Secondary Gout Associated with Myeloproliferative Diseases* imt. Sinai Hospital

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1 Chapter VI Secondary Gout Associated with Myeloproliferative Diseases* By TS'AI-FAN Yu, M.D. imt. Sinai Hospital In a variety of disorders of hemopoiesis, the turnover of nucleic acids is greatly augmented, and an excess of purine metabolites, including uric acid, is released. Under such circumstances, the blood and urine concentrations of uric acid may be markedly increased, and the patient may occasionally develop symptomatic gout, characterized by recurrent acute arthritis and tophaceous deposits. The mere association of gout with some other disorder usually is coincidental; such an association does not necessarily establish a pathogenetic relationship between the two conditions. This can hardly apply, however, to polycythemia Vera and/or myeloid metaplasia, in which the incidence of gout has been reported to be as high as 59 per cent. Even here, however, one must be circumspect in interpretation. In some instances, because of the chronicity and uncertain date of onset of both conditions, it may be impossible to establish the order of precedence of the two diseases. Occasionally there may be a familial history of gout, and the gouty trait may be presumed to be present but to have remained dormant until uncovered by the stimulus of the provocative disease. I should like to present the clinical features of 49 cases of what we have classified as secondary gout observed at the Mount Sinai Hospital. In 42 cases gout was secondary to polycythemia Vera and/or myeloid metaplasia; in seven it was secondary to other blood disorders. Of the first group of 42 cases, gout followed in the wake of active polycythemia in 16, it developed during the transition from active polycythemia to the myelofibrotic stage in 9, and during the stage of advanced myeloid metaplasia in 17. In 13 of these latter 17 cases of myeloid metaplasia, a history of preceding polycythemia was not obtained; in 4 of the 17 cases there was antecedent polycythemia, but symptomatic gout did not occur until the patient developed anemia, leukocytosis, abnormal platelets, and immature white cells and tear-drop red cells in the blood smear. When gout first became manifest, there was already considerable hepatosplenomegaly, and the general condition of the patient was often precarious. The interval between the discovery of the underlying blood disorder and the development of gout varied considerably. In 18 of the 42 cases in the first group, the interval between recognition of the blood disorder and onset of "These studies were supported in part by a grant-in-aid, A-162, from the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, U. S. Public Health Service. 765 ARTHRITIS AND RHEUMATISM, VOL. 8, NO. %-PART 1 (OCTOBER), 1965

2 766 GOUT AND PURINE METABOLISM Table 7a. Secondary Gout Primary Gout (42 eaxs) (1110 cases) Average age at onset Incidence in females 17% 4% Positive family history 7% 30% Table 8. Secondary Gout (42 eases) % Tophaceous Deposits None 38 Minimal 29 Moderate 19 Extensive 14 Primary Gout (1110 cases) 70 Nephrolithiasis gout was 1-4 years, and in 13 it was more than 10 years; the mean interval was approximately 7 years. The average age of onset of overt gout in this group of patients was 59 years, as compared with an average age of 40 years for onset of symptoms in our series of 1,110 cases of primary gout (Table 7a). Since male predominance is not marked in polycythemia Vera and/or myeloproliferative disease, the incidence of secondary gout among females is higher than in primary gout, In our series of 42 cases, there were 7 females ( 17 per cent ), The incidence of females in our series of patients with primary gout is only 4 per cent. Since secondary gout is an acquired disorder, it is to be expected that the incidence of a positive familial history would be low. Three of the 42 patients gave a positive family history of gout; one was the father, one a first cousin and another a second cousin of the patient studied. A positive family history in our series of primary gout was obtained in about 30 per cent. The clinical course of secondary gout varied more than that of primary gout. Although many patients did have typical acute attacks of arthritis, some presented rather atypical and bizarre clinical pictures. Not only was the diagnosis sometimes not easy to make, but also the therapeutic measures employed not infrequently were ineffectual, partly due to the underlying disease, partly due to the variety of drugs the patients had to take. Prophylactic colchicine, if instituted early in an uncomplicated stage of the disease, was beneficial, but the results were rather unpredictable when given in the late, complicated stage of the underlying disease. Tophaceous deposits occurred in 26 of the 42 cases, or almost two-thirds. Of those who had tophi, almost half had more than minimal deposits. In five instances the appearance of tophi preceded the onset of the first acute attack of gout, a very unusual sequence in primary gout. The incidence of nephrolithiasis is higher in secondary gout; 16 of the 42 patients, or more than one-third, had uric acid stone, and many had recurrent attacks, which

3 SECONDARY GOUT AND MYELOPROLIFERATIVE DISEASE SERUM URATE mg.% Fig. 68. were accompanied by urinary tract infection. At least 7 patients had nephropathy, and uremia was the cause of death in 4. The incidence of nephrolithiasis and/or tophaceous deposits in cases of secondary gout was particularly high in the group with myeloid metaplasia. Thus of the 26 cases of secondary gout with myeloid metaplasia, nine had both tophi and nephrolithiasis, had either tophaceous deposits or 13 nephrolithiasis, and only 4 had neither tophi nor nephrolithiasis. The serum urate level in secondary gout is, on the average, higher than that in primary gout (Fig. 68). More than half of the patients had serum urate levels greater than 12 mg. per cent. The mean for the group was 11.7 mg. per cent, as compared to the mean serum urate in our 1,110 cases of primary gout of 9.2 mg. per cent. The urinary excretion of uric acid, as a rule, was excessive in patients who did not have marked renal damage. Figure 69 shows the distribution of urinary uric acid excretion figures in cases of secondary gout compared with that in primary gout. That these subjects should have higher serum and urinary uric acid is not unexpected, in view of their rapid nucleic acid turnover. The miscible pool of uric acid was determined in four representative cases of secondary gout. Table 8 shows that patient J. B. had a uric acid pool slightly in excess of normal. The study was made when he had hyperuricemia only, without manifest gout. The daily renal excretion of uric acid was 570 mg.; About 60 per cent of the daily uric acid production was excreted by the kidneys and 40 per cent was eliminated by extrarenal routes. Patients L. M. and J. K. had symptomatic gout and minimal tophaceous deposits. Their miscible uric acid pools were 2,270 mg. and 3,070 mg., respectively, and both had definitely high turnover rates and extrarenal disposal of substantial proportions of the daily uric acid production. Case J. C. was markedly tophaceous; the pool size was 3,180 mg., or 60 mg./kg. This man had renal calculi, causing pyelonephritis and hydronephrosis. His renal function was markedly impaired. Although his urinary excretion of uric acid was over 800 mg. daily, there

4 768 GOUT AND PURINE METABOLISM a SECONDARY GOUT IRY GOUT v) w 30 v) a URINARY URATE mg./24hrs. Fig. 69. was extrarenal disposal of over 60 per cent of his daily production of uric acid. Since his daily extrarenal disposal amounted to almost 1.5 Gm., it is conceivable that only a part of this quantity was actually excreted by way of the intestinal tract, and some was retained to form tophi, which eventually became immiscible. Augmented hemopoiesis in polycythemia is also reflected in the rate and magnitude of g1y~ine-n~~ incorporation into uric acid. As shown in Figure 70, a consistently different pattern was obtained in the patients with polycythemia as compared to those with primary gout. The heavy line indicates that the uric acid-n15 incorporation apparently was less than normal in the first few days after ingestion of g1ycine-nl5, and progressive enrichment of uric acid-ni5 occurred more slowly than in primary gout, the peak abundance not being reached until the fifteenth day; then there was a very slow decline over a period of weeks. The cumulative incorporation of g1y~ine-n~~ into urinary uric acid demonstrates overproduction of uric acid. (Case L. M., Fig. 71) Of the 42 cases, 26 have died. Eleven succumbed from direct sequelae of the blood disorder, such as hemorrhage, thrombosis, embolism, or cardiac insufficiency. Four died of uremia due to pyelonephritis and hydronephrosis associated with uric acid calculi. The average duration from recognition of the blood disorder to death was a little over 12 years. This span is comparable to that in other reported series of myeloproliferative disease, suggesting that gout did not usually appreciably alter the life expectancy of these subjects. Table 9.--Miscible Pool of Uric Acid in Secondary Gout Miscible Turnover Urinary Serum Tophaeeous Pool Rate Uric Acid Urate Case Deposits (mg.) (mg./day) (mg./day) (mg. %) J. B. None 1, (61%)" 8.2 L. M. Early 2,270 1, (70%) 14.0 J. K. Moderate 3,070 1, (45%) 11.5 J. C. Advanced 3,180 2, (37%) 14.5 *Per cent of daily uric acid production.

5 SECONDARY GOUT AND MYELOPROLIFERATIVE DISEASE 769 Postmortem examination was performed in 13 of the 26 patients who died. Apart from abnormalities pertinent to the underlying myeloproliferative disorder, the prominent findings relevant to gout were chiefly locaited in the kidneys, other than subcutaneous or osseous tophi. In many cases, uric acid crystals appeared as diffuse deposits or microcalculi in the collecting tubules. Clusters or aggregates of uric acid crystals at times caused cavitations in the parenchyma, or were present in various parts of the calyces. In others, pyelonephritis and hydronephrosis were evident, particularly when the calculi were strategically placed. In the seven remaining cases, gout occurred as a secondary complication of various conditions other than polycythemia Vera or myeloid metaplasia (Table 9). In two instances, gout was secondary to chronic myelocytic leukemia during the terminal acute blastic phase. In one, there was one attack of gouty arthritis only during the terminal stage of leukemia, and that attack was resistant to therapy. In the other, there were two attacks of acute gouty arthritis during a span of four years of leukemia; the first attack occurred after 6-mercaptopurine therapy, the second during the patient's terminal blastic stage complicated by septicemia. Both subjects had recurrent attacks of calculi, but no tophi. A third patient with chronic myelocytic leukemia developed his first attack of gout after taking allopurinol. He, too, had nephrolithiasis, and in addition was beginning to show tophi. One case of secondary gout was due to marked polycythemia secondary to congenital heart disease, with a rather typical picture of recurrent gouty arthritis with extensive tophaceous deposits since the age of 35. He finally

6 770 GOUT AND PURINE METABOLISM Fig. 71. (See text. Symbols same as Fig. 70.) died of pulmonary embolism at the age of 50. Tophaceous deposits began to appear shortly after the first attack of acute gouty arthritis. Another case of gout associated with secondary polycythemia occurred in a much older person in whom manifest gout started much later. Nevertheless, his first tophus was discovered during the first attack of acute gouty arthritis. In summary, certain hemopoietic diseases characterized by increased turn-

7 SECONDARY GOUT AND MYELOPROLIFERATIVE DISEASE 771 Table 10. Age at Onset Nephro- Secondary Gout Due to No. of Gout Tophi lithiasis Chronic myelocytic leukemia 3 30,4(P, Secondary polycythemia Congenital heart disease f 0 Pulmonary emphysema Chronic hemolytic anemia Gaucher s disease over of nucleic acid may be associated with marked hyperuricemia, an increased uric acid pool, and augmented renal excretion of uric acid. In some of these patients a clinical syndrome similar to that seen in primary gout develops. However, the incidence of a positive family history is distinctly less than in primary gout. They develop manifest gout at a later age, and the incidence of males is less preponderant. The serum uric acid is apt to be higher, the urinary uric acid excretion greater, nephrolithiasis is more frequent. The incidence of tophi is greater and in some instances tophi may appear before the first attack of acute gouty arthritis.