Gout and hyperuricemia associated with sickle-cell Anemia

Gout and Hyperuricemia

Associated

with Sickle-Cell

Anemia

Michael D. Reynolds

I

N 1958, Talbott and coauthors described a case of gouty arthritis occurring in a man with sickle-cell anemia (SCA).’ They noted that they had not found any similar cases in a reviewing of the literature on gout in Negroes or upon inquiry to several hematologists. Talbott later reported a second example of concurrent gout and SCA,2 and other writers have presented at least 10 more cases (Table 1). Five additional cases not previously reported are described below and in Table 2. CASE

REPORT

The patient, a 30-year-old black man (case 15, Table 2), reported that at least 2 of his 12 siblings had SCA. The first symptoms of sickle cell disease, consisting of pain in the anterior chest and low back, reportedly appeared when he was 15 years old, and a diagnosis of SCA was made at that time. Crises were infrequent until the patient was in his late 20s. when they began occurring about monthly. By age 30, he had cardiac, pulmonary, hepatic, renal, and osseous disease attributed to the hematologic disorder, to alcohol abuse, and to hypertension. Electrophoretic analysis of the patient’s hemoglobin on several occasions showed hemoglobin S with 1.7% hemoglobin F. In 1976 the patient was noted to have hyperuricemia and allopurinol was prescribed, but he did not take the medicine. In the same year, he was admitted to a hospital because of pain in the shoulders, elbows, and wrists, which had begun abruptly on the day of admission. Initial examination of these joints disclosed only pain during movement. The symptoms were attributed to sickle cell crisis. On the second hospital day, however, the right wrist became swollen, red, and hot. The wrist joint was aspirated and microscopic examination of the fluid showed birefringent crystals consistent with sodium urate. In 1980, the patient began making frequent visits to the Emergency Care Area of Howard University Hospital, complaining of pain. About 50% of these visits were for sickle cell crises, manifested by widespread pain in the chest, lower back, or limbs, and often by fever. The remainder of the visits were for localized painful swelling usually involving one hand or foot; inflammation of a first metatarsophalangeal joint was never specifically documented. These latter attacks were mostly diagnosed as gouty arthritis. One attack involved the right knee, and the joint was aspirated. Six milliliters of

From the Department of Medicine, College of Medicine, Howard University, Washington, DC. Address reprint requests IO Michael D. Reynolds, M.D., Department of Medicine, Howard University Hospital, 2041 Georgia Ave., N. W., Washington. DC, 20060. 0 1983 by Grune & Stratton. Inc. 0049-I 72/83/l 207-0007$02.00/0

404

straw-colored, viscous synovial fluid were obtained, which contained 400 WBC/pl (58% polymorphonuclear, 42% mononuclear). The fluid was not examined for crystals. Various regimens of indomethacin, colchicine, and allopurinol were prescribed for symptoms of gout, but the patient did not take the medicines as directed. He had persistent hyperuricemia, with serum uric acid (SUA) measurements ranging from 6.8 to 22.0 mg/dl (normal: 3.9-9.0 mg/dl), and averaging about 15mg/dl (excluding samples obtained while he was under treatment for hyperuricemia in the hospital). During this time, blood urea was often elevated, to a maximum of 52 mg/dl (normal: IO-26 mg/dl), but normal values were recorded intermittently until October 1981 and serum creatinine remained normal. A diuretic (furosemide) had been prescribed for the patient’s cardiovascular disease, but his compliance with this treatment was uncertain. In May 1981 the patient was hospitalized because of a sickle cell crisis manifested by pain in the lower back, lower limbs, and left upper limb. At the time of admission, the interphalangeal joints of the right fifth finger were noted to be enlarged. The serum uric acid level was 13.5 mg/dl. The patient was given liquids intravenously, packed red blood cells, and meperidine. Because allopurinol had been prescribed previously, this drug was administered in a dose of 300 mg daily. On the second hospital day, painful swelling, initially interpreted as “edema,” was observed at the right elbow. The following day, swelling, warmth, and tenderness were noted at the right hand and distal forearm; these signs were attributed to the sickle cell crisis. By the fourth hospital day, the widespread pain of the sickle crisis seemed to be less, but the elbow remained painful. The next day the right foot swelled and was tender. The presence of gouty arthritis was recognized, and rheumatologic consultation was obtained. Examination of the joints on the seventh hospital day showed synovial swelling, with varying degrees of tenderness, at the proximal interphalangeal and metacarpophalangeal joints of the right index and long fingers, at the interphalangeal joint of the left thumb, and at the proximal interphalangeal joint of the left index finger. The right wrist was painful at extremes of motion. The right olecranon bursa and the right knee were distended by effusion; the knee was warm. A 1S-cm rubbery mass was present about the distal interphalangeal joint of the right little finger, which was not painful. Roentgenograms of the hands and wrists showed destruction of the distal interphalangeal joint of the right little finger, with an erosion having an elevated, overhanging bony edge, and dense soft-tissue swelling about the joint. The appearance was typical of chronic gouty arthritis and tophus formation.9’pp258~*60’Narrowing of intercarpal joint spaces in the right wrist, with “cystic” lesions in several carpal bones, also was seen. Articular symptoms, which now were the patient’s major complaint, subsided quickly after treatment with indomethatin was begun. By the tenth hospital day, the SUA level had returned to normal (7.1 mg/dl). This change accompanied a decrease in the proportion of reticulocytes from 16.8% to 0.8%, representing a fall in the absolute reticulocyte count from 321,000 to 22,500/& The relative roles of decreased

Seminars in Arthritis and Rheumatism, Vol. 12, No. 4 (May).

1983

GOUT ASSOCIATED WITH SICKLE-CELL ANEMIA

405

Table 1. Previously Reported

-

Cases of Gout Accompanying

Sickle Cell Anemia

Ageat Casa Number

A”thOl Rutha’s Case Number)

1

et

*q”ih”a

Year

a, I

Sex

Onset of Gout iYears

Serum “rlc Acnd,ma/d1

Jol”,S Affected’

“rate Crystals ,n Synawal Flu,d

RBSDOnsa t0 Colchlclne

1st toe, A. K. IP. hand. E

X6-13

NOt

Yes

34

A

10

ND

“es

female

32,

1st MTP

8.1-12.8

NO

“es

1968

female

16

1st toe. k-et. A

12-16

NO

“es

1968

female

befrxxe17

A. K. W. E

6.2

ND

“es

1968

Inale

K.W.E

6.1

1st toe. A. K, f,nger*. w. s

7.8-I

1968

Ill&

43?

1969

Inale

Sm,th and Kemw’

,961

Jarw’

Icase 21 2

Talbon’ Icase 21

3 4

Icase 11 6

JwvlS’ ,ca*e 2)

6

JarvlS’

16

ND

Yes

NO

Yes

ND

7

10.8

Yes

ND

13 8

not

ND

(case 71 7

Gold et al 5

1968

female

before 63

1.6

8

,caJe 11 Gold et aI.’

1968

mate

307

“podaga”

3.6. 7 4

9

lcase 41 Ball and Swensen’

1970

male

271

feet. A. K. E

10

P.31*1

1973

female

48

1st MTP. K

11

Rothschildet al.’

1980

Inale

49

1st MTP. A. K. H. PIP. MCP, W. E, S

14

1960

In&

28

MTP ,ncludmg Ist. A. K. PIP. MC?,

10.1

1

,case 1, 12

Rothsch,ldet al ’ icase 2) =

ND

yes (2 of 21

ND

W.E.S

-

lMTP

yest1 0‘2,

metatarsophalangeal;

A = ankle; K = knee: H = hip: IP = interphalangeal of finger (PIP = proximal); W = wrist,

E = elbow; S = shoulder. tND

= not done.

SDiagnosis of gouty arthritis said to have been established by synovectomy. erythropoiesis,

allopurinol,

hydration,

and abstinence

from

responsive to colchicine, often accompanied by hyperuricemia. Cases 5 and 6, in which hyperuricemia was not demonstrated, can be regarded as only possible instances of gout; the remaining 6 patients reported before 1970 are probable cases. The cases reported subsequently (9-12), in which urate crystals were demonstrated microscopically, can be regarded as definite. Descrintions of the arthritis often were incomplete. Eight of the 12 patients were said to have podagra,-or arthritis of the first toe or first MTP joint. Ten had arthritis of the ankle or knee. In four cases (2, 3,9, 10) attacks of arthritis involving a single joint were recorded. Nine patients had arthritis of more than one joint but it is not arthritis

alcohol in correcting the hyperuricemia could not be assessed. In September 1981 the patient sustained a laceration on the palmar side of the right little finger, over the distal interphalangeal joint previously noted to be the site of a tophus. The injury became infected and incision and drainage were performed. Tophaceous material was removed during surgery; microscopic examination of the specimen showed amorphous material, crystals, and multinucleated giant cells. Specific examination for sodium urate was not performed.

1

CHARACTERISTICS

OF GOUT IN SCA

The putative cases of gout shown in Table 1 do not have the same degree of certainty of diagnosis. None of the 8 cases reported before 1970 was confirmed by synovianalysis; diagnosis in these cases was based upon the presence of Table 2. Previously Unreported

Cases of Gout Accompanying

Sickle Cell Anemia

Age at OllSEl of Gout

CaFX

Joints

Serum Uric

Affected’

Acid, mgidl

Urate CrYstals in Sync&alFluId

Responseto

Number

Year

sex

13 14

1969 1975

male male

35 34

A. K 1st toe

7.9-13.2 7.1-10.9

Yes NDt

ves

15

1976

male

25

toes, MTP,

6.8-22.0

yas

?

ND

ND

ND

?

@fears)

Colchicine

ND

foot, K, DIP, 16

1977

male

17

1982

female

before 24 12

hand, W 1st toe

15.2,

1st MTP

10.7-12.8

16.0

lMTP = metatarsophalangaal; A = ankle; K = knee; DIP = distal interphalangeal of finger: W = wrist. tND

= not

done.

406

always clear in the reports whether multiple joints were affected simultaneously. Polyarticular attacks were documented in cases 1, 6, 7, 11, and 12. Only one case (12) was noted to have a tophus and roentgenographic signs of gout. No cases of uric acid nephrolithiasis have been reported in association with SCA. It is noteworthy that 42% (5/12) of the patients previously reported have been women. This is a much larger proportion than in other groups of gouty persons cited in textbooks, where the proportion of women is 3%26% and averBecause 2 of the 7 male ages about 5%. 9(p28)~‘o(p32) patients (1 and 3) were encountered in Veterans Administration Hospitals, where women are only a small minority of patients, the reports may be biased in favor of men. In an investigation of the epidemiology of gout, 3 1% of black patients but only 17% of white patients with primary gout were women;” and in a study of gout in blacks, Talbott et al.‘* found that 30% of the patients were women. Hematologic disorders other than SCA have not been found to cause secondary gout in women with unusual frequency; over 80% of persons with gout associated with leukemia, myeloid metaplasia, and polycythemia vera are male.‘31’4 The high proportion of women among reported cases of gout in SCA probably represents a racial characteristic rather than a feature of SCA itself. Also noteworthy are the ages of the patients. Omitting cases 5 and 7, in which the age at onset of gout is uncertain, the average age at onset was 32 years (identical for men and women). Whereas most studies of gout have shown onset to be most common during the fifth and sixth decades of life,9(p29)among the patients with SCA the ages of onset were almost evenly divided among the decades from the second to the fifth. In none of the cases was gout reported to have begun after age 49. The 5 previously unreported cases of gout in SCA shown in Table 2 include 2 definite cases confirmed by synovianalysis and 3 probable instances manifested by hyperuricemia and podagra. In most respects they are similar to the previously reported examples. Four patients had podagra; all had documented monarthritis and 2 had attacks involving more than one joint. Roentgenograms in case 16 showed a lucent

MICHAEL D. REYNOLDS

cystlike area in the proximal end of the proximal phalanx of one first toe, but only case 15 had typical roentgenographic signs of gouty arthritis, as well as a tophus. Eighty percent of the author’s cases were in men, but because of the small numbers of patients, the difference from previously reported cases in the proportion of women is not significant. The average age of onset of gout (omitting case 16) was 27 years. The number of instances of gout accompanying SCA that are recognized and reported must be influenced by the fact that identifying gouty arthritis is difficult when it occurs in conjunction with a disease which itself is frequently manifested by arthritis.15 This difficulty has been mentioned by several authors. 1(p3~).‘o(p’68) The case history presented here suggests that recognition of an attack of gout is most difficult when it is polyarticular and when it occurs in conjunction with a sickle cell crisis. The arthritides of both gout and SCA usually occur in episodes that begin acutely, persist for several days, and subside completely even without treatment. Differences between the two forms of arthritis include the tendency of gout, during initial attacks, to be monoarticular and confined to joints distal to the hip, while the arthritis of SCA is typically polyarticular and affects both upper and lower limbs. Gouty arthritis is likely to be more severe, accompanied by heat and erythema and followed by desquamation over the affected joint. Response to colchitine has been used by several authors as a criterion for diagnosis of gout,‘-’ but this has been criticized because of the absence of information about the effect of colchicine on the arthritis of SCA.’ The reports of gout accompanying SCA led to studies of the prevalence of hyperuricemia (Table 3) and of the metabolism of uric acid (UA) in persons with SCA. A high rate of hyperuricemia, defined as a serum concentration of UA exceeding that at which supersaturation occurs (6.4-6.8 mg/dl), has been found in groups of sickle-cell patients, children as well as adults. The prevalence of hyperuricemia in populations of healthy blacks apparently has never been determined; the rate in SCA is about six times that of hyperuricemia in white Americans.‘(P27’ Hyperuricemia and gouty arthritis also have been reported in association with sickle cell trait (SA hemoglobinopathy),’ SC hemoglobinopa-

GOUT ASSOCIATED WITH SICKLE-CELL ANEMIA

407

Table 3. Prevalence

Author

of Hyperuricemia

in Sickle Cell Anemia

Number of

Age Range,

Mean Age,

Subjects

years

years

Number with Hyperwcemia

Percentage with Hyperuricemla

Gold et aL5

13

l-53

26

6

46

Diamond et al.‘O

95

1 ‘h-45

?

30

32

De Ceulaer et al.”

44

9-61

26

18

41

54

36

Total

152

S-thalassemia,4 tb,4x5.‘s

and other abnormal These associations will hemoglobins. 9(p353),‘o(p’99) not be discussed in this review. METABOLISM

AND

EXCRETION

OF URIC ACID

Results of investigation of the metabolism of UA in persons with SCA were first published’ a decade after the initial case report of gout in SCA, and several such studies followed. Almost all these investigations have been limited to renal excretion of UA. A brief review of the relevant aspects of UA metabolism will be helpful for understanding these reports. Uric acid is mostly derived from the catabolism of nucleic acids, but some is also produced during the synthesis of purine nucleotides. In addition to this endogenous UA, about 33% of the UA present in the body or excreted from it is derived from food, when an average American diet is being eaten. Excretion of UA occurs mostly through the kidneys, but about 33% of the daily loss is through the digestive tract, in secretions and exfoliated cells. There is some absorption of both dietary and endogenous UA in the stomach and small intestine. Once the enteric UA reaches the large bowel, it is mostly catabolized by resident bacteria to allantoin-a transformation that humans, unlike most mammals, cannot perform by their own metabolic processes. Renal excretion of UA is a rather complex process and is incompletely understood. The model shown in Figure 1 is a satisfactory representation for most purposes. Plasma urate is filtered into the glomerulus, and its concentration in glomerular fluid is essentially the same as in plasma. The filtered UA is largely reabsorbed in the initial segment of the proximal tubule. Therefore, unless glomerular function is greatly reduced, urate excretion is determined by tubular secretion and absorption occurring beyond the segment in which the filtered UA is reabsorbed. These tubular processes probably take

place simultaneously along the length of the proximal tubule. However, the net movement of urate after reabsorption of filtered UA can be represented, as in Figure 1, by a more proximal secretion into the urine and a more distal reabsorption from the urine. To understand the kinetics of UA in the body, the concept of a metabolic pool is helpful (Fig. 2). The UA content of the body can be represented as a volume of liquid in a container; normally, the volume of the container (representing the body’s capacity for UA) is much larger than the amount of UA present inside. Uric acid is added to the pool in the container from two faucets, representing endogenous production and ingestion. Uric acid is removed from the pool by two faucets, representing renal excretion and enteric excretion. Normally the inflow

Glomerular filtration

a-

Tubular reabsorption of filtered uric acid

Tubular secretion by pyrazinamide

Tubular reabsorption of secreted uric acid by probenecid

Fig. 1.

Model of excretion

of uric acid.

408

MICHAEL D. REYNOLDS

c -

Insesied

purlnes

Uric acid pool

Fig. 2.

Model

of uric acid kinetics.

and outflow of UA are equal, and the volume of the pool remains constant. Measurement of the volume of the urate pool requires difficult metabolic techniques. Changes in the pool size, however, ordinarily are manifested in the SUA level, which has a coefficient of correlation (r) with the pool size of 0.88.19 Serum uric acid therefore can be represented as a float on the pool, which rises and falls in parallel with changes in the volume of the pool. MECHANISMS

OF HYPERURICEMIA IN SICKLE CELL ANEMIA

Provided with these models of urate excretion and kinetics, it now is practical to consider the studies of these processes in SCA. Because these investigations have been intended to elucidate the causes of hyperuricemia in SCA, they are best summarized in terms of the proposed causes. These are (1) hemolysis, (2) increased synthesis of nucleic acid during erythropoiesis, (3) decreased enteric excretion of UA, and (4) decreased renal excretion of UA. Hemolysis Hemolysis as a suggested cause of hyperuricemia2’ is based upon the fact that red blood cells (RBC) contain UA in a concentration of 0.8-3.0 mg/dl of blood.2’ Considering the kinetic model of Figure 2, however, it is obvious that hemolysis does not increase the amount of UA in the pool; it causes only a movement of urate from one compartment of the pool (RBC) to another (plasma). Hemolysis cannot increase the content of UA in

the body, which is necessary for the development of gout.* Erythrocytes containing mainly hemoglobin S have a short life; this is the basis of the anemia. Lysis of red cells in persons with SCA does liberate the UA contained in the cells. Unless renal function is seriously impaired, however, this amount of urate is readily excreted in the urine, and should not affect the SUA level. A transient rise in the SUA level (but not in the UA pool) conceivably could result from sudden, extensive hemolysis;? but this degree of hemolysis occurs infrequently, if ever, in SCA.23 Increased Synthesis of Nucleic Acids Proliferation of hemopoietic cells increases the amount of nucleic acid available for catabolism.r4 The sustained high level of erythropoiesis in SCA24 should result in increased “turnover” of purines and generation of greater than normal amounts of UA.2.4.5*20Synthesis and turnover of UA have been measured in a single patient with SCA (the patient had gout and is included in Table 1 as case 9).6 After administration of radioactive glycine as a precursor, this man produced 14 mg/kg of UA daily, compared with a normal rate of 10 mg/kg/24 hr. In a separate experiment, radioactive UA was administered, and a urate turnover of 9 18 mg/24 hr calculated; a normal turnover is 5 13-l 108 mg/24 hr.9(p1’3) The normal response of the body to an increased rate of entry of UA into the urate pool *Serum uric acid and total body mate can be raised transiently by sudden destruction of large numbers of nucleated cells, such as sometimes occurs when cytotoxic drugs are administered to persons with lymphoma or similar cancers. In such cases nucleic acids are released and catabolized to urate,9(P376).10(Pl96) Konsider hypothetically a 50-kg man with SCA, having a blood volume of 3000 ml (60 ml/kg), a “steady state” volume of packed red cells of 24%,** and a plasma volume of 2280 ml. Lysis of half of the erythrocytes during a hyperhemolytic crisis, reducing the hematocrit to 12%, might release about 24 mg of UA. (If the RBCs in 1 dl of blood with a normal hematocrit of 46% contain 3.0 mg of UA, the hypothetical subject would have 0.24/0.46 x 3.0 = 1.6 mg of UA in the RBC of 1 dl of blood. Lysis of RBCs equivalent to half of the person’s RBC volume would release 1.6mg/dl x 15 dl = 24 mg of UA.) This amount, diluted in the initial plasma volume, would raise the plasma concentration of UA only by 1.1 mg/dl, even if all the released UA remained in the blood.

GOUT ASSOCIATED

WITH SICKLE-CELL ANEMIA

is increased excretion of UA, so as to prevent more than small rises in serum urate.“.*’ Therefore, augmented production of UA will cause hyperuricemia only if this compensatory behavior of the kidneys fails to keep pace with the increased production. The 40% increase in urate synthesis measured in the study just described is within the normal excretory capacity of the kidney. Therefore, it is not surprising that investigators have found no correlation between the SUA levels of persons with SCA, and indices of erythropoiesis such as hematocrit,5 reticulocyte count,5.‘7 and serum bilirubin.” Because of the renal response to the influx of mate into the pool, urinary excretion of UA is an indirect measure of urate production.9’r”7’ The validity of this measure depends upon normal transport of UA by the kidneys, so the appropriateness of using it as evidence regarding the cause of hyperuricemia, when the renal behavior has not been shown to be normal, is questionable. This limitation being noted, the SUA levels of persons with SCA have been found not to correlate with urinary urate excretion, measured as UA in a 24-hour specimen,16 as the ratio of 24-hour urate excretion to creatinine excretion or as the ratio of urinary urate (UlJ,VUc,v)~20 concentration to creatinine concentration (U,,/ Uc,).” The evidence therefore indicates that the increased synthesis of UA caused by increased erythropoiesis in SCA is ordinarily not capable, by itself, of producing hyperuricemia. Decreased Enteric Excretion of UA Reduced nonrenal excretion of UA has been suggested as a possible cause of hyperuricemia by De Ceulaer et al.” However, this has not been shown to be responsible for elevated SUA levels in any situation,9’P’54’ and there is no evident reason why gastrointestinal secretion, exfoliation, or bacterial uricolysis should be significantly diminished in persons with SCA. This proposed mechanism may therefore be disregarded, in the absence of any evidence for it. Decreased Renal Excretion of UA Impaired urinary excretion of UA was first proposed as the cause of hyperuricemia in SCA by Jarvis4 in 1968. She noted that “Impaired

409

glomerular filtration rate and tubular excretion, could . . . account for retention of uric acid. . . .” In support of this hypothesis, Jarvis presented creatinine clearance (Cc,) measurements for 5 of 6 patients with SCA and hyperuricemia or alleged gout. The ages of the patients ranged from 17 to 40 years. Four of the five had decreased Ccr, the values ranging from 48 to 82 ml/min. The single patient whose UA metabolism was studied by Ball and Sorensen6 also had impaired renal function, manifested by a glomerular filtration rate of 55 ml/min. Urate clearance (C,,) was reduced to 5.2 ml/min (normal: about 9 ml/min). The estimated urate excretion “per nephron” was determined by dividing urate excretion by clearance of inulin.25 It was concluded that “the urate transport system has retained its functional integrity within the residual nephrons.” The hyperuricemia was attributed in part to “diminished excretion of uric acid that results from a decrease in nephron mass.“” These early case reports suggested that hyperuricemia in SCA is a consequence of the general decrease in renal function caused by the disease. Since 1970, however, studies of urate excretion in groups of patients have indicated that a more specific tubular abnormality in transport of UA is present in patients with SCA and hyperuricemia. The first of these studies was carried out by Walker and Alexander,” who found that when the data from 4 hyperuricemic persons with SCA were averaged, urate clearance was low (5 ml/ min) in comparison with 4 normouricemic patients with SCA (9 ml/min) and with 20 normal subjects (9 ml/min). The hyperuricemic subjects also had a decreased creatinine clearance (103 ml/min) in comparison with the controls (138 ml/min), but not with the normouricemic patients (127 ml/min). Thus far, the data could be viewed as resulting from nonspecific impairment in renal function. A “corrected” urate clearance was then calculated by dividing this value by the creatinine clearance. The ratio was found to be significantly lower in the hyperuricemic than in the normouricemic patients (0.05 versus 0.07). This indicates a disproportionate impairment in urate clearance. Walker and Alexander further indicated a specific basis

410

for the reduced urate clearance by showing that “corrected” 24-hour urate excretion (U,,V/ Uc,V) was significantly increased in the normouricemic patients (0.67 versus 0.43 in controls) but not in the hyperuricemic patients (0.50). It was concluded, however, that “It appears that hyperuricemia can occur in sickle-cell disease with only modest reduction in renal function because of the underlying increased purine metabolism.“20 It was not suggested that the reduction in urate excretion might be a result of impaired tubular function. The findings of Walker and Alexander were amplified and extended by Diamond and associates.‘6,26 They confirmed the earlier report that hyperuricemic patients with SCA have decreased urate clearance, whether clearance is expressed directly (5.0 ml/min in 13 hyperuricemic patients versus 8.3 ml/min in 12 control subjects), or divided by creatinine clearance (0.038 versus 0.077). Diamond et a1.16 also confirmed the discovery by Walker and Alexander of increased urinary uric acid excretion in SCA patients whose serum urate is normal. Twothirds (14/21) of normouricemic patients had 24-hour uric acid rates exceeding 600 mg (while on a purine-free diet); only 40% (6/ 15) of hyperuricemic patients had hyperuricosuria. Unlike Walker and Alexander, Diamond et a1.16 found increased urate clearance (13.6 ml/min) in the hyperuricosuric patients, compared with normal subjects (8.3 ml/min). These results suggest that most patients with SCA excrete greater than normal amounts of UA. Hyperuricemia results from loss of this increased excretory ability. To explain the hyperuricemia, the mechanism of hyperuricosuria in SCA must be determined. Because of the dominant role of tubular processes in urate excretion, there are three possible mechanisms (see Fig. 1): (1) decreased reabsorption of filtered UA, (2) increased secretion, and (3) decreased reabsorption of secreted UA. Diamond et a1.‘6,26 attempted to determine which process was operating by using drugs that affect tubular transport of UA. Pyrazinamide is believed to suppress tubular secretion of urate. This drug abolished the augmented urate clearance found in patients whose SUA level is norma1.‘6.26 Pyrazinamide would not affect hyperuricosuria caused by failure to reab-

MICHAEL

D. REYNOLDS

sorb filtered urate, so such decreased reabsorption is not the mechanism of increased excretion of urate in SCA. Tubular secretion of UA can be assessed by administering pyrazinamide and probenecid together. With reabsorption of secreted urate blocked by probenecid, the effect of pyrazinamide on urate excretion should be an index of tubular secretion. After the two drugs were administered to normouricemic patients with SCA, their excretion (and clearance) of UA were much less (149 pg/min and 3.5 ml/min) than those of normal subjects who took the drugs (543 pg/min and 10.0 ml/min). Thus, the patients’ pyrazinamide-suppressible Co, was 30% greater than that of normal subjects, indicating an increased secretion of UA.26 Probenecid is believed to act primarily as an inhibitor of reabsorption of previously secreted UA in the proximal tubule. If hyperuricosuria in SCA were caused by decreased reabsorption, then the effect of probenecid on urate excretion would be expected to be less than in normal persons, because it would be superimposed upon an already reduced transport of UA. However, the uricosuric response to probenecid was the same in hyperuricosuric sickle-cell patients and control subjects.26 This suggests that reabsorption of secreted urate is not impaired in SCA. Diamond et a1.16 next studied the effects of these drugs on sickle-cell patients who were hyperuricemic and who lacked the hyperuricosuria commonly present in SCA. Administration of pyrazinamide showed that most of the urate excretion by the hyperuricemic patients was suppressed by the drug (as it was in normouricemic patients and in control subjects), indicating that reabsorption of filtered urate was not diminished. After administration of probenecid, however, hyperuricemic patients had a much smaller increase in excretion of urate (931 pg/min) than did normouricemic, hyperuricosuric patients (1739 pg/min) or normal subjects (1541 pg/ min). Since the probenecid largely eliminated postsecretory urate reabsorption, this result indicates that tubular secretion of UA was diminished in the hyperuricemic patients.16 Diamond et a1.l6 studied a sufficient number of patients of varied ages to formulate a picture of the natural history of urate overproduction in SCA. Urate production, as indicated by U,,/

GOUT ASSOCIATED WITH SICKLE-CELL ANEMIA

UCr, was increased in 75% (9/ 12) of children under 10 years of age. Hyperuricemia was found in 14% (4/28) of children under 16 years of age, and was present in 39% (26/67) of adults (older than 15 years) with SCA. Hyperuricosuria was found in 68% (15/22) of patients aged 16 to 25 years, but only in 36% (5/14) of patients older than 25 yearsI It was concluded that overproduction of UA in SCA begins in childhood. Patients with SCA maintain normal serum UA levels by excreting greater than normal amounts of UA; this increased excretion is present over a range of SUA levels.26 Hyperuricemia develops only when urate clearance falls, probably as a result of impaired tubular function. Urinary excretion of UA in SCA has recently been studied by De Ceulaer et al.,” with results similar to those of previous investigations. Fortyone percent (18/44) of the patients tested were hyperuricemic, and the “corrected” urate clearance C,,,/Cc, was significantly lower in 12 hyperuricemic patients than in 25 normouricemic patients or 27 control subjects.* Urate excretion, expressed as UUr/UCr, was significantly higher in normouricemic patients (0.80) than in hyperuricemic ones (0.54). Hyperuricosuria was present in 58% (15/26) of patients whose SUA level was normal, and only 6% (l/18) of hyperuricemic patients. Semantic problems in description of renal excretion of uric acid. The logical expression of the results of studies of urate excretion in SCA may be impaired by excessive reliance on the concept of clearance. One must keep in mind that clearance is a model of function, not an observed variable; values for it are calculated, not measured. When Diamond et alI6 write that “urate clearance was inversely correlated with serum uric acid levels . . . this suggested that urate clearance, rather than urate production was the major determinant of serum uric acid . . .“; and De Ceulaer et al” state that “Serum urate concentration correlated inversely with &/Cc, .., in males,” the expressions have the same form they would have as if clearance and serum uric acid were independent variables. The actual logic

*The published clearances were derived by an unspecified logarithmic transformation of the original data and cannot be expressed in a form comparable with the measurements in other studies discussed here.

411

of the statements is made apparent by replacing the words for these quantities with the symbols used to express them mathematically: UV/P was correlated with l/P. This suggested that UV/P was the major determinant of P. This formulation makes it clear that the first sentence is necessarily true because it is a tautology and that the relevant variable is not clearance of urate but excretion of urate (UV). The relationship between plasma urate content and urinary urate excretion is obscured when it is expressed in terms of urate clearance. Thus, graphs showing the relationship between plasma urate (P) and urate clearance (UV/P) in patients with SCA (Figure 1 of Diamond et al. and the figure from De Ceulaer et al.) depict clearance falling as P rises; but this would happen in all situations except when UV was increasing more rapidly than P. From such graphs it is not apparent that diminished urate excretion is the cause of elevated serum urate, for similar graphs would result whether patients with high levels of serum urate excreted the same amount, less, or, indeed, more uric acid than patients with lower serum levels. Calculating clearance is not always the best way to relate excretion of a substance to its concentration in the blood, and the clearest way to show this relationship graphically is to plot it directly, as P against UV. Cause of the impairment of urate excretion. Decreased urinary excretion of UA in some patients with SCA has usually been attributed to renal damage produced by the disease. Jarvis4 was one of the first to propose this explanation, remarking that “Most adults with sicklecell anemia have developed irreversible renal damage. . . .” Ball and Sorensen6 concluded that the patient they studied with urate metabolism had “a significant reduction in the nephron population,” but they made no statements about the nature of the renal disease. Walker and Alexander” assumed that “anoxic changes secondary to intrarenal sickling” were the most likely cause of reduced renal function in patients they studied, and Talbott and Yij’“(p’98)state that such changes could produce hyperuricemia. Diamond et a1.16 similarly mentioned “microinfarctions” as a cause of hyperuricemia. De Ceulaer et al.” observed that the seven patients who had proteinuria (the criteria for a diagnosis of proteinuria were not stated), among the patients with SCA

412

MICHAEL D. REYNOLDS

whom they studied, had higher SUA levels than 37 patients without proteinuria (9.1 versus 6.2 mg/dl). Urate clearance was not significantly lower in the patients with proteinuria, however. They suggested that “proteinuric patients . . . had more severe tubular damage than the nonproteinuric ones.” They assumed that renal tubular injury, probably caused by damage to the renal medullary vasculature by the sickling process, “is the major determinant of hyperuricemia” in SCA. An important question about which no information is available is the possible role of hyperuricemia and hyperuricosuria themselves in producing renal disease in SCA. This was first suggested by Walker and Alexander,20 who noted that hyperuricemia is associated with a number of renal abnormalities observed in SCA, including a urinary concentrating defect, glomerulosclerosis, interstitial fibrosis, and inflammation with tubular atrophy. They noted that “uric acid metabolism in sickle-cell nephropathy . . . is a potentially treatable aspect of an otherwise progressive disease.” Diamond et a1.,16 and Talbott and Yti’“(p’99) also mentioned the possibility of renal damage secondary to hyperuricemia or hyperuricosuria. The answer to this question probably will require correlation of histologic evidence of urate nephropathy2’ with indices of renal function. Correlation of hyperuricemia or hyperuricosuria with biochemical indices of renal function is likely to be inadequate to determine whether urate nephropathy develops in SCA, since the excess UA either could be the cause or result of renal impairment. Controlled studies of the effect of long-term administration of allopurinol on renal function in SCA may be warranted. RELATION AlTACKS

OF SICKLE

CELL CRISES

OF GOUTY

TO

ARTHRITIS

Talbott’ in 1959 suggested that crises in SCA might affect metabolism of UA in such a way as to cause gout, but he did not note any concurrence of sickle cell crises with attacks of gouty arthritis. Jarvis4 postulated that a sickle cell crisis could promote acute gouty arthritis in two ways. First, hemolysis would release UA from RBCs and increase SUA. Second, thrombosis (presumably within joints) could cause anoxia and acidosis, which would lead to precipitation of

crystalline urate. However, Jarvis also did not report any correlation between crises and acute gouty arthritis in her patients. (Conversely, in explanation of the apparent rarity of gout in SCA, it has recently been proposed that “congestion and thrombosis of small vessels [in articular synovium] may prevent white blood cells from responding to the chemotactic stimulus of uric acid crystals,” and that leukocytes may not be able to initiate inflammation under hypoxic conditions that might be present in SCA.*) As described in the case history above, the patient had an attack of apparent polyarticular gout during a crisis of SCA. Patient 13 also developed sudden pain and swelling, at both ankle joints, during a crisis manifested by pain in the chest, fever, worsening anemia, leukocytosis, and hyperbilirubinemia. Arthrocentesis was not performed, but 21/zyears later urate crystals were found in synovial fluid from one knee. In case 14, podagra appeared a few days after a crisis manifested by polyarthralgia (which was the patient’s usual symptom during crises) and worsening anemia. This patient also was recovering from pneumococcal pneumonia. Patients 13 and 15 were heavy drinkers of alcoholic beverages. None of these 3 patients was regularly taking other drugs that cause hyperuricemia, such as aspirin or a diuretic, at the time the attacks of gouty arthritis began. These incidents of acute gouty arthritis during sickle-cell crises suggest that the hypothesis of Jarvis may be correct. In addition to the mechanisms she postulated, dehydration and systemic acidosis occur commonly during sickle cell crises and would promote attacks of gout, and increased erythropoiesis in response to increased hemolysis would produce uric acid. Cases should be studied with regard to a role of crises in precipitating attacks of gout; serial measurements of SUA during crises might demonstrate a relationship between temporary increases in SUA and acute arthritis. SUMMARY

AND

CONCLUSIONS

Since the initial description, in 1958, of gouty arthritis occurring in association with SCA, more than 12 cases have been reported. The high proportion of women and the relatively young ages are noteworthy. Since 1968, studies of patients with SCA have

GOUT ASSOCIATED

WITH SICKLE-CELL ANEMIA

413

shown a high prevalence of hyperuricemia, beginning during childhood. The initial event in the development of hyperuricemia presumably is increased synthesis of nucleic acids occurring as part of the erythropoietic response to hemolysis. Catabolism of the nucleic acids generates urate. Increased production of UA normally is compensated for by increased urinary excretion of UA. This response occurs in patients with SCA, but during the third decade of life hyperuricosuria can be reduced, probably by damage to the renal tubules caused by infarction and hypoxia resulting from sickling. Impairment of the compensatory renal response leads to more severe and sustained hyperuricemia, and gouty arthritis may then develop. A number of questions about hyperuricemia and gout in SCA remain unanswered. The prevalence of gout among patients with SCA, both in

general and in relation to age and sex, has not been determined. The relationships between specific aspects of SCA and of hyperuricemia and gout need to be determined. These include any effect of sickle cell crises on SUA and attacks of gout, and correlation of abnormalities in renal handling of urate with other indices of tubular function and with the pathologic anatomy of the kidney. Finally, it is important to learn whether hyperuricemia and hyperuricosuria contribute to the renal manifestations of SCA; if so, allopurino1 might be useful in the prevention and treatment of the renal disease. ACKNOWLEDGMENT Dr. C. Reindorf suggested and encouraged this work. The manuscript was reviewed by Dr. A. Hosten, V. Reynolds, and Dr. R. Taylor. Dr. 0. Castro made possible the inclusion of case 17.

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dis-

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