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The Pathogenesis of Gout
The Pathogenesis of Gout* From the Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina
JAMES B. WYNGAARDEN, M.D. Professor of Medicine and Assoc1:aie Professor of Biochemistry
O. W. JONES, M.D. Senior Assistant Resident in Medicine
syndrome of gout comprises several etiologically distinct varieties. Hence a discussion of the pathogenesis of gout in reality becomes an inquiry into the etiology of each subtype presently recognized. Recent advances in the knowledge of gout, gained from e1inical observations and laboratory studies, suggest the following e1assification: I. Primary gout: hyperuricemia genetically determined A. Attributable to overproduction of uric acid de novo, and/or B. Attributable to undcrexcretion of uric acid H. Secondary gout: hyperuricemia a manifestation of diseases of the hematopoietic system associated with increased turnover of nueleoproteins To the category of secondary gout can perhaps bc added a second f-!ubtype, that of hyperuricemia and articular gout induced in previously normal persons by the action of certain drugs. This type of case if-! difficult to classify with certainty since the data necessary to establish that the subject is not predisposed toward development of gout are in all published cases rather incomplete. This paper will present illustrative cases of several sub types of gout, and thereafter a brief appraisal of the current status of knowledge regarding the various metabolic defects responsible for hyperuricemia in gout. THE CLINICAL
CASE REPORTS
Primary Gout
Classic primary gout is now viewed as an inborn error of metabolism, ill which the cardinal feature if-! hyperuricemia. It is this feature which
* Supported in
part by a grant (A-l:391) from the U. S.
P\lbli(~
Health Service.
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is genetically determined. The disease is pre-eminently a disorder of adult males and is eharaeterized both by reeurrent attacks of acute arthritis of unknown cause and by chronic arthritis associatf'd with deposits of urate in joints and other tissues. The hyperurieemia itself is defined statistically on the basis of analyses of the distributions of serum urie aeid values in the general population. In males hyperurieemia is indicated by values above 6.3 mg. per 100 m!. by colorimptric methods, or above 7.5 mg. per 100 m!. by enzymatic speetrophotometric mpthods. 37 In females normal values average about 20 per cent lower than in males. The prevalence of hyperuricemia is about 2 per cent in the general population, but it varies widely in gouty families, ranging up to 72 per cent.30 Hyperuricemia may antedate clinical gout by many years. In genetically predisposed males hyperuricemia may develop at puberty, whereas in females it usually develops after the menopause. Articular gout complicates hyperuricemia relatively infrequently. Currpnt estimates are that only about 20 per cent of hyperuricemic individuals develop gout. A smaller percentage may develop uric acid calculi, and very occasionally hyperuricemic subjects may develop parenchymal renal disease, so-called hyperurieemie nephropathy,7 in the absence of articular gout. Four cases of primary gout will be presented. The first two illustrate primary gout in which hyperuricemia is attributable, at least in part, to overproduction of uric acid. The second two illustrate primary gout ill which hyperuricemia is attributable, at least in part, to underexcretioll of uric acid. In each pair, one subject has characteristic articular gout, and one has asymptomatic hyperuricemia. CASE 1. H.H. is a 230 pound Negro male who wail seen at Duke Hospital in 1955, at the age of 45, with his first attack of acute gouty arthritis. Blood pressure was 200/120. No tophi were noted. Complete blood count and urinalysis were normal. Nonprotein nitrogen was 33 mg. per cent. Whole blood uric acid values were 5.0, 5.0 and 7.1 mg. per 100 m!. On subsequent therapy with probenecid, 1.0 gram per day, his serum uric acid values dropped to 4.5 mg. per 100 m!. He returned in 1957 with an acute arthritic attack involving the left knee and foot and later the right knee. He responded partially to colchicine and later dramatically to phenylbutazone therapy. Phenolsulfonphthalein excretion was .55 per cent in 2 hours, and an NPN was 37 mg. per cent. Serum uric acid values were 7.7 and 8.5 mg. per 100 m!. Uric acid excretion was 685 ± 82 mg. per 24 hours over a 5-day period. He incorporated 0.18 per cent of a tracer dose of glycine l-C14 into urinary uric acid in 4 days (normal, 0.13 per cent in 4 days).34 X-rays of involved joints revealed no abnormalities. Probenecid therapy was reinstituted, and serum urate levels have since ranged from 4.8 to 7.3 mg. per ] 00 m!. He has had no attack of gouty arthritis for approximately 18 months. mood pressure is now 168/88.
Comment. This obese patient has hyperuricernia and recurrent aeute gouty arthritis of six years' duration. Urinary excretion of uric aeid,
The Pathogenesis oj Gout
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incorporation of glycine l-C14 into urinary uric acid, and turnover of phosphoribosylpyrophosphate (PRPP), a key precursor of purine nucleotides (sec Urate Production in Primary Gout, p. 1248), are all elevated above normal levels. Hence, hyperuricemia is attributable to overproduction of urate in this patient. CASE n. R.A. is a white male who was studied in 1956 at the age of 21. He was admitted for treatment of an active duodenal ulcer, and was found to have serum uric acid values of 7.6 and 7.8 mg. per 100 ml. and a urinary urate excretion of 343 ± 31 mg. per day. There was no personal or familial history of arthritis or renal disease. His urinalysis was normal, with specific gravity of 1.028, and his hemoglobin was 13.8 grams per 100 ml. He incorporated 0.29 per cent of a test dose of glycine l_C14 into urinary uric acid in 7 days34 (normal, 0.11 to 0.22 per cent in 7 days). He has developed no clinical evidence of gout or renal disease.
Comment. This patient with asymptomatic hyperuricemia shows a moderate degree of overincorporation of glycine l-C14 into urinary uric acid, indicating that hyperuricemia is attributable, at least in part, to overproduction of urate. Concomitant underexcretion of urate is suggested by the relatively low urate output in the presence of hyperuricemia. CASE Ill. J.P. is a 22-year-old graduate student who first experienced a typical attack of acute gouty arthritis in his left instep at age 17. One year later an attack in his right great toc responded characteristically to colchicine. Serum uric acid was then 12.6 mg. per 100 ml., and he was treated with probenecid but it was tolerated poorly and discontinued. Over the next two years he had frequent mild and occasional severe gouty attacks in several joints and noted development of tophi in the helices of the ears. Proteinuria has been noted since age 14. There is no family history of gout or renal stone, although the patient's mother had had a few episodes of unexplained mild joint soreness. Her serum uric acid values were 6.9 and 4.9 mg. per 100 ml. on two occasions; his father's serum uric acid was 6.2 mg. per 100 ml., a normal value by the enzymatic method. His maternal grandmother had been found elsewhere to be hyperuricemic. At age 21 he entered Duke graduate school and was found to have a serum uric acid level of 12.1 mg. per 100 ml. and a urinary urate excretion of 317 mg. per 24 hours. Blood urea nitrogen was 19 mg. per 100 ml. Urinalysis showed 2-plus protein, and PSP excretion was 50 per cent in 2 hours. Renal function studies showed inulin clearance = 67 ml./min./1.73 M2, para-aminohippuric acid clearance = 367 ml./min./1.73 M2, filtration fraction = 18.2 per cent. Both clearances are definitely low. Curate/CtnuUn values averaged 5.9 per cent and showed a correlation with urine flow. At a flow rate of 3.1 ml./min., Curate/CtnuUn was 4.7 per cent; at a flow of 6.7 ml./min. the clearance ratio was 7.1 per cent. Glycine I-C14 incorporation into urinary uric acid was 0.15 per cent in 7 days, a low normal value possibly reflecting the large dilution of C14 urate in the expanded body pool of uric acid. One year later, when his serum urate level was 6 to 7 mg. per cent, glycine incorporation was 0.22 per cent, also a normal value. Turnover of PRPP was found to be within normal limits.
Comment.
This 22-year-old subject has had albuminuria smce age
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14, and gout since age 17. The patient's mother and maternal grandmother are hyperuricemic. The patient's hyperuricemia is associated with low excretion of uric acid and moderate renal functional impairment, and he shows no evidence of overproduction of uric acid. CASE IV. J.E. is a 16-year-old white male whose father and paternal uncle have severe tophaceous gouty arthritis. The patient has been asymptomatie except for one brief episode of tenderness of both heels and another of soreness at the base of both thumbs. Physical examination was unremarkable. Serum uric acid was 5.2 mg. per 100 m!. at age 14. Two years later it was 9.2 mg. per 100 ml. and his urate excretion was 270 mg. per 24 hours (enzymatic method). IJrinalysis, BUN and PSP excretion tests have all been within normal limitf'. Renal function studies showed ClnuJln = 116 ml./min./1.73 M2, C PAH = 583 ml./min. /1.73 M2, and a filtration fraction of 18.9 per cent. These are all normal values. Curate/ClnuJln was 4.7 per cent, a relatively low value, well below the mean normal value of 7.6 per cent. 9 , 21 Because of the hyperuricemia and the familial tendency toward development of severe tophaceous gout at an early age, this boy was placed on zoxazolamine, and serum urate levels have been reduced to 6.3 mg. per 100 ml. The patient remains asymptomatic.
Comment. This young patient, a member of a gouty family, had a normal serum uric acid value at age 14. At age 16 he was found to have hyperuricemia. Study of discrete renal functions then showed normal inulin and PAH clearances, but a low uric acid clearance and Curate/Cinulin ratio. Uric acid production has not been studied. This case suggests that the low renal clearance of uric acid is of recent origin and causally related to the hyperuricemia. Secondary Gout
In many cases the coexistence of articular gout and a second disease doubtless represents the chance concurrence of two relatively common disorders. There is good reason for believing, however, that such is not always true. 8 There is a group of disorders involving enhanced turnover of nucleoprotein elements in which hyperuricemia is common and in which acute gouty arthritis and chronic tophaceous gout occur with greater frequency than would be anticipated on the basis of chance alone. These include polycythemia vera (especially those cases merging into the phase of myeloid metaplasia), occasionally secondary polycythemia, chronic myelogenous leukemia, acute leukemia, pernicious anemia, Cooley's anemia and other chronic hemolytic anemias in the adult, and multiple myeloma. The incidence of secondary gout in polycythemia vera, reportedly ranging from 2 to 10 per cent, is too high to be due to chance concurrence. In Yu and Gutman's series39 females comprised 30 per cent of cases of secondary gout and only 3 or 4 per cent of primary gout, and the mean age of onset of articular involvement was 14 years later than in primary gout. Moreover, there may be a distinct temporal
The Pathogenesis of Gout
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relationship between the acute gouty attack and therapy such as radiation or chemotherapy in polycythemia or leukemia, or administration of liver or vitamin B12 in pernicious anemia. The common denominator of disorders leading to this type of secondary gout appears to be an enhanced turnover of nucleoprotein elements. 35 The purine moieties of these nucleoproteins generate excessive quantities of uric acid, and overproduction of uric acid would seem to be a constant feature of this group of disorders. CASE V. J.H., a white male, was 6:3 years of age in 1955 when he was first seen at the Duke Medical Center. Two years prior to his admission polycythemia vera and acute gout were diagnosed simultaneously, although in retrospect plethora had been present at lcast two additional years. Thereafter he had experienced recurrent attacks of acute arthritis involving chiefly the hands and feet. The polycythemia had been treated with multiple phlebotomies. Physical examination revealed plethora, easy bruising, massive hepatosplenomegaly and large tophaceous deposits on the ankles, metatarsal and interphalangeal joints. X-rays of the hands and feet revealed small, punched out cystie areas characteristic of tophaceous gout. Laboratory data revealed a hemoglobin of 18.5 grams, a hematocrit of 57 per cent, white cell count of 13,500 and a platelet count of 944,500. PSP excretion was 55 per cent in 2 hours. NPN waH 35 mg. per 100 m!. and serum urate 12.0 mg. per 100 m!. Uric acid excretion was 851 ± 124 mg. per day. Microscopic examination of material draining from joint nodules revealed urate crystals which gave a positive murexide test. Bone marrow examination revealed a hypercellular marrow with increased number of myeloid elements and megakaryocytes. A glycine 1_C14 study revealed a normal first phase of incorporation into urinary uric acid, 0.20 per cent in 7 days, but thereafter there occurred a second phase of enrichment that eventually reached 0.49 per cent incorporation of C14 into uric acid in 20 days.35 The patient was subsequently treated with P32. The gouty arthritis was treated with probenecid, l.0 to 1.5 grams per day, and colchicine, 1.0 mg. per day. Serum urate levels have ranged from 4.3 to 12.5 mg. per 100 ml., depending upon his consistency in taking probenecid. He has had frequent attacks of acute gouty arthritis which have responded to colchicine.
Comment. In this patient polycythemia vera was diagnosed at the time of the initial gouty episode, but in retrospect had probably been present for at least two additional years. Hyperuricemia was due to overproduction of uric acid, as indicated by the large urinary excretion of uric acid and the excessive incorporation of glycine I-CH into urinary uric acid in 20 days. The second week rise in specific activity of uric acid corresponds with the turnover time of certain ribonucleic acids and indicates that increased turnover of nucleic acids, probably chiefly of hematopoietic elements in this patient, is responsible for the increased production of uric acid. Gout Secondary to Hyperuricemogenic Drugs
Hyperuricemia is a common complication of iSeveral drugiS in frequent dinical use at the present time. A number of episodes of typical a(~lIte
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gouty arthritis have been reported during administration of such drugs as chlorothiazide, hydrochlorothiazide and pyrazinamide. A review of available published cases (e.g., references 4, 12, 15, 18, 20, 22) discloses abundant evidence that these agents may precipitate acute attacks of articular gout in patients who have never before had such attacks. However, we discovered no published case in which the uric acid level was unequivocally normal prior to institution of therapy with chlorothiazide or a similar agent, or consistently normal following its discontinuance unless uricosuric agents were given. The limits of normal accepted for these purposes were: up to 4.0 mg. per 100 ml. of whole blood and up to 4.5 mg. per 100 ml. in men; up to 5.4 mg. per 100 ml. of serum in women, and up to 6.0 mg. in men, by colorimetric methods; up to 5.9 mg. per 100 ml. of serum in women, and up to 7.2 mg. in men, by enzymatic spectrophotometric methods. 37 Thus it is not possible at the present time to exclude the prior existence of hyperuricemia or of an unrecognized genetic propensity toward development of gout in these cases. It is clear that drugs such as pyrazinamide, ehlorothiazide and hydrochlorothiazide may precipitate acute gout in patients predisposed toward development of gout because of pre-existing hyperuricemia of primary or secondary variety. Each of these three drugs has been shown to cause a reduction in renal clearance of urate, although the mechanism by which this reduction is brought about requires further study. It is also not established that the sole disturbance of purine metabolism caused by these agents is that of renal urate retention. Unless such patients are studied carefully the offending drug may be falsely incriminated in a primary etiologic sense when in reality it may have acted only in a precipitating capacity. Two cases are presented which illustrate the difficulty in knowing with certainty the contribution of the drug in question. CASE VI. L.T., a 48-year-old colored female, was admitted to Duke Hospital with rheumatic heart disease and symptoms of congestive heart failure in March 1960. She had been treated with oral diuretics briefly in 1959. Her local physician placed her on chlorothiazide, 500 mg. twice a day in February, 1 month before admission. Two weeks later she suddenly developed swelling, tenderness and redness in the right ankle. These symptoms persisted for 3 days and then subsided. Two days htter, she developed redness and exquisite tenderness in the left great toe, so severe that she slept with the foot propped up and uncovered. She was treated with small doses of colchicine which resulted in complete remission of symptoms within 8 hours. She had had no similar episodes in the past and had no family history of arthritis. On admission to Duke Hospital, she had no objective joint changes. Serum uric acid was 6.4 mg. per 100 ml., BUN was 24 mg. per 100 ml., and PSP excretion test revealed 40 per cent excretion in 2 hours. Chlorothiazide was stopped, and within one week the serum urate had dropped to 5.4 and 5.6 mg. per 100 ml. During the next three months she had no further joint symptoms. She was then readmitted for mitral valvulotomy.
The Pathogenesis of Gout
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Serum uric acid was 6.0 mg. per 100 m!. by the colorimetric method. She was still in mild congestive failure but had a normal BUN.
Comment. This patient developed an acute attack of gouty arthritis less than three weeks after institution of chlorothiazide therapy. After withdrawal of the drug, serum uric acid values returned to near normal values, but three months later after no further therapy with chlorothiazide she was unequivocally hyperuricemic. Thus, chlorothiazide may have precipitated the acute attack, but the drug cannot be held solely responsible for the hyperuricemia. This case illustrates that prolonged observation may be required before a diagnosis of drug-induced hyperuricemia and gout may be established or excluded. CASE VII. C.J., a 33-year-old eolored male, was admitted to Duke Hospital in 1958 and a diagnosis of Boeck's sarcoid was made on the basis of granulomatous uveitis and mediastinal adenopathy. He gave no history of arthritis and no family history of gout. NPN, serum protein, FBi:'), calcium, phosphorus and cholesterol were all within normal limits. PSP excretion test was 72 per cent in 2 hours and serum uric acid was 8.6 mg. per 100 m!. In July 1958, he was found to be hypertensive and was given chlorothiazide, 250 to 500 mg. per day. In March 1959, therapy was changed to hydrochlorothilLzide, 50 mg. twice a day. In August 1959, he developed typical podagra involving the left great toe. Two week>; Inter he had a similar but more severe attack in the same joint. Serum uric acid was 12.8 mg. per 100 m!. The second episode was treated with eolehicine and there was complete relief of pain and inflammation. All oral diuretic therapy was then stopped. The patient has had no further arthritic attack>; during an 18-month period. Serum uric acid was 7.2 mg. per 100 Ill!. in February 1961.
Comment. This patient has hyperuricemia associated with Boeck's sarcoid. He had two attacks of podagra after la months of therapy with chlorothiazide and hydrochlorothiazide, and was then found to have a considerable increase in degree of hyperuricemia. After these drugs were stopped he had no further attacks for 18 months, and the hyperuricemia decreased in severity. This case illustrates the precipitation of an acute gouty attack and accentuation of hyperuricemia by hydrochlorothiazide in a patient with previously asymptomatic hyperuricemia associated with sarcoidosis. Other Environmental Factors
Gout has traditionally been associated with intemperate living and excesses of food and drink. Although these factors have now been largely discredited with the recognition of hereditary and metabolic aspects of gout, there remain in some patients important contributory roles of the environment. Considerable importance attaches to the observation that cases of acute gout were far less frequent in Germany and France during the late 1940's when food, in particular protein, was scarce than prior to 1945 or since 195:3. Zi:illner 41 has summarized the published reports
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and has indicated that acute gout once again became common when protein became available to the general populace. Bien and associates 2 have shown that the rate of synthesis of uric acid in the body of both normal and gouty subjects is enhanced on a high protein diet. About 35 years ago Lennox l7 reported that total caloric restriction was followed by development of marked hyperuricemia, occasionally reaching 20 mg. per 100 ml. of whole blood or even higher. This hyperuricemia was attributed to a decrease in renal clearance of uric acid. Return of calories as fat or amino acids had little effect on hyperuricemia, but ingestion of carbohydrates was followed by a prompt diuresis of urates and a return of the uric acid level to normal. Recently the repetition of this experiment has been witnessed in patients who were placed on virtually total caloric restriction for weight reduction. Serum uric acid levels of 14 to 21 mg. per 100 ml. have been observed, and in one subject with pre-existing gout a severe gouty attack was precipitated. THE METABOLIC DEFECT(S) OF GOUT
Any current inquiry into the metabolic basis of gout must take into (:onsideration certain relevant clinical and accessory observations: (1) Hyperuricemia is common in the general population, perhaps five times as common as clinical gout. (2) Only about one-half of patients with recurrent acute gout eventually develop tophi,! whereas about 2 per cent of patients with gOUG have tophi at the time of their first acute attack. (3) Acute gout may occasionally develop in a patient with a normal serum uric acid level, but rarely, if ever, will a patient fail to show hyperuricemia on some occasions if repeated tests are made. (4) Despite hyperuricemia 67 per cent of patients with primary gout show 24-hour urinary excretions of urate within the normal range as defined statistically (M ± 2 s.d. = 278 to 558 mg. per day), whereas 29 per cent show excretions above normal and 4 per cent below normal. 9 (5) Hyperuricemie nephropathy, though rarely of severe degree in young hyperuricemic subjects,7 is present at autopsy in about 80 per cent of patients with gout. 31 , 33 These and other observations have led various workers interested in gout to postulate that three types of metabolic derangements may exist in this disorder: those responsible for (1) hyperuricemia, (2) the acute gouty attack and (3) tissue depositions of urate, including those in the kidney. We shall consider finit the basis for hyperuricemia in patients with primary gout. Urate Production in Primary Gout
The rate of generation of uric acid has been studied in both normal and gouty subjects by observing the rate at which isotope appears in
The Pathogenesis of Gout
1~49 H~ }H2 C
I
' / ' /H o N'C/H
H-~--:I
(+GLYCINE~ H-~-::JH0
--',
I
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I
CH20P03H2
J!'RIBOSE ~-PHOSPHATE
cr-5-PHOSPHO-,QRIBOSYL -1- PYROPHOSPHATE
(3'5 'PHOSPHO'Q-
GLYCINEAMIDE
RIBOSYL -1- AMINE
RIBOTIDE (GAR)
(PRPP)
(R5P)
(PRA)
o
0
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C HN / "
1
HC~ URIC ACID
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INOSINIC ACID (INOSINE
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I
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5 - AMINO -4-IMIDAZOLECARBOXAMIDE RI80TlDE (AIC'RIBOSIDE 5'-MONOPHOSPHATE. AICRMP)
Fig. I. Biosynthesis of purines. This abbreviated sequence diagram shows some of the major early and late intermediates in the synthesis of uric acid de novo.
urinary uric acid when a labeled precursor is administered. Most such studies have employed labeled glycine, since glycine is a fundamental building block of the purine ring (Fig. 1). When labeled glycine is administered orally and urinary uric acid is isolated over succeeding days, the uric acid shows an increasing isotopic enrichment during the first few days and then declines in isotope concentration. In normal subjects the cumulative incorporation of glycine 1_C14 into urinary uric acid amounts to 0.11 to 0.22 per cent (mean, 0.17 per cent) in seven days.a8 The cumulative incorporation of glycine 1_C14 into urinary uric acid in gouty subjects is to some extent correlated with urinary uric acid excretion. To date, all gouty subjects with excessive urate excretion who have been studied with glycine 1_C14 or glycine N15 have shown excessive incorporation of isotope into urinary uric acid (e.g., Case I). These subjects may quite confidently be regarded as overproducers of uric aeid. In contrast, only about one-half of gouty subjects with normal urate excretion have shown excessive incorporation of isotope into urinary uric acid when glycine 1-Cl4 was employed (cf. Cases II and Ill), and even fewer when glycine N15 was the test material. a7 , 38 Since gouty subjects have a larger pool of uric acid in their bodies than do normal subjects, newly synthesized uric acid will be diluted within this pool to a greater extent in gouty than in control subjects, and this greater dilution will reduce the concentration of isotope in uric acid in urine. When corrections for this dilution factor are applied to results obtained
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,- -- - - I
I
~
~e
- -
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t
Acids etc.'
--ADPATP~Nucleic
Adenosine 5'- P
t
(ATP) (glycine,etc.) Ribose 5-P~ PP-ribose-P---+P-ribosylomine ~ Inosine 5'-P~
~
t
t
Uric Acid Fig. 2. Feedback control of purine synthesis. The enzyme converting PP-ribose-P to P-ribosylamine is inhibited by ATP and ADP, which thus act to regulate the rate of purine synthesis de novo.
on gouty subjects, some apparently normal incorporation values are now shown in reality to be abnormal and to indicate excessive incorporation of glycine into uric acid. However, there still remain some gouty subjects whose glycine incorporation into uric acid appears to be normal despite correction for all known artifacts of the experimental design. 28 It is therefore not possible at present to state that all subjects with primary gout show overproduction of uric acid, although it does appear that the majority do. Overproduction of uric acid appears most likely to involve the same intermediates of purine nucleotide synthesis and degradation as are involved in normal subjects. as A number of metabolic studies are best interpreted as indicating a defect in control of the rate of purine nucleotide synthesis in primary gout. The excess of purine nucleotides synthesized because of this defect of rate control may then be promptly degraded and the purine bases oxidized to uric acid and excreted or stored as urates. A study of factors concerned with control of rates of purine nucleotide synthesis in pigeon liver and bacterial systems has implicated an early step as the site of an autoregulatory mechanism known as feedback control, in which adenosine triphosphate (ATP) acts as regUlator of the rate of purine nucleotide synthesis (Fig. 2).36 The early step involves the first reaction which is specifically and irreversibly concerned with the elaboration of purine nucleotides. This is the reaction in which "active ribose"-phosphoribosylpyrophosphate-is converted to phosphoribosylamine. Phosphoribosylamine has no other function but to serve as a precursor of purine nucleotides. The finding that this early reaction constitutes a site of rate control of purine synthesis has quite naturally led to certain hypotheses regarding the gouty defect. An increase in the PRPP-ATP ratio might tend to promote purine synthesis, but in pigeon liver and bacterial systems the introduction of compounds which compete for PRPP has relatively little effect on rates of purine synthesis.l3 Therefore by implication it would seem that the quantity of PRPP is probably not the rate-controlling factor of this key reaction. The next possibility, that the enzyme mediating this key reaction is itself abnormal and not inhibited by ATP as effectively as in
1251
The Pathogenesis of Gout 1)
IAA
+
PP-ribose-p IAA-ribose-P
2)
IAA-ribose-P
ATP
+
pp i IAA-rlbose
+ Pi
Fig. 3. Biosynthesis of imidazoleacetic acid riboside. Administered IAA reacts with PP-ribose-P to form its ribotide, which then loses its phosphate and is excreted in urine as the riboside. When IAA is given together with glucose-0 4 to label the ribose moiety of PP-ribose-P the metabolic turnover of PP-ribose-P can be studied.
normal persons, is an attractive hypothesis which is currently the subject of study. A series of experiments recently conducted on three gouty subjects with excessive urinary excretion of uric acid strengthens the notion that a defect in rate control at the reaction cited above may be involved in the gouty defect. 14 Glucose CH was administered to label the ribose moiety of PRPP, and imidazole acetic acid was administered to sample PRPP (Fig. 3) as imidazole acetic acid riboside, which appears in good yield in urine under these circumstances. The specific activity of the ribose was found to be considerably greater in the hyperexcretor gouty subjects (e.g., Case I) than in the controls, and the percentage of the test dose of glucose-C14 excreted as imidazoleacetic acid riboside was similarly greater in the gouty subjects than in the controls. These results are consistent with the notion that PRPP is being turned over more rapidly in purine nucleotide synthesis in these gouty subjects than in normals, because of enhanced utilization. In one gouty subject with a normal urinary excretion of uric acid (Case Ill) the turnover of PRPP was not abnormal. Studies by Seegmiller and associates,26, 27 in which the purine precursor aminoimidazolecarboxamide was administered to control and gouty subjects, have shown that in many gouty subjects this compound exerts less of an inhibitory effect upon de novo purine synthesis than in controls. Since this compound is a precursor of ATP, the most likely explanation of these results is that a feedback mechanism normally mediated by ATP is not entirely competent in the gouty subject. Thus, several types of study cast suspicion upon the same mechanism in certain patients with gout. It must not be concluded that the site of the metabolic defect is established by these studies, but these recent developments have focused attention on the early steps of purine synthesis as being possibly the site of a regulatory defect in those patients who overproduce uric acid. Urate Excretion in Primary Gout
There has also been renewed intcrest in the quantitative study of renal handling of uric acid in gouty subjects, and studies from several different laboratories have now shown that the pereentage of the filtered load of uric acid appearing in urine of patients with gout is on the
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Table 1.
GOUT
% 7.6 7.8 7.9 8.3
61 9 13
±
Table 2. CONTROLS
±
O. W.
150 7 9 56
DIFFERENCE
SIGNIFICANCE
%
P
%
No. 2.4 1.4
WYNGAARDEN,
JONES
Excretion of Uric Acid in Primary Gout
CONTROLS
No.
B.
6.8 6.2 4.4 4.2
±
±
2.1 0.5
0.8 1.6 3.5 4.1
< < < <
RE~'.
.02 .02 .01 .01
H 21 1H 25
Excretion of Uric Acid in Subtypes of Primary Gout SUBJECTS WITH GOUT
DIFFER-
SIGNIFICANCE
ENCE
No. til
% 7.6
±
Type 2.4 (A) All subjects (B) Hyperexcretors with GFR > 100 (C) Normoexcretors with GFR > 100 (D) Asymptomatic hyperuricemics (B) vs. (C)
%
No.
% p p
> >
.01 .02
1.7
P
<
.01
2.1
P
<
.01
p
>
.0.1
150 40
6.8 6.6
± ±
2.1 2.0
0.8 1.0
54
5.9
±
1.7
11
5.5
±
0.74
0.7
.02 .05
0.1
> >
>
Values given are percentages of the filtered uric acid load excreted in the urint', recalculated from Gutman and Yu. 9
average somewhat lower than in normal persons (Cases Ill, IV).9, 19,21,25 The difference between a given gouty subject and a given normal subject is generally so small that one can approach this problem only by statifltical analysis of data obtained on groups of subjects. Such an evaluation of four recent studies is given in Table 1, where it is seen that the differences, though small, are significant. Additionally, in Table 2 are presented data recalculated from the paper of Gutman and Yu. 9 In this analysis data are grouped for those gouty subjects whose urinary urate excretion is within the normal range, and again for those whose urate excretion is above the normal range as defined in the original publication. Only those subjects of both groups with inulin clearance of 100 m!. per minute or greater have been included, so as to minimize secondary effects introduced by declining renal function. Recalculated data are also presented for the asymptomatic hypcruricemic group. Note that the differences in tubular handling of urate are not restricted to any one subgroup of hyperuricemic subjects. Those subjects with excessive urinary urate excretion show the renal defect also, although the data on subjects with normal urate excretion do appear to deviate from normal more strikingly than do those on the hyperexcretor group.
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From data presently at hand it appears that overproduction and underexcretion of uric acid both contribute to hyperuricemia of primary gout. There is as yet no proof that both factors operate simultaneously in a given patient with gout, but data on subjects with excessive excretion of uric acid, in whom overproduction is virtually certain, suggest that they may. In Seegmiller's28 extensive study there appear to be overlapping spectrums of the two defects in the gouty population, the extreme!" representing patients with overproduction and excessive isotope incorporation values on the one hand (cf. Case I) and patients with normal isotope incorporation values and high grade defects in urate clearance on the other (cf. Case Ill), many subjects showing evidence of both defects to variable degrees. The nature of the renal defect is uncertain. Gutman et al.1° have recently demonstrated the existence of a tubular secretory mechanism for uric acid excretion in man. Urinary uric acid is not viewed as the sum of filtered uric acid escaping reabsorption in the proximal tubule and of uric acid secreted, probably at the level of the distal tubule. The current working hypothesis is that the tubular secretory mechanism is for some reason less effective in thc gouty than the normal person. This reduced effectiveness might be a consequence of a fundamental defect of the transport mechanism, either quantitative or qualitative, or the result of action of an inhibitor of urate transport. There is at least one prototype for the co-existence of metabolic defects involving both production and excretion of a given compound. In the xanthinuria syndrome, in which there appears to be a total absence of xanthine oxidase activity, there is also a defect in tubular reabsorption of xanthine. 6 The relationship between production and excretory defects in human gout remains uncertain. Perhaps these are linked genetic phenomena; perhaps there are common sequences of polypeptides in two key enzymes, both of which are affected by one genetic aberration; or perhaps a single metabolic defect leads simultaneously to overproduction of uric acid and excessive elaboration of an inhibitory intermediate which secondarily affects uric acid transport in the kidney. Genetics of Primary Gout
The studies of the genetic transmission of the trait for hyperuricemia are complicated in that they have considered hyperuricemia to be a homogeneous trait, i.e., caused by the same metabolic defect in all hyperuricemic subjects. If and when it is possible to segregate from the hyperuricemic population a specific subtype based on a characterizable metabolic lesion, further genetic studies may bring greater clarity to this important topic. The present status may be summarized as follows: When viewed in successive generations of a family, hyperuricemia appears to be inherited as an autosomal dominant trait with a low degree
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of penetrance, particularly in women. 29, 32 On the other hand, when studies are done on siblings of gouty patients the data suggest a cumulative gene action, i.e., hyperuricemia influenced by more than one gene. l l The information discussed above implicating bot.h production and excretion defects renders the hypothesis of multiple genetic factors quite plausible, although the possibility that more than one defect results from a single genetic abnormality is by no meallS excluded. ACUTE GOUT
The mechanism underlying the acute gouty paroxysm is unknown. It has been presumed that precipitation of urate in the synovial membrane may trigger the attack, but this is unproved. There is no consistent change in level of serum uric acid before, during or after an acute gouty attack, and the therapeutic specific, colchicine, has no detectable influence on serum or urinary uric acid levels. Biopsies of synovial membrane during acute gouty attacks have sometimes shown urate crystals of apparently recent origin. 31 , 40 This finding has not becn invariable, and even in those instances in which crystals were detected there was no proof that they were causally related to the paroxysm. Infusion of uric acid intravenously or even in the vicinity of or into the joint does not produce an acute gouty attack even in the susceptible subject. These are of course short-term studies and scarcely simulate the prolonged periods of hyperuricemia which antedate development of gout in most patients. Precipitation of acute gout by hyperuricemogenic drugs or by the rigorous dietary proscriptiolls mentioned above may more nearly approximate a valid model for study of gout, but even these "experiments" do not constitute proof that uric acid is itself related to the acute attack, since these measures may also cause other disturbances of body metabolism. Nevertheless, despite valid critical reservations held by many workers regarding the role of uric acid in the genesis of acute gout, hyperuricemia remains the one common denominator of virtually all instances of acute gout. Furthermore, gouty patients who take uricosuric agents faithfully frequently notice an accentuation of acute symptoms initially when urate mobilization is proceeding briskly and an impressive reduction in number of acute attacks aftcr the initial six to twelve months of therapy, when the bulk of mobilizable urate has been excreted. These observations suggest that the role of uric acid itself in the production of the paroxysm cannot yet be dismissed, although a few clues have recently becn found which suggcst that other metabolic factors must also be com;idered. There are minor changes in the urinary excretion of two purine compounds during the acute attack. The urinary excretion of succinoadenine, a purine base which in nucleotide linkage is a precursor of ATP, declines during the acute attack, whereas that of 7-methyl-8-hydroxyguanine, a
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purine base of uncertain origin, increases during acute gout. 8 Changes observed arc small, involving alterations of a few milligrams per day, but these are pcrcentualJy large changes since the basal excretions are very low. It is of interest that the urinary excretion of the 7-methyl-8hydroxyguanine is uniformly elevated in those conditions associated with secondary gout due to disorders of the myeloproliferative system. The observation that colchicine and phenylhutazone inhibit uric acid riboside phosphorylase! 6 has raised the question whether uric acid riboside might he related to the acute gouty episode. This compound is present in beef erythrocyte but has never been detected in human tissue. 23 In the syndrome xanthinuria, in which there is an apparent absence of xanthine oxidase activity, the inability to synthesize uric acid is virtually complete. 5 • 6 This observation suggests that uric acid is formed exclusively by oxidation of xanthine and hypoxanthine and raises a serious doubt regarding the presence of uric acid riboside in human tissues. The questions of "allergy" and of "pituitary-adrenal alarm" continue to be raised but rest on inadequate evidence, as discussed elsewhere. 37 Thus, despite much progress in understanding the etiology of hyperuricemia in gout, the mechanism of the acute attack remains obscure. TISSUE FACTORS
Even if all factors responsible for hyperuricemia and for the acute gouty attack were known, this knowledge would not in itself constitute a full explanation for the disease, for it would not adequately explaill the local tissue factors leading to precipitation of urate. Little is knowll regarding such factors, and indeed they may not require equal cOImideration in all gouty subjects, for visible tophi appeared in only about half of the gouty population even prior to the advent of effective uricosuric therapy.! Two general categories of mechanisms have been proposed regarding deposition of urate in gout. Borrowing some terms from concepts of pathologic calcification, Sokoloff31 has grouped these as follows: (1) metastatic, implying that urate is deposited in tissues because excessive quantities are presented to them by circulating blood, and (2) dystrophic, implying that urate is deposited in tissues because the latter have undergone some primary pathologic alteration rendering them susceptible of urate deposition. These two categories are not mutually exelusive. It has been pointed out that urates tend to deposit in relatively avascular tissue. 3! Tissue alterations of unknown type, including evolution of substances in the intercrystalline matrix, may play a role in precipitating or maintaining the tophus. Such alterations, possibly the result of previous injury, might be expected to occur more readily ill tissues with a limited blood supply or in tissues such as cartilage whidl
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depend on perfusion by body fluids for their nutrition. Cartilage hatl an affinity for absorbing urates in vitro, 3 and tarsal bones of swine will cause precipitation of needles such as seen in gout when suspended in saturated solutions of urate. 24 Sokoloff31 has pointed out that several sites of urate deposition in gout-articular and other cartilages, synovial tissues, interstitial tissue of the renal pyramid, and sclerae and heart valves-have in common ground substance containing acid mucopolysaccharide. To be kept in mind is the possibility that certain patients with gout may have tissues with abnormal affinity for urates. If such exist, one might anticipate that information might come from study of young patients with severe tophaceous gout or severe hyperuricemic nephropathy. SUMMARY
1. Classic primary gout is an inborn error of metabolism in which the cardinal feature is hyperuricemia. Most patients with primary gout show evidence for overproduction of uric acid, but as a group they also :-;how evidence for underexcretion of uric acid. These two factors may operate in concert, though to different degrees, in various patients. 2. Secondary gout occurs as an acquired complication of a number of disorders in which an increase in nucleoprotein turnover occurs. There is a suspicion that gout may also be drug-induced on occasion, but published cases have not unequivocally excluded pre-existent hyperuricemia or a genetic propensity toward development of gout. 3. The acute gouty attack may have a different pathogenesis from that of chronic gouty arthritis. 4. Illustrative eases of various subtypes of gout are presented. REFERENCES I. Bartels, E. C. and Matossian, G. S.: Gout: Six-Year Follow-up on Probenecid
(Benemid) Therapy. Arthritis & Rheum. 2: 193, 1959. 2. Hien, E. J., Yu, T. F., Benedict, J. D., Gutman, A. B. and Stetten, D. Jr.: ltelation of Dietary Nitrogen Consumption to Rate of Uric Acid Synthesis ill Normal and Gouty Man. J. Clin. Invest. 32: 778, 1953. 3. Brugsch, T. and Citron, J.: Ueber die Absorption der Harnsaure durch Knorpel. Ztschr. exper. Path. u. Therap. iJ: 401, 1908. 4. Cullen, J. H., Early, L. J. A. and Fiore, J. M.: Occurrence of Hyperuricemia during Pyrazinamide-Isoniazid Therapy. Am. Rev. Tuberc. 74: 289, 1956. 5. Dent, C. E. and Philpot, G. F.: Xanthinuria, an Inborn Error (or Deviation) of Metabolism. Lancet 1: 182, 1954. G. Dickinson, C. J. and Smellie, J. M.: Xanthinuria. Brit. M. J. 2: 1217, 1959. 7. Duncan, H. and Dixon, A.: Gout, Familial Hyperuricaemia, and Renal Disease. Quart. J. Med. 29: 127, 1960. 8. Gutman, A. B., Vu, T. F. and Weissmann, B.: The Concept of Hecondary Gout; Relation to Purine Metabolism in Polycythemia and Myeloid Metaplasia.. Tr. A. Am. Physicians 69: 229, 1956. 9. Gutman, A. B. and Vu, T. F.: Renal Function in Gout with Commentary 011
The Pathogenesis of Gout 10. 11. 12. 1:3. 14. 15. 16. 17. J 8.
HI.
:W. 21. 22. 23. 24. 25.
26. 27.
28. 29. 30.
:n. :32.
33.
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Henal Hcgulation of Urate Excretion, and Role of Kidney in Pathogenesis of Gout. Am. J. Med. 23: 600, 1957. Gutman, A. B., Yu, T. F. and Berger, L.: Tubular Secretion of Urate in Man. J. Clin. Invest. 38: 1778, 1959. Hauge, M. and Harvald, B.: Heredity in Gout and Hyperuricemia. Acta med. scandinav. 152: 247, 1955. Healey, L. A., Magid, G. J. and Decker, J. L.: Uric Acid Retention Due to Hydrochlorothiazide. New England J. Med. 261: 1358, 1959. Higgins, J. T., Ashton, D. M., Speas, M. and Wyngaarden, J. B.: Evaluation of Relative Roles of Substrate Diversion and Feedback Inhibition in Control of Purine Synthesis. CHn. Res. 9: 181, 1961. Jones, O. W., Ashton, D. M. and Wyngaarden, J. B.: Increased Turnover of Phosphoribosylpyrophosphate, a Purine Nucleotide Precursor, in Certain Gouty Subjects (Abstr.). J. Clin. Invest. 40: June, 1961. Lane, P.: Drug-induced Gout. Brit. M. J. 2: 1383,1960. Laster, L. and Blair, A.: Uric Acid Riboside Phosphorylase in Human TissuesInhibition by Colchicine, and Other Properties. J. Clin. Invest. 37: 909,1958. Lennox, W. G.: Study of Retention of Uric Acid during Fasting. J. BioI. Chem. 66: 521, 1925. Monroe, K. E., Grant, L. H., Sasahara, A. A. and Littman, D.: Effect of Chlorothiazide Therapy on Serum Uric Acid and Uric Acid Excretion. New England J. Med. 261: 290, 1959. Mugler, A., Pernet, A. and Friedrich, S.: Le Pourvior d'Epuration du Rein pour I' Acide Urique chez I'Hyperuricemique d'apres l'Etude de 400 Clearances. In Goslings, J. and Van Swaay (eds.): Contemporary Rheumatology. Amsterdam, Elsevier Pub. Co., 1956, p. 581. Naimark, A. and Fyles, T. W.: Gout as a Complication of Chlorothiazidc Therapy. Canad. M. A. J. 83: 819, 1960. Nugent, C. A. and Tyler, F. H.: Renal Excretion of Uric Acid in Patients with Gout and in Nongouty Subjects. J. Clin. Invest. 38: 1890, 1959. Orcn, B. G., Rich, M. and Belle, M. S.: Chlorothiazide (Diuril) as a Hyperuricacidemic Agent. J.A.M.A. 168: 2128, 1958. Overgaard-Hansen, K. and Nielsen, A. T.: Does Human Blood Contain Uric Acid Riboside? Scandinav. J. Clin. & Lab. Invest. 9: 194. 1947. Roberts, W.: Croonian Lectures on Chemistry and Therapeutics of Uric: Acid Gravel and Gout. Brit. M. J. 2: 61,1892. Sala, G, Ballabio, C. B., Amira, A., Ratti, G. and Cirla, E.: Renal Mechanisms for Urate Excretion in Normal and Gouty Subjects. In Goslings, J. and Van Swaay (eds.): Contemporary Rheumatology. Amsterdam, Elsevier Pub. Co., 1956, p. 581. Seegmiller, J. E., Laster, L. and Stetten, D. Jr.: Incorporation of 4-Amino-5imidazolecarboxamide-4-CJ3 into Uric Acid in Normal Human .•J. BioI. Chem. 216: 653, 1955. Seegmiller, J. E., Laster, L. and Stetten, D. Jr.: Uric Acid Formation in Patients with Gout. Incorporation of 4-Amino-5-imidazolccarboxamide-C13 into Uric Acid. Ninth International Congress on Rheumatic Diseases, 2: 207, 1957. Seegmiller, J. E.: Decreased Henal Excretion of Uric Acid as Cause of Hyperuricemia in Gout. Seventh Interim Scientific Session of American Rheumatism Association, Dec. 9-10, 1960, p. 21. Smyth, C. J., Cotterman, C. W. and Freyberg, R. H.: Genetics of Gout and Hypermicemia. Analysis of Nineteen Families. J. Clin. Invest. 27: 749, 1948. Smyth, C. J.: Hereditary Factors in Gout. Review of Recent Literature. Metabolism 6: 218, 1957. Sokoloff, L.: Pathology of Gout. Metabolism 6: 230, 1957. Stecher, R. M., Hersh, A. H. and Solomon, W. M.: Heredity of Gout and Hs Relationship to Familial Hyperuricemia. Ann. Int. Med. 31: 595, 1949. Talbott, J. H. and Tcrplan, K. L.: The Kidney in Gout. Medicine 39: 405,1960.
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34. Wyngaarden, J. B.: Overproduction of Uric Acid as Cause of Hyperuricemia in Primary Gout. J. Clin. Invest. 36: 1508, 1957. 35. Wyngaarden, J. B., Blair, A. E. and Hilley, L.: On Mechanism of Overproduction of Uric Acid in Patients with Primary Gout. J. Clin. Invest. 37: 579,1958. 36. Wyngaarden, J. B. and Ashton, D. M.: Regulation of Activity of Phosphoribosylpyrophosphate Amidotransferase. J. BioI. Chem. 234: 1492, 1959. 37. Wyngaarden, J. B.: Gout. 1 n Stanbury, J. B., Wyngaardell, J. B. and Fredrickson, D. S. (eds.): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill Book Co., 1960, p. 679. 38. Wyngaarden, J. B.: On the Dual Etiology of Hyperuricemia in Primary Gout. Arthritis & Rheum. 3: 414, 1\)60. 39. Yu, T. F. and Gutman, A. B.: Secondary Gout-Observations in 20 Cases. Second Pan-American Congress on Rheumatic Diseases, Washington, D.C., June 2-6, 1959, p. 44. 40. Zeveley, H. A., French, A. J., Mikkclson, W. M. and Duff, I. F.: Synovial Specimens Obtained by Knee Joint Punch Biopsy. Am. J. Med. 20: 510, 1956. 41. Ziillner, N.: Moderne Gichtprobleme. In Heilmeyer, L., Schoen, R. and DcRudder B. (comps.): Atiologie, Pathogenese, Klinik, in Ergebnisse der inneren Medizin und Kinderkeilkunde. Berlin, Springer-Verlag, 1960, p. 21.
Duke University Medical Center Durham, North Carolina
JAMES B. WYNGAARDEN, M.D. Professor of Medicine and Assoc1:aie Professor of Biochemistry
O. W. JONES, M.D. Senior Assistant Resident in Medicine
syndrome of gout comprises several etiologically distinct varieties. Hence a discussion of the pathogenesis of gout in reality becomes an inquiry into the etiology of each subtype presently recognized. Recent advances in the knowledge of gout, gained from e1inical observations and laboratory studies, suggest the following e1assification: I. Primary gout: hyperuricemia genetically determined A. Attributable to overproduction of uric acid de novo, and/or B. Attributable to undcrexcretion of uric acid H. Secondary gout: hyperuricemia a manifestation of diseases of the hematopoietic system associated with increased turnover of nueleoproteins To the category of secondary gout can perhaps bc added a second f-!ubtype, that of hyperuricemia and articular gout induced in previously normal persons by the action of certain drugs. This type of case if-! difficult to classify with certainty since the data necessary to establish that the subject is not predisposed toward development of gout are in all published cases rather incomplete. This paper will present illustrative cases of several sub types of gout, and thereafter a brief appraisal of the current status of knowledge regarding the various metabolic defects responsible for hyperuricemia in gout. THE CLINICAL
CASE REPORTS
Primary Gout
Classic primary gout is now viewed as an inborn error of metabolism, ill which the cardinal feature if-! hyperuricemia. It is this feature which
* Supported in
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is genetically determined. The disease is pre-eminently a disorder of adult males and is eharaeterized both by reeurrent attacks of acute arthritis of unknown cause and by chronic arthritis associatf'd with deposits of urate in joints and other tissues. The hyperurieemia itself is defined statistically on the basis of analyses of the distributions of serum urie aeid values in the general population. In males hyperurieemia is indicated by values above 6.3 mg. per 100 m!. by colorimptric methods, or above 7.5 mg. per 100 m!. by enzymatic speetrophotometric mpthods. 37 In females normal values average about 20 per cent lower than in males. The prevalence of hyperuricemia is about 2 per cent in the general population, but it varies widely in gouty families, ranging up to 72 per cent.30 Hyperuricemia may antedate clinical gout by many years. In genetically predisposed males hyperuricemia may develop at puberty, whereas in females it usually develops after the menopause. Articular gout complicates hyperuricemia relatively infrequently. Currpnt estimates are that only about 20 per cent of hyperuricemic individuals develop gout. A smaller percentage may develop uric acid calculi, and very occasionally hyperuricemic subjects may develop parenchymal renal disease, so-called hyperurieemie nephropathy,7 in the absence of articular gout. Four cases of primary gout will be presented. The first two illustrate primary gout in which hyperuricemia is attributable, at least in part, to overproduction of uric acid. The second two illustrate primary gout ill which hyperuricemia is attributable, at least in part, to underexcretioll of uric acid. In each pair, one subject has characteristic articular gout, and one has asymptomatic hyperuricemia. CASE 1. H.H. is a 230 pound Negro male who wail seen at Duke Hospital in 1955, at the age of 45, with his first attack of acute gouty arthritis. Blood pressure was 200/120. No tophi were noted. Complete blood count and urinalysis were normal. Nonprotein nitrogen was 33 mg. per cent. Whole blood uric acid values were 5.0, 5.0 and 7.1 mg. per 100 m!. On subsequent therapy with probenecid, 1.0 gram per day, his serum uric acid values dropped to 4.5 mg. per 100 m!. He returned in 1957 with an acute arthritic attack involving the left knee and foot and later the right knee. He responded partially to colchicine and later dramatically to phenylbutazone therapy. Phenolsulfonphthalein excretion was .55 per cent in 2 hours, and an NPN was 37 mg. per cent. Serum uric acid values were 7.7 and 8.5 mg. per 100 m!. Uric acid excretion was 685 ± 82 mg. per 24 hours over a 5-day period. He incorporated 0.18 per cent of a tracer dose of glycine l-C14 into urinary uric acid in 4 days (normal, 0.13 per cent in 4 days).34 X-rays of involved joints revealed no abnormalities. Probenecid therapy was reinstituted, and serum urate levels have since ranged from 4.8 to 7.3 mg. per ] 00 m!. He has had no attack of gouty arthritis for approximately 18 months. mood pressure is now 168/88.
Comment. This obese patient has hyperuricernia and recurrent aeute gouty arthritis of six years' duration. Urinary excretion of uric aeid,
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incorporation of glycine l-C14 into urinary uric acid, and turnover of phosphoribosylpyrophosphate (PRPP), a key precursor of purine nucleotides (sec Urate Production in Primary Gout, p. 1248), are all elevated above normal levels. Hence, hyperuricemia is attributable to overproduction of urate in this patient. CASE n. R.A. is a white male who was studied in 1956 at the age of 21. He was admitted for treatment of an active duodenal ulcer, and was found to have serum uric acid values of 7.6 and 7.8 mg. per 100 ml. and a urinary urate excretion of 343 ± 31 mg. per day. There was no personal or familial history of arthritis or renal disease. His urinalysis was normal, with specific gravity of 1.028, and his hemoglobin was 13.8 grams per 100 ml. He incorporated 0.29 per cent of a test dose of glycine l_C14 into urinary uric acid in 7 days34 (normal, 0.11 to 0.22 per cent in 7 days). He has developed no clinical evidence of gout or renal disease.
Comment. This patient with asymptomatic hyperuricemia shows a moderate degree of overincorporation of glycine l-C14 into urinary uric acid, indicating that hyperuricemia is attributable, at least in part, to overproduction of urate. Concomitant underexcretion of urate is suggested by the relatively low urate output in the presence of hyperuricemia. CASE Ill. J.P. is a 22-year-old graduate student who first experienced a typical attack of acute gouty arthritis in his left instep at age 17. One year later an attack in his right great toc responded characteristically to colchicine. Serum uric acid was then 12.6 mg. per 100 ml., and he was treated with probenecid but it was tolerated poorly and discontinued. Over the next two years he had frequent mild and occasional severe gouty attacks in several joints and noted development of tophi in the helices of the ears. Proteinuria has been noted since age 14. There is no family history of gout or renal stone, although the patient's mother had had a few episodes of unexplained mild joint soreness. Her serum uric acid values were 6.9 and 4.9 mg. per 100 ml. on two occasions; his father's serum uric acid was 6.2 mg. per 100 ml., a normal value by the enzymatic method. His maternal grandmother had been found elsewhere to be hyperuricemic. At age 21 he entered Duke graduate school and was found to have a serum uric acid level of 12.1 mg. per 100 ml. and a urinary urate excretion of 317 mg. per 24 hours. Blood urea nitrogen was 19 mg. per 100 ml. Urinalysis showed 2-plus protein, and PSP excretion was 50 per cent in 2 hours. Renal function studies showed inulin clearance = 67 ml./min./1.73 M2, para-aminohippuric acid clearance = 367 ml./min./1.73 M2, filtration fraction = 18.2 per cent. Both clearances are definitely low. Curate/CtnuUn values averaged 5.9 per cent and showed a correlation with urine flow. At a flow rate of 3.1 ml./min., Curate/CtnuUn was 4.7 per cent; at a flow of 6.7 ml./min. the clearance ratio was 7.1 per cent. Glycine I-C14 incorporation into urinary uric acid was 0.15 per cent in 7 days, a low normal value possibly reflecting the large dilution of C14 urate in the expanded body pool of uric acid. One year later, when his serum urate level was 6 to 7 mg. per cent, glycine incorporation was 0.22 per cent, also a normal value. Turnover of PRPP was found to be within normal limits.
Comment.
This 22-year-old subject has had albuminuria smce age
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14, and gout since age 17. The patient's mother and maternal grandmother are hyperuricemic. The patient's hyperuricemia is associated with low excretion of uric acid and moderate renal functional impairment, and he shows no evidence of overproduction of uric acid. CASE IV. J.E. is a 16-year-old white male whose father and paternal uncle have severe tophaceous gouty arthritis. The patient has been asymptomatie except for one brief episode of tenderness of both heels and another of soreness at the base of both thumbs. Physical examination was unremarkable. Serum uric acid was 5.2 mg. per 100 m!. at age 14. Two years later it was 9.2 mg. per 100 ml. and his urate excretion was 270 mg. per 24 hours (enzymatic method). IJrinalysis, BUN and PSP excretion tests have all been within normal limitf'. Renal function studies showed ClnuJln = 116 ml./min./1.73 M2, C PAH = 583 ml./min. /1.73 M2, and a filtration fraction of 18.9 per cent. These are all normal values. Curate/ClnuJln was 4.7 per cent, a relatively low value, well below the mean normal value of 7.6 per cent. 9 , 21 Because of the hyperuricemia and the familial tendency toward development of severe tophaceous gout at an early age, this boy was placed on zoxazolamine, and serum urate levels have been reduced to 6.3 mg. per 100 ml. The patient remains asymptomatic.
Comment. This young patient, a member of a gouty family, had a normal serum uric acid value at age 14. At age 16 he was found to have hyperuricemia. Study of discrete renal functions then showed normal inulin and PAH clearances, but a low uric acid clearance and Curate/Cinulin ratio. Uric acid production has not been studied. This case suggests that the low renal clearance of uric acid is of recent origin and causally related to the hyperuricemia. Secondary Gout
In many cases the coexistence of articular gout and a second disease doubtless represents the chance concurrence of two relatively common disorders. There is good reason for believing, however, that such is not always true. 8 There is a group of disorders involving enhanced turnover of nucleoprotein elements in which hyperuricemia is common and in which acute gouty arthritis and chronic tophaceous gout occur with greater frequency than would be anticipated on the basis of chance alone. These include polycythemia vera (especially those cases merging into the phase of myeloid metaplasia), occasionally secondary polycythemia, chronic myelogenous leukemia, acute leukemia, pernicious anemia, Cooley's anemia and other chronic hemolytic anemias in the adult, and multiple myeloma. The incidence of secondary gout in polycythemia vera, reportedly ranging from 2 to 10 per cent, is too high to be due to chance concurrence. In Yu and Gutman's series39 females comprised 30 per cent of cases of secondary gout and only 3 or 4 per cent of primary gout, and the mean age of onset of articular involvement was 14 years later than in primary gout. Moreover, there may be a distinct temporal
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relationship between the acute gouty attack and therapy such as radiation or chemotherapy in polycythemia or leukemia, or administration of liver or vitamin B12 in pernicious anemia. The common denominator of disorders leading to this type of secondary gout appears to be an enhanced turnover of nucleoprotein elements. 35 The purine moieties of these nucleoproteins generate excessive quantities of uric acid, and overproduction of uric acid would seem to be a constant feature of this group of disorders. CASE V. J.H., a white male, was 6:3 years of age in 1955 when he was first seen at the Duke Medical Center. Two years prior to his admission polycythemia vera and acute gout were diagnosed simultaneously, although in retrospect plethora had been present at lcast two additional years. Thereafter he had experienced recurrent attacks of acute arthritis involving chiefly the hands and feet. The polycythemia had been treated with multiple phlebotomies. Physical examination revealed plethora, easy bruising, massive hepatosplenomegaly and large tophaceous deposits on the ankles, metatarsal and interphalangeal joints. X-rays of the hands and feet revealed small, punched out cystie areas characteristic of tophaceous gout. Laboratory data revealed a hemoglobin of 18.5 grams, a hematocrit of 57 per cent, white cell count of 13,500 and a platelet count of 944,500. PSP excretion was 55 per cent in 2 hours. NPN waH 35 mg. per 100 m!. and serum urate 12.0 mg. per 100 m!. Uric acid excretion was 851 ± 124 mg. per day. Microscopic examination of material draining from joint nodules revealed urate crystals which gave a positive murexide test. Bone marrow examination revealed a hypercellular marrow with increased number of myeloid elements and megakaryocytes. A glycine 1_C14 study revealed a normal first phase of incorporation into urinary uric acid, 0.20 per cent in 7 days, but thereafter there occurred a second phase of enrichment that eventually reached 0.49 per cent incorporation of C14 into uric acid in 20 days.35 The patient was subsequently treated with P32. The gouty arthritis was treated with probenecid, l.0 to 1.5 grams per day, and colchicine, 1.0 mg. per day. Serum urate levels have ranged from 4.3 to 12.5 mg. per 100 ml., depending upon his consistency in taking probenecid. He has had frequent attacks of acute gouty arthritis which have responded to colchicine.
Comment. In this patient polycythemia vera was diagnosed at the time of the initial gouty episode, but in retrospect had probably been present for at least two additional years. Hyperuricemia was due to overproduction of uric acid, as indicated by the large urinary excretion of uric acid and the excessive incorporation of glycine I-CH into urinary uric acid in 20 days. The second week rise in specific activity of uric acid corresponds with the turnover time of certain ribonucleic acids and indicates that increased turnover of nucleic acids, probably chiefly of hematopoietic elements in this patient, is responsible for the increased production of uric acid. Gout Secondary to Hyperuricemogenic Drugs
Hyperuricemia is a common complication of iSeveral drugiS in frequent dinical use at the present time. A number of episodes of typical a(~lIte
1246
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gouty arthritis have been reported during administration of such drugs as chlorothiazide, hydrochlorothiazide and pyrazinamide. A review of available published cases (e.g., references 4, 12, 15, 18, 20, 22) discloses abundant evidence that these agents may precipitate acute attacks of articular gout in patients who have never before had such attacks. However, we discovered no published case in which the uric acid level was unequivocally normal prior to institution of therapy with chlorothiazide or a similar agent, or consistently normal following its discontinuance unless uricosuric agents were given. The limits of normal accepted for these purposes were: up to 4.0 mg. per 100 ml. of whole blood and up to 4.5 mg. per 100 ml. in men; up to 5.4 mg. per 100 ml. of serum in women, and up to 6.0 mg. in men, by colorimetric methods; up to 5.9 mg. per 100 ml. of serum in women, and up to 7.2 mg. in men, by enzymatic spectrophotometric methods. 37 Thus it is not possible at the present time to exclude the prior existence of hyperuricemia or of an unrecognized genetic propensity toward development of gout in these cases. It is clear that drugs such as pyrazinamide, ehlorothiazide and hydrochlorothiazide may precipitate acute gout in patients predisposed toward development of gout because of pre-existing hyperuricemia of primary or secondary variety. Each of these three drugs has been shown to cause a reduction in renal clearance of urate, although the mechanism by which this reduction is brought about requires further study. It is also not established that the sole disturbance of purine metabolism caused by these agents is that of renal urate retention. Unless such patients are studied carefully the offending drug may be falsely incriminated in a primary etiologic sense when in reality it may have acted only in a precipitating capacity. Two cases are presented which illustrate the difficulty in knowing with certainty the contribution of the drug in question. CASE VI. L.T., a 48-year-old colored female, was admitted to Duke Hospital with rheumatic heart disease and symptoms of congestive heart failure in March 1960. She had been treated with oral diuretics briefly in 1959. Her local physician placed her on chlorothiazide, 500 mg. twice a day in February, 1 month before admission. Two weeks later she suddenly developed swelling, tenderness and redness in the right ankle. These symptoms persisted for 3 days and then subsided. Two days htter, she developed redness and exquisite tenderness in the left great toe, so severe that she slept with the foot propped up and uncovered. She was treated with small doses of colchicine which resulted in complete remission of symptoms within 8 hours. She had had no similar episodes in the past and had no family history of arthritis. On admission to Duke Hospital, she had no objective joint changes. Serum uric acid was 6.4 mg. per 100 ml., BUN was 24 mg. per 100 ml., and PSP excretion test revealed 40 per cent excretion in 2 hours. Chlorothiazide was stopped, and within one week the serum urate had dropped to 5.4 and 5.6 mg. per 100 ml. During the next three months she had no further joint symptoms. She was then readmitted for mitral valvulotomy.
The Pathogenesis of Gout
1247
Serum uric acid was 6.0 mg. per 100 m!. by the colorimetric method. She was still in mild congestive failure but had a normal BUN.
Comment. This patient developed an acute attack of gouty arthritis less than three weeks after institution of chlorothiazide therapy. After withdrawal of the drug, serum uric acid values returned to near normal values, but three months later after no further therapy with chlorothiazide she was unequivocally hyperuricemic. Thus, chlorothiazide may have precipitated the acute attack, but the drug cannot be held solely responsible for the hyperuricemia. This case illustrates that prolonged observation may be required before a diagnosis of drug-induced hyperuricemia and gout may be established or excluded. CASE VII. C.J., a 33-year-old eolored male, was admitted to Duke Hospital in 1958 and a diagnosis of Boeck's sarcoid was made on the basis of granulomatous uveitis and mediastinal adenopathy. He gave no history of arthritis and no family history of gout. NPN, serum protein, FBi:'), calcium, phosphorus and cholesterol were all within normal limits. PSP excretion test was 72 per cent in 2 hours and serum uric acid was 8.6 mg. per 100 m!. In July 1958, he was found to be hypertensive and was given chlorothiazide, 250 to 500 mg. per day. In March 1959, therapy was changed to hydrochlorothilLzide, 50 mg. twice a day. In August 1959, he developed typical podagra involving the left great toe. Two week>; Inter he had a similar but more severe attack in the same joint. Serum uric acid was 12.8 mg. per 100 m!. The second episode was treated with eolehicine and there was complete relief of pain and inflammation. All oral diuretic therapy was then stopped. The patient has had no further arthritic attack>; during an 18-month period. Serum uric acid was 7.2 mg. per 100 Ill!. in February 1961.
Comment. This patient has hyperuricemia associated with Boeck's sarcoid. He had two attacks of podagra after la months of therapy with chlorothiazide and hydrochlorothiazide, and was then found to have a considerable increase in degree of hyperuricemia. After these drugs were stopped he had no further attacks for 18 months, and the hyperuricemia decreased in severity. This case illustrates the precipitation of an acute gouty attack and accentuation of hyperuricemia by hydrochlorothiazide in a patient with previously asymptomatic hyperuricemia associated with sarcoidosis. Other Environmental Factors
Gout has traditionally been associated with intemperate living and excesses of food and drink. Although these factors have now been largely discredited with the recognition of hereditary and metabolic aspects of gout, there remain in some patients important contributory roles of the environment. Considerable importance attaches to the observation that cases of acute gout were far less frequent in Germany and France during the late 1940's when food, in particular protein, was scarce than prior to 1945 or since 195:3. Zi:illner 41 has summarized the published reports
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and has indicated that acute gout once again became common when protein became available to the general populace. Bien and associates 2 have shown that the rate of synthesis of uric acid in the body of both normal and gouty subjects is enhanced on a high protein diet. About 35 years ago Lennox l7 reported that total caloric restriction was followed by development of marked hyperuricemia, occasionally reaching 20 mg. per 100 ml. of whole blood or even higher. This hyperuricemia was attributed to a decrease in renal clearance of uric acid. Return of calories as fat or amino acids had little effect on hyperuricemia, but ingestion of carbohydrates was followed by a prompt diuresis of urates and a return of the uric acid level to normal. Recently the repetition of this experiment has been witnessed in patients who were placed on virtually total caloric restriction for weight reduction. Serum uric acid levels of 14 to 21 mg. per 100 ml. have been observed, and in one subject with pre-existing gout a severe gouty attack was precipitated. THE METABOLIC DEFECT(S) OF GOUT
Any current inquiry into the metabolic basis of gout must take into (:onsideration certain relevant clinical and accessory observations: (1) Hyperuricemia is common in the general population, perhaps five times as common as clinical gout. (2) Only about one-half of patients with recurrent acute gout eventually develop tophi,! whereas about 2 per cent of patients with gOUG have tophi at the time of their first acute attack. (3) Acute gout may occasionally develop in a patient with a normal serum uric acid level, but rarely, if ever, will a patient fail to show hyperuricemia on some occasions if repeated tests are made. (4) Despite hyperuricemia 67 per cent of patients with primary gout show 24-hour urinary excretions of urate within the normal range as defined statistically (M ± 2 s.d. = 278 to 558 mg. per day), whereas 29 per cent show excretions above normal and 4 per cent below normal. 9 (5) Hyperuricemie nephropathy, though rarely of severe degree in young hyperuricemic subjects,7 is present at autopsy in about 80 per cent of patients with gout. 31 , 33 These and other observations have led various workers interested in gout to postulate that three types of metabolic derangements may exist in this disorder: those responsible for (1) hyperuricemia, (2) the acute gouty attack and (3) tissue depositions of urate, including those in the kidney. We shall consider finit the basis for hyperuricemia in patients with primary gout. Urate Production in Primary Gout
The rate of generation of uric acid has been studied in both normal and gouty subjects by observing the rate at which isotope appears in
The Pathogenesis of Gout
1~49 H~ }H2 C
I
' / ' /H o N'C/H
H-~--:I
(+GLYCINE~ H-~-::JH0
--',
I
H-C
I
CH20P03H2
J!'RIBOSE ~-PHOSPHATE
cr-5-PHOSPHO-,QRIBOSYL -1- PYROPHOSPHATE
(3'5 'PHOSPHO'Q-
GLYCINEAMIDE
RIBOSYL -1- AMINE
RIBOTIDE (GAR)
(PRPP)
(R5P)
(PRA)
o
0
11
C HN / "
1
HC~ URIC ACID
11
C /N~
11
\H
.
~')
C " H2N /
/"/
N
'R-5'-P
INOSINIC ACID (INOSINE
5'-MONOPHOSPHATE,
IMP)
I
I
I I
I :
I I(+"FORMYL" I GLUTAMINE I ASPARTATE I C02)
I I
C/N' \
11
~CH
I
I
/"/
H2N
'R-5'- P
5 - AMINO -4-IMIDAZOLECARBOXAMIDE RI80TlDE (AIC'RIBOSIDE 5'-MONOPHOSPHATE. AICRMP)
Fig. I. Biosynthesis of purines. This abbreviated sequence diagram shows some of the major early and late intermediates in the synthesis of uric acid de novo.
urinary uric acid when a labeled precursor is administered. Most such studies have employed labeled glycine, since glycine is a fundamental building block of the purine ring (Fig. 1). When labeled glycine is administered orally and urinary uric acid is isolated over succeeding days, the uric acid shows an increasing isotopic enrichment during the first few days and then declines in isotope concentration. In normal subjects the cumulative incorporation of glycine 1_C14 into urinary uric acid amounts to 0.11 to 0.22 per cent (mean, 0.17 per cent) in seven days.a8 The cumulative incorporation of glycine 1_C14 into urinary uric acid in gouty subjects is to some extent correlated with urinary uric acid excretion. To date, all gouty subjects with excessive urate excretion who have been studied with glycine 1_C14 or glycine N15 have shown excessive incorporation of isotope into urinary uric acid (e.g., Case I). These subjects may quite confidently be regarded as overproducers of uric aeid. In contrast, only about one-half of gouty subjects with normal urate excretion have shown excessive incorporation of isotope into urinary uric acid when glycine 1-Cl4 was employed (cf. Cases II and Ill), and even fewer when glycine N15 was the test material. a7 , 38 Since gouty subjects have a larger pool of uric acid in their bodies than do normal subjects, newly synthesized uric acid will be diluted within this pool to a greater extent in gouty than in control subjects, and this greater dilution will reduce the concentration of isotope in uric acid in urine. When corrections for this dilution factor are applied to results obtained
1250
JAMES
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,- -- - - I
I
~
~e
- -
O.
W. JONES
t
Acids etc.'
--ADPATP~Nucleic
Adenosine 5'- P
t
(ATP) (glycine,etc.) Ribose 5-P~ PP-ribose-P---+P-ribosylomine ~ Inosine 5'-P~
~
t
t
Uric Acid Fig. 2. Feedback control of purine synthesis. The enzyme converting PP-ribose-P to P-ribosylamine is inhibited by ATP and ADP, which thus act to regulate the rate of purine synthesis de novo.
on gouty subjects, some apparently normal incorporation values are now shown in reality to be abnormal and to indicate excessive incorporation of glycine into uric acid. However, there still remain some gouty subjects whose glycine incorporation into uric acid appears to be normal despite correction for all known artifacts of the experimental design. 28 It is therefore not possible at present to state that all subjects with primary gout show overproduction of uric acid, although it does appear that the majority do. Overproduction of uric acid appears most likely to involve the same intermediates of purine nucleotide synthesis and degradation as are involved in normal subjects. as A number of metabolic studies are best interpreted as indicating a defect in control of the rate of purine nucleotide synthesis in primary gout. The excess of purine nucleotides synthesized because of this defect of rate control may then be promptly degraded and the purine bases oxidized to uric acid and excreted or stored as urates. A study of factors concerned with control of rates of purine nucleotide synthesis in pigeon liver and bacterial systems has implicated an early step as the site of an autoregulatory mechanism known as feedback control, in which adenosine triphosphate (ATP) acts as regUlator of the rate of purine nucleotide synthesis (Fig. 2).36 The early step involves the first reaction which is specifically and irreversibly concerned with the elaboration of purine nucleotides. This is the reaction in which "active ribose"-phosphoribosylpyrophosphate-is converted to phosphoribosylamine. Phosphoribosylamine has no other function but to serve as a precursor of purine nucleotides. The finding that this early reaction constitutes a site of rate control of purine synthesis has quite naturally led to certain hypotheses regarding the gouty defect. An increase in the PRPP-ATP ratio might tend to promote purine synthesis, but in pigeon liver and bacterial systems the introduction of compounds which compete for PRPP has relatively little effect on rates of purine synthesis.l3 Therefore by implication it would seem that the quantity of PRPP is probably not the rate-controlling factor of this key reaction. The next possibility, that the enzyme mediating this key reaction is itself abnormal and not inhibited by ATP as effectively as in
1251
The Pathogenesis of Gout 1)
IAA
+
PP-ribose-p IAA-ribose-P
2)
IAA-ribose-P
ATP
+
pp i IAA-rlbose
+ Pi
Fig. 3. Biosynthesis of imidazoleacetic acid riboside. Administered IAA reacts with PP-ribose-P to form its ribotide, which then loses its phosphate and is excreted in urine as the riboside. When IAA is given together with glucose-0 4 to label the ribose moiety of PP-ribose-P the metabolic turnover of PP-ribose-P can be studied.
normal persons, is an attractive hypothesis which is currently the subject of study. A series of experiments recently conducted on three gouty subjects with excessive urinary excretion of uric acid strengthens the notion that a defect in rate control at the reaction cited above may be involved in the gouty defect. 14 Glucose CH was administered to label the ribose moiety of PRPP, and imidazole acetic acid was administered to sample PRPP (Fig. 3) as imidazole acetic acid riboside, which appears in good yield in urine under these circumstances. The specific activity of the ribose was found to be considerably greater in the hyperexcretor gouty subjects (e.g., Case I) than in the controls, and the percentage of the test dose of glucose-C14 excreted as imidazoleacetic acid riboside was similarly greater in the gouty subjects than in the controls. These results are consistent with the notion that PRPP is being turned over more rapidly in purine nucleotide synthesis in these gouty subjects than in normals, because of enhanced utilization. In one gouty subject with a normal urinary excretion of uric acid (Case Ill) the turnover of PRPP was not abnormal. Studies by Seegmiller and associates,26, 27 in which the purine precursor aminoimidazolecarboxamide was administered to control and gouty subjects, have shown that in many gouty subjects this compound exerts less of an inhibitory effect upon de novo purine synthesis than in controls. Since this compound is a precursor of ATP, the most likely explanation of these results is that a feedback mechanism normally mediated by ATP is not entirely competent in the gouty subject. Thus, several types of study cast suspicion upon the same mechanism in certain patients with gout. It must not be concluded that the site of the metabolic defect is established by these studies, but these recent developments have focused attention on the early steps of purine synthesis as being possibly the site of a regulatory defect in those patients who overproduce uric acid. Urate Excretion in Primary Gout
There has also been renewed intcrest in the quantitative study of renal handling of uric acid in gouty subjects, and studies from several different laboratories have now shown that the pereentage of the filtered load of uric acid appearing in urine of patients with gout is on the
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Table 1.
GOUT
% 7.6 7.8 7.9 8.3
61 9 13
±
Table 2. CONTROLS
±
O. W.
150 7 9 56
DIFFERENCE
SIGNIFICANCE
%
P
%
No. 2.4 1.4
WYNGAARDEN,
JONES
Excretion of Uric Acid in Primary Gout
CONTROLS
No.
B.
6.8 6.2 4.4 4.2
±
±
2.1 0.5
0.8 1.6 3.5 4.1
< < < <
RE~'.
.02 .02 .01 .01
H 21 1H 25
Excretion of Uric Acid in Subtypes of Primary Gout SUBJECTS WITH GOUT
DIFFER-
SIGNIFICANCE
ENCE
No. til
% 7.6
±
Type 2.4 (A) All subjects (B) Hyperexcretors with GFR > 100 (C) Normoexcretors with GFR > 100 (D) Asymptomatic hyperuricemics (B) vs. (C)
%
No.
% p p
> >
.01 .02
1.7
P
<
.01
2.1
P
<
.01
p
>
.0.1
150 40
6.8 6.6
± ±
2.1 2.0
0.8 1.0
54
5.9
±
1.7
11
5.5
±
0.74
0.7
.02 .05
0.1
> >
>
Values given are percentages of the filtered uric acid load excreted in the urint', recalculated from Gutman and Yu. 9
average somewhat lower than in normal persons (Cases Ill, IV).9, 19,21,25 The difference between a given gouty subject and a given normal subject is generally so small that one can approach this problem only by statifltical analysis of data obtained on groups of subjects. Such an evaluation of four recent studies is given in Table 1, where it is seen that the differences, though small, are significant. Additionally, in Table 2 are presented data recalculated from the paper of Gutman and Yu. 9 In this analysis data are grouped for those gouty subjects whose urinary urate excretion is within the normal range, and again for those whose urate excretion is above the normal range as defined in the original publication. Only those subjects of both groups with inulin clearance of 100 m!. per minute or greater have been included, so as to minimize secondary effects introduced by declining renal function. Recalculated data are also presented for the asymptomatic hypcruricemic group. Note that the differences in tubular handling of urate are not restricted to any one subgroup of hyperuricemic subjects. Those subjects with excessive urinary urate excretion show the renal defect also, although the data on subjects with normal urate excretion do appear to deviate from normal more strikingly than do those on the hyperexcretor group.
The Pathogenesis of Gout
1253
From data presently at hand it appears that overproduction and underexcretion of uric acid both contribute to hyperuricemia of primary gout. There is as yet no proof that both factors operate simultaneously in a given patient with gout, but data on subjects with excessive excretion of uric acid, in whom overproduction is virtually certain, suggest that they may. In Seegmiller's28 extensive study there appear to be overlapping spectrums of the two defects in the gouty population, the extreme!" representing patients with overproduction and excessive isotope incorporation values on the one hand (cf. Case I) and patients with normal isotope incorporation values and high grade defects in urate clearance on the other (cf. Case Ill), many subjects showing evidence of both defects to variable degrees. The nature of the renal defect is uncertain. Gutman et al.1° have recently demonstrated the existence of a tubular secretory mechanism for uric acid excretion in man. Urinary uric acid is not viewed as the sum of filtered uric acid escaping reabsorption in the proximal tubule and of uric acid secreted, probably at the level of the distal tubule. The current working hypothesis is that the tubular secretory mechanism is for some reason less effective in thc gouty than the normal person. This reduced effectiveness might be a consequence of a fundamental defect of the transport mechanism, either quantitative or qualitative, or the result of action of an inhibitor of urate transport. There is at least one prototype for the co-existence of metabolic defects involving both production and excretion of a given compound. In the xanthinuria syndrome, in which there appears to be a total absence of xanthine oxidase activity, there is also a defect in tubular reabsorption of xanthine. 6 The relationship between production and excretory defects in human gout remains uncertain. Perhaps these are linked genetic phenomena; perhaps there are common sequences of polypeptides in two key enzymes, both of which are affected by one genetic aberration; or perhaps a single metabolic defect leads simultaneously to overproduction of uric acid and excessive elaboration of an inhibitory intermediate which secondarily affects uric acid transport in the kidney. Genetics of Primary Gout
The studies of the genetic transmission of the trait for hyperuricemia are complicated in that they have considered hyperuricemia to be a homogeneous trait, i.e., caused by the same metabolic defect in all hyperuricemic subjects. If and when it is possible to segregate from the hyperuricemic population a specific subtype based on a characterizable metabolic lesion, further genetic studies may bring greater clarity to this important topic. The present status may be summarized as follows: When viewed in successive generations of a family, hyperuricemia appears to be inherited as an autosomal dominant trait with a low degree
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of penetrance, particularly in women. 29, 32 On the other hand, when studies are done on siblings of gouty patients the data suggest a cumulative gene action, i.e., hyperuricemia influenced by more than one gene. l l The information discussed above implicating bot.h production and excretion defects renders the hypothesis of multiple genetic factors quite plausible, although the possibility that more than one defect results from a single genetic abnormality is by no meallS excluded. ACUTE GOUT
The mechanism underlying the acute gouty paroxysm is unknown. It has been presumed that precipitation of urate in the synovial membrane may trigger the attack, but this is unproved. There is no consistent change in level of serum uric acid before, during or after an acute gouty attack, and the therapeutic specific, colchicine, has no detectable influence on serum or urinary uric acid levels. Biopsies of synovial membrane during acute gouty attacks have sometimes shown urate crystals of apparently recent origin. 31 , 40 This finding has not becn invariable, and even in those instances in which crystals were detected there was no proof that they were causally related to the paroxysm. Infusion of uric acid intravenously or even in the vicinity of or into the joint does not produce an acute gouty attack even in the susceptible subject. These are of course short-term studies and scarcely simulate the prolonged periods of hyperuricemia which antedate development of gout in most patients. Precipitation of acute gout by hyperuricemogenic drugs or by the rigorous dietary proscriptiolls mentioned above may more nearly approximate a valid model for study of gout, but even these "experiments" do not constitute proof that uric acid is itself related to the acute attack, since these measures may also cause other disturbances of body metabolism. Nevertheless, despite valid critical reservations held by many workers regarding the role of uric acid in the genesis of acute gout, hyperuricemia remains the one common denominator of virtually all instances of acute gout. Furthermore, gouty patients who take uricosuric agents faithfully frequently notice an accentuation of acute symptoms initially when urate mobilization is proceeding briskly and an impressive reduction in number of acute attacks aftcr the initial six to twelve months of therapy, when the bulk of mobilizable urate has been excreted. These observations suggest that the role of uric acid itself in the production of the paroxysm cannot yet be dismissed, although a few clues have recently becn found which suggcst that other metabolic factors must also be com;idered. There are minor changes in the urinary excretion of two purine compounds during the acute attack. The urinary excretion of succinoadenine, a purine base which in nucleotide linkage is a precursor of ATP, declines during the acute attack, whereas that of 7-methyl-8-hydroxyguanine, a
The Pathogenesis ()f G01d
1255
purine base of uncertain origin, increases during acute gout. 8 Changes observed arc small, involving alterations of a few milligrams per day, but these are pcrcentualJy large changes since the basal excretions are very low. It is of interest that the urinary excretion of the 7-methyl-8hydroxyguanine is uniformly elevated in those conditions associated with secondary gout due to disorders of the myeloproliferative system. The observation that colchicine and phenylhutazone inhibit uric acid riboside phosphorylase! 6 has raised the question whether uric acid riboside might he related to the acute gouty episode. This compound is present in beef erythrocyte but has never been detected in human tissue. 23 In the syndrome xanthinuria, in which there is an apparent absence of xanthine oxidase activity, the inability to synthesize uric acid is virtually complete. 5 • 6 This observation suggests that uric acid is formed exclusively by oxidation of xanthine and hypoxanthine and raises a serious doubt regarding the presence of uric acid riboside in human tissues. The questions of "allergy" and of "pituitary-adrenal alarm" continue to be raised but rest on inadequate evidence, as discussed elsewhere. 37 Thus, despite much progress in understanding the etiology of hyperuricemia in gout, the mechanism of the acute attack remains obscure. TISSUE FACTORS
Even if all factors responsible for hyperuricemia and for the acute gouty attack were known, this knowledge would not in itself constitute a full explanation for the disease, for it would not adequately explaill the local tissue factors leading to precipitation of urate. Little is knowll regarding such factors, and indeed they may not require equal cOImideration in all gouty subjects, for visible tophi appeared in only about half of the gouty population even prior to the advent of effective uricosuric therapy.! Two general categories of mechanisms have been proposed regarding deposition of urate in gout. Borrowing some terms from concepts of pathologic calcification, Sokoloff31 has grouped these as follows: (1) metastatic, implying that urate is deposited in tissues because excessive quantities are presented to them by circulating blood, and (2) dystrophic, implying that urate is deposited in tissues because the latter have undergone some primary pathologic alteration rendering them susceptible of urate deposition. These two categories are not mutually exelusive. It has been pointed out that urates tend to deposit in relatively avascular tissue. 3! Tissue alterations of unknown type, including evolution of substances in the intercrystalline matrix, may play a role in precipitating or maintaining the tophus. Such alterations, possibly the result of previous injury, might be expected to occur more readily ill tissues with a limited blood supply or in tissues such as cartilage whidl
1256
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depend on perfusion by body fluids for their nutrition. Cartilage hatl an affinity for absorbing urates in vitro, 3 and tarsal bones of swine will cause precipitation of needles such as seen in gout when suspended in saturated solutions of urate. 24 Sokoloff31 has pointed out that several sites of urate deposition in gout-articular and other cartilages, synovial tissues, interstitial tissue of the renal pyramid, and sclerae and heart valves-have in common ground substance containing acid mucopolysaccharide. To be kept in mind is the possibility that certain patients with gout may have tissues with abnormal affinity for urates. If such exist, one might anticipate that information might come from study of young patients with severe tophaceous gout or severe hyperuricemic nephropathy. SUMMARY
1. Classic primary gout is an inborn error of metabolism in which the cardinal feature is hyperuricemia. Most patients with primary gout show evidence for overproduction of uric acid, but as a group they also :-;how evidence for underexcretion of uric acid. These two factors may operate in concert, though to different degrees, in various patients. 2. Secondary gout occurs as an acquired complication of a number of disorders in which an increase in nucleoprotein turnover occurs. There is a suspicion that gout may also be drug-induced on occasion, but published cases have not unequivocally excluded pre-existent hyperuricemia or a genetic propensity toward development of gout. 3. The acute gouty attack may have a different pathogenesis from that of chronic gouty arthritis. 4. Illustrative eases of various subtypes of gout are presented. REFERENCES I. Bartels, E. C. and Matossian, G. S.: Gout: Six-Year Follow-up on Probenecid
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Duke University Medical Center Durham, North Carolina