1975, she had been treated with 900 mg of parenteral gold and low dose corticosteroids. In April she was admitted and a diagnosis of Sjogren's syndrome was also established. She was treated with ibuprofen and prednisone, 5 mg. Dpenicillamine, 250 mg three times a day, was started 15 April 1975, because of progressive disability. Two weeks before admission, the patient developed a nonproductive cough without documented fever. About 1 week before admission, she began experiencing palpitation about twice daily. Three days before admission, she had become so weak that she could not get out of bed and, by admission, she was unable to feed herself. When fed, she was unable to swallow solids. She denied myalgias or arthralgias. She also denied regular ingestion of alcohol. On examination, the patient appeared chronically ill. There were bilateral pea-sized anterior and posterior cervical lymph nodes. Similar-sized nodes were noted in the supraclavicular, axillary, and inguinal regions. There was a grade TT/VI systolic murmur and an S4. The patient had muscle weakness, proximal greater than distal, such that she was unable to lift
her head, arms, or legs off the bed. No evidence of peripheral or cranial neuropathy was noted. There was mild synovitis present at the metacarpophalangeal joints and ulnar deviation. No skin lesions were observed. Hemoglobin was 10.3 g, leukocyte count, 7200/mm3; erythrocyte sedimentation rate, 40. The urine was brown, protein 1 + , hemoglobin 4+ (Multistix*), and there were 10 to 15 leukocytes, and 0 to 2 erythrocytes per high-powered field. There were numerous hyaline and granular casts. The urine was negative for myoglobin and hemoglobin by the ammonium sulfate precipitation technique. Serum glutamic-oxalacetic transaminase was 647 IU/litre; lactic dehydrogenase, 575 IU/litre; creatinine phosphokinase, 7000 IU/litre; and hydroxybutyric dehydrogenase, 1256 IU/litre; Ca, 41 units, (normal 55 to 120); C4 10 units (normal 20 to 50); 24-h urine for protein, 1.47 g/litre. Antinuclear antibody, 1:4096; anti-DNA, 18.6% (normal, 1 to 14), rheumatoid factor, 1:512. Viral titers when the patient was acutely ill, and convalescent, showed no infection. Electrocardiogram on admission demonstrated a complete right bundle branch block with inverted T waves in V2 and V3. Electromyogram demonstrated increased insertional activity with positive waves and fibrillations. There were many brief, short polyphasic potentials. Muscle biopsy from the left deltoid showed acute and severe inflammatory myopathy (Figure 1). All medications were stopped, and the patient was begun on high-dose prednisone. Her course was complicated by transient dysrhythmias that responded to digoxin. Within 1 month, the patient was able to ambulate without assistance. Steroids were subsequently withdrawn and all values, with the exception of the antinuclear antibody and rheumatoid factor, have remained normal for the 6 months her course has been followed. Although this patient fulfills all the criteria proposed by Bohan and Peter (4) for the diagnosis of polymyositis, the association of myocarditis, proteinuria, and hypocomplementemia is not typical of polymyositis. This particular constellation has not been reported in previous D-penicillamine-induced polymyositis (3) or lupus-like syndromes (2). Because of the temporal relationships involved and the response to therapy, we believe that this case represents an immune complex disorder secondary to D-penicillamine treatment. The pathophysiology is still unclear. In view of this report and the established toxicity of this drug, caution is warranted in further trials with D-penicilla* Ames Co., Elkhart, Indiana
Figure. 1 . Biopsy of left deltoid muscle, demonstrating mononuclear inflammatory cell infiltrate and muscle necrosis with associated sarcolemmal proliferation. (Hematoxylin and eosin; original magnification, X 110). Letters
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615
mine in patients with rheumatoid arthritis, a disease that is rarely life threatening. BOBB G. CUCHER, M.D. A. L. GOLDMAN, M.D.
Department of Medicine Columbia Hospital; and The Medical College of Wisconsin Milwaukee, WI 53226 Received 13 February 1976. References 1. MULTICENTRE TRIAL GROUP: Controlled trial of D-penicillamine
in severe rheumatoid arthritis. Lancet 1:275-280, 1973 2. HARPEY JP, CAILLE B, MOULIAS P, et al: Lupus-like syndrome
induced by D-penicillamine in Wilson's disease. Lancet 1:292, 1971 3. SCHRAEDER PL, PETERS HA, DAHL DS: Polymyositis and peni-
cillamine. Arch Neurol 27:456-457, 1972 4. BOHAN A, PETER JB: Polymyositis and dermatomyositis. N Engl
J Med 292:344-347, 403-407, 1975
Diffuse Intervertebral Disk Calcification in Primary Amyloidosis DIFFUSE CALCIFICATION of many lumbar and thoracic in-
tervertebral disks has been thought to be highly suggestive, if not pathognomonic, of ochronosis. A patient with widespread intervertebral disk calcification that was unexplained during life, was found at autopsy to have primary amyloidosis with infiltration of the intervertebral disks by both amyloid deposits and calcification. This association has not been noted previously. Amyloidosis may be responsible for diffuse intervertebral disk calcification. In December 1962, a 63-year-old Puerto Rican musician was noted to have calcification of several thoracic intervertebral disks on routine chest Xray. In 1965 an upper gastrointestinal contrast X-ray examination, performed because of dyspepsia, showed benign antral gastritis and a duodenal diverticulum. In addition, diffuse calcification of the thoracic and lumbar intervertebral disks was noted (Figure 1A and IB). A urine specimen was tested at this time for the presence of homogentisic acid using 10% NaOH and Benedict's solution; no color change was noted. There was no evidence of parathyroid abnormalities, renal disease, or calcification of peripheral joints. A chest Xray in 1968 demonstrated mild cardiomegaly for the first time. There was no hypertension or evidence of valvular disease. In December 1971 he was found to be in mild congestive heart failure; treatment with digoxin and diuretics
was initiated, but symptoms of congestive heart failure persisted. There was no proteinuria. In February 1973 he developed atrial fibrillation. Three weeks later he was hospitalized because of sudden onset of right-side weakness. Initial physical examination revealed flaccid right hemiparesis and congestive heart failure. Electrocardiogram showed atrial fibrillation; chest Xray demonstrated marked cardiomegaly; urinalysis, complete blood count, and values for blood chemistry were within normal limits. Serum albumin was 4/dl and globulin, 3/dl. He was treated for congestive heart failure and discharged with moderate improvement of his hemiparesis. Continued follow-up showed persistence of mild congestive heart failure. Repeated examinations of the urine showed no color change either on prolonged standing or on alkalinization of urine. In October 1973 he was readmitted with a 2-day history of vomiting. Shortly after admission he complained of chest pain and shortness of breath. Electrocardiograms and serum enzymes showed an acute inferior wall myocardial infarction. Soon thereafter he developed cardiogenic shock; he died 3 days later. Gross examination showed biventricular myocardial hypertrophy; the myocardium itself was slightly pale. The coronary arteries were relatively free of atherosclerosis. There was a 2-cm pyloric ulcer in the stomach, and a large diverticulum was evident in the second portion of the duodenum. The rest of the findings at gross examination were unremarkable. Microscopic examination showed generalized amyloidosis, most marked in the heart, and also involving the lungs, liver, gastrointestinal tract, spleen, kidneys, pancreas, testes, and adrenals. The intervertebral disks showed destruction with calcification and widespread amyloid deposits. No evidence of ochronotic pigment was found. Recent reviews (1, 2) have emphasized the variable presentation and protean clinical manifestations of systemic amyloidosis. Although involvement of joints and periarticular structures has been noted in some patients with this condition ( 3 ) , amyloidosis of the intervertebral disks has not been reported. It seems likely that diffuse intervertebral disk calcification in this patient occurred consequent to local amyloid deposition. It is recognized that local amyloid deposits can precede the clinical recognition of systemic disease by many years, and calcification of such deposits has been noted by several authors in sites such as lung and endocardium (4, 5 ) . Furthermore, other explanations of intervertebral disk calcification are not consistent with the findings in this patient. Calcification due to degenerative
Figure 1A and IB. Lateral and anteroposterior views of thoracic and lumbar spine of the patient in the present report. C. Anteroposterior view of thoracic and lumbar spine of a patient with documented ochronosis. 616
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disk disease is usually discrete and localized to the lumbar spine, where degenerative disk disease is most frequent. Diffuse, widespread calcification of the intervertebral disks, as seen in this patient, is not characteristic of degenerative disk disease. Similarly, there was no evidence either when the patient was alive or at autopsy for the diagnosis of ochronosis. Localized calcification in ochronosis is felt to occur secondary to destruction of disks by infiltration with homogentistic acid. The current report demonstrates that amyloid infiltration can similarly lead to destruction and secondary calcification of intervertebral disks. The radiographic appearance and distribution of disk calcification seen in ochronosis does not differ significantly from that seen in the patient reported here (Figure 1C). These findings add amyloidosis to ochronosis as a recognized cause of diffuse calcification of intervertebral discs and suggest that other infiltrative processes may similarly lead to calcification at these sites. STANLEY P. BALLOU, M.D. MUHAMMAD ASIM KHAN, M.D., M.R.C.P. IRVING KUSHNER, M.D., F.A.C.P.
Department of Medicine Case Western Reserve University School of Medicine at Cleveland Metropolitan General Hospital Cleveland OH 44109 REFERENCES
1. KYLE RA, BAYRD ED: Amyloidosis: review of 236 cases. Medicine (Baltimore) 54:271-299, 1975 2. BRANDT K, CATHCART ES, COHEN AS: A clinical analysis of the
course and prognosis of forty-two patients with amyloidosis. Am J Med 44:955-969, 1968 3. WIERNIK PH: Amyloid joint disease. Medicine (Baltimore) 51: 465-479, 1972 4. WEISS L: Isolated multiple nodular pulmonary amyloidosis. Am J Clin Pathol 33:318-329, 1960 5. KOLETSKY S, STECHER RM: Primary systemic amyloidosis: involvement of cardiac valves, joints and bones, with pathologic fracture of the femur. Arch Path 27:267-288, 1939
women. (The slope for men was 0.0094 mg/day • ml and women, 0.0072, and the average slope was 0.0084 mg/ day • ml.) The regression line for men was significantly higher (F < 0.05) but parallel to that of women. As a result of these findings, the upper limit of normal range of 24-h urine oxalic acid will vary according to urine volume, in men being approximately 46, 55, and 63 mg/ day for urine volumes 1000, 2000 and 3000 ml/day, respectively, while in women the corresponding values are slightly lower at approximately 42, 50, and 58 mg/day. A similar positive correlation was found when the urine oxalic acid/g of creatinine was plotted against 24-h volume (Figure 1); this suggests that the observed correlation was not due to incomplete urine collection. It is interesting to note that in this correlation the regression line for men still was parallel but was significantly lower than that for women. After this observation, we studied the correlation between 24-h urine oxalic acid and 24-h urine volume in a group of 20 patients with recurrent calcium containing kidney stones who had two or more 24-h urine collections. Again we showed that even in the same person this correlation between 24-h urine volume and 24-h urine oxalic acid exists (P < 0.001). The average slope for these 20 patients was 0.020 mg/day • ml. Our findings agree with those of Pinto and colleagues (4), who observed an increase in the clearance of oxalic acid parallel to urine flow rate up to 3.2 ml/min. We conclude that reliable comparisons between normal subjects and those who form stones cannot be made on the absolute amount of urinary oxalic acid excreted in 24 h, unless the 24-h urine volume also is taken into consideration. Of course, an alternative method would be to
Urine Oxalic Acid: Relation to Urine Flow FINLAYSON (1) has emphasized that merely measuring the 24-h excretion rates of different urinary constituents will be of little value in the study of patients with kidney stones or in determining the effectiveness of different therapeutic regimens, since the formation of kidney stones depends mainly on the concentration of urinary salts. This fundamental point has not been sufficiently emphasized in most papers on renal stones. Comparisons of patients with kidney stones and normal control subjects based on 24-h urine excretion rates are also unreliable because the excretion rates of some constituents are dependent on the rate of urine flow (24-h urine volumes) (2). We recently showed this relation between the amount of oxalic acid excreted in 24 h and the 24-h urine volume. Urine anhydrous oxalic acid was measured by a modification of the method of Hodgkinson and Williams (3). The mean value for a group of 42 men and women was 32.9 mg/day with a range between 21.9 and 49.2 mg/day, similar to the normal ranges observed by Hodgkinson and Williams (3). However, there was a significant positive correlation (P < 0.05) between the 24-h urine excretion of oxalic acid and the 24-h volume in both men and
Figure 1. Correlation between urine anhydrous oxalic acid and 24-h urine volume in a group of normal subjects. Letters
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determine the actual concentration calcium oxalate ( 5 ) .
(activity products) of
D. G. OREOPOULOS, M.D.
H. HUSDAN, PH.D. M. LEUNG, B.SC. D . B. W. REID, M.SC. A. RAPOPORT, M.D.
Metabolic-Renal Unit, The Toronto Western Hospital and the Departments of Medicine, Clinical Biochemistry and Preventive Medicine and Biostatistics, University of Toronto, Toronto, Ontario, Canada. The Toronto Western Hospital and Departments of Medicine, Clinical Biochemistry and Preventive Medicine and Biostatistics University of Toronto
Toronto, ONT, Canada Received 16 April 1976. REFERENCES
1. FINLAYSON B: Renal lithiasis in review. Urol Clin North Am 1:181-212, 1974 2. OREOPOULOS DG, WALKER D, AKRIOTIS DJ, et al: Excretion of
inhibitors of calcification in urine. Part I: Findings in control subjects and patients with renal stones. Can Med Assoc J 112:827-831, 1975 3. HODGKINSON A, WILLIAMS A: An improved colorimetric procedure
for urine oxalate. Clin Chim Acta 36:127-132, 1972 4. PINTO B, CRESPI G, SOLE-BALCELLS F, et al: Patterns of oxalate
metabolism in recurrent oxalate stone formers. Kidney Int 5:285291, 1974 5. ROBERTSON WG, PEACOCK M, NORDIN BEC: Activity products in
stone forming and non stone forming urine. Clin Sci 34:579-594, 1968
The World, 1976, Through the Eyes of the Chinese Medical Journal The current international situation is excellent, there is great disorder under heaven. All the basic contradictions in the world are daily sharpening. The factors for both revolution and war are visibly increasing. Phoney "goulash" communism has gone bankrupt. The Marxist-Leninist Parties and organizations in various countries are growing stronger in the struggle against modern revisionism. The countries and people of the third world have been playing their role as the main force in the struggle against imperialism, colonialism and great-power hegemonism. The contention between the two hegemonic powers, the Soviet Union and the United States, is intensifying; strategically Europe is the focus of their contention. Soviet social-imperialism, which is "making a feint to the east while attacking in the west" and most energetically playing the fraudulent game of "detente," is precisely the most dangerous source of war today. We must heighten our vigilance and be prepared against war. We must continue to carry out the strategic principles advanced by Chairman Mao: "Dig tunnels deep, store grain everywhere, and never seek hegemony"; "Be prepared against war, be prepared against natural disasters, and do everything for the people." The People's Liberation Army and the masses of militiamen should carry forward their glorious revolutionary traditions, strengthen preparedness against war, train hard, be strict with themselves and always be ready to wipe out any invading enemy. We are determined to liberate Taiwan Province, our sacred territory. Nothing Is Hard in This World If You Dare to Scale the Heights. 1976 New Year's Day editorial. By "Renmin Ribao," "Hongqi," and "Jiefangjun Bao" Chinese Medical Journal 2 (new series) (1, special supplement): 3-8, 1976.
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