The Pathogenesis of Hyperuricemia and

Gout in Sickle Cell Anemia

Gene V. Ball and Leif B. Sorensen

A patient with sickle cell disease complicated by gouty arthritis is reported.

Studies with 1% labeled uric acid and glycine, and discrete renal function tests
indicate that both overproduction of uric acid and diminished excretion of
urate due to decreased nephron mass contributed to hyperuricemia.

Gouty arthritis is recognized as a n occa- duration and magnitude of the hyperurice-

sional secondary manifestation of polycy- mia. T h e other factor bearing on the infre-
themia, leukemia and severe chronic hemo- quency of reported gout i n sickle cell ane-
lytic anemias, all characterized by a n in- mia may relate to the rheumatism expected
creased catabolism of nucleic acids. Re- in this disease. This is described as episodic
ports of secondary gouty arthritis in sickle aching pain in the bones and joints and
cell anemia patients are notably rare, con- occurs in the majority of patients with
sidering the increased red cell turnover sickle cell hemoglobinopathy (1).
that occurs in this disorder. It is doubtful Gold et al (2) in their recent report of
that other chronic hemolytic anemias are, sickle cell anemia in a 53-year-old woman
on the whole, associated with a red cell whose gouty arthritis was not proven by
turnover greater than that of sickle cell joint aspiration but appeared to be charac-
anemia. Sickle cell anemia itself is not rare, teristic, stressed the necessity of a careful
having been observed in about 1-1.5% of evaluation of the history and physical ex-
blacks examined for this disorder, although amination in patients with sickle cell ane-
i t is uncommon in adults over the age of mia who had joint pain. Of their 13 pa-
30; perhaps this circumstance explains .the tients with sickle cell anemia, 6 had serum
infrequency of associated gouty arthritis, urate levels in excess of 6 mg/100 ml; 2
since clinical gout is dependent upon the of these may have had clinical gout.
I n the present study uric acid production
GENEV. BALL,MD: Division of Rheumatology,
has been evaluated i n a patient with sickle
The University of Alabama in Birmingham, The cell disease by measuring the dilution of
Medical Center, and the Veterans Administration intravenously injected iEotopic uric acid
Hospital, Birmingham, Alabama. L E ~ FB. SORENSEN,
MD, PhD: Department of Medicine, T h e Univer-
and by determining the rate and extent of
sity of Chicago Pritzker School of Medicine, and conversion of a labeled precursor into uric
the Argonne Cancer Research Hospital (operated acid. T o our knowledge, kinetic studies of
by the University of Chicago for the United States
Atomic Energy Commission) , Chicago, Illinois.
this kind have not been previously applied
Address for reprint requests: Leif B. SorenEen, to patients with hemoglobinopathy.
MD, PhD, University of Chicago, Dzpartment of
Medicine, 950 East 59th Street, Box 420, Chicago, PATIENT AND METHODS
Illinois 60637.
Submitted for publication June 30, 1970; accepted This 37-year-old black man illustrates the ease
August 4, 1970. with which gouty arthritis can be overlooked in a

846 Althritis and Rheumatism, Vol. 13, No. 6 (November-December 1970)

SICKLE CELL ANEMIA

patient with sickle cell anemia. The first episode of Table 1. Uric Acid Production and Excretion
gouty arthritis probably occurred when he was 27 in a Patient with Sickle Cell Disease
years old. Thereafter he experienced what in
retrospect seem to have been monoarticular attacks Plasma uric acid (mg/100 ml) 10.83
of gout occurring about once a year until age 34. Miscible pool of uric acid (rng) 2086
The attacks then increased in frequency to one Uric acid turnover (mg/day) 918
every 3 or 4 months. At age 35, these were recog- Urine uric acid (mg/day) 369
nized as gouty arthritis, and 1 year later urate Urine uric acid (% of turnover) 40.2
crystals were identified in joint fluid aspirated from Recovery of uric acid-14C,7 days
a knee (3). The ankles, elbows and feet were other (% of dose) 34.4
joints that had been similarly involved. There was GlycineJ4C incorporation into urinary
no history of symptomatic kidney disease. T h e uric acid (% of dose*) 0.0953
family history was negative for gout. There were lnulin clearance (ml/min/1.73 sq m) 55
no clinically or radiologically detectable tophi. The Uric acid clearance (ml/min) 5.16
hematocrit a t the time of hospitalization was his Urate excretion per nephron
customary 20, with a reticulocyte count of 9"/0. 10.2
(UV,,.&g/m iWCinuiin)
For 4 days before as well as during the study, the
patient was maintained on a purine-free diet with * Corrected for extrarenal disposal of uric acid.
protein sufficient to ensure nitrogen balance. Plasma
and urinary uric acid were measured .by an enzy-
matic spectrophotometric method (4). On the fifth DPM/mg
day, glycine-l-"C was injected in a dose of 54.3
pCi. Uric acid was isolated from the urine and
purified to determine the rate of incorporation of 'O°F
precursor glycine into purine. Seven days later, the 00 -
patient was given uric acid-W to determine the
miscible pool of uric acid and its daily turnover. 60 -
The procedures involved in the clinical radioisotope
studies have been reported elsewhere (5. 6 ) . Inulin
clearance was done with catheter collection at
three periods of 20 minutes each. lnulin was de-
termined by the method of Schreiner (7).

RESULTS AND DISCUSSION
T h e results of the studies are given in
Table 1. T h e miscible pool of uric acid was
2086 mg, a value that is about twice the
normal size when the patient's body weight
is taken into account. T h e uric acid pro-
duction was 918 mg/day or 14 mg/kg body
weight with a normal value of about 10
mg/kg body weight. T h e mean daily urine
uric acid content of 369 mg was only 40y0
of the turnover value, whereas normal sub-
jects excrete from two-thirds to three-quar-
ters of the formed uric acid by the renal
route. T h e recovery of uric acid-14C from
urine in percent of the dose, in 7 days,
corresponds acceptabIy to the urinary uric
acid in pcrcent of turnover, validating the
I
1 2 3 4 5 6 7
DAYS
Fig 1. Incorporation of "C-1-glycine into uric acid.
54.3 r C i of "C was injected at zero time.
calculation of the urate pool and turnover.
T h e pattern of incorporation of labeled
glycine-l-14C into uric acid (Fig 1) was not
unlike that observed in patients with pri-
mary or secondary polycythemia (8,9).
This pattern is different from those seen in
either normal subjects or patients with
primary gout related to overproduction of
uric acid. I n polycythemia, the isotope con-
centration rises slowly and does not reach
maximum until 12-14 days after the la-

Arthritis and Rheumatism, Vol. 13, No. 6 (November-December 1970) 847


beled precursor is administered. The acid that results from a decrease in nephron
cumulative incorporation of glycine i n t o mass.
urinary uric acid was O.O9530j, after 7 days,
when corrected for extrarenal disposal of
uric acid. T h i s value, which in itself does
not suggest excessive incorporation, should
be interpreted i n t h e light of similar d a t a
i n patients with increased formation of red
blood cells, i n whom overincorporation d i d
not become evident until more t h a n a week
after labeled glycine was administered.
I n addition to chronic hemolytic anemia,
patients with sickle cell disease usually
show signs of renal manifestations of their
disease, which may range from the inability
to concentrate urine appropriately to gross
hematuria a n d renal insufficiency which, i n
rare instances, may lead to uremia.
T h e glomerular filtration rate of o u r
patient was diminished to 5.5 m l / m i n ,
reflecting a significant reduction in t h e
nephron population. T h e clearance of uric
acid was decrea5etl to 5.16 m l / m i n . Howev- 7. Schreiner GE: Determination of inulin by
er, assuming that urinary uric acid is de-
rived predominantly from tubular secre-
tion (lo), the value of urate excretion per
nephron a t a plasma concentration of
about 11 mg/lOO m l indicates that the urate
transport system has retained its functional
integrity within the residual nephrons.
From the data obtained i n the present
study of a single case of sickle cell disease,
it may b e concluded that t h e etiology of
hyperuricemia a n d gout, in this patient, is 10. Steele TH, Rieselbach RE: T h e renal
based o n both the overproduction of uric
acid a n d the diminished excretion of uric
Arthritis and Rheumatism, Vol. 13, No. 6 (November-December 1970)
BALL & SORENSEN
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