- Email: [email protected]
Triglyceride concentrations in primary gout and gout of chronic lead nephropathy
Metabolism Clinical and Ewperimental VOL. XX, NO. 8
AUGUST, 1971
Triglyceride Concentrations in Primary Gout and Gout of Chronic Lead Nephropathy B y BRYAN T. EMMERSON AND BRIAN R. KNOWLES Serum cholesterol and triglyceride values were compared in two groups of patients with gouty arthritis, one in which the gout was associated with chronic lead nephropathy and another in which lead could be excluded and the gout be regarded as primary. Significant hypertriglyceridemia without hypercholesterolemia was found in the primary gout group. Comparison confirmed greater obesity and alcohol consumption in the primary gout group, but their presence did not correlate well with the hypertri-
glyceridemia. Analysis showed that the greater hypertriglyceridemia in the primary gout group persisted even when allowance was made for their greater weight and alcohol consumption. N o correlation was demonstrable between the degree of hypertriglyceridemia and the degree of overproduction of urate, as judged by the urinary excretion of uric acid. It is suggested that it is important to define the features of this type of gout associated with hypertriglyceridemia in order to elucidate its mechanism.
LTHOUGH ARTERIAL DISEASE HAS BEEN RECOGNIZED as a common feature of the syndrome of gout, reports of disorders of lipid metabolism in patients with gout have been remarkable chiefly for the inconstancy of the associated abnormality. Some report an association between hyperurieemia and both hypercholesterolemia and hypertriglyceridemia,1 while others find the association to be with hypercholesterolemia alone2 or with hypertriglyceridemia alone.3-5 Diminished carbohydrate tolerance has also been a frequent finding in gouty patients with hypertriglyceridemia.~ It is possible either that the primary association may be between gout and abnormalities of carbohydrate metabolism
A
From the Department of Medicine, University of Queensland, Brisbane, Australia. Received for publication March 17, 1971. Supported by grants from the Mayne Bequest Fund of the University of Queensland and the National Health and Medical Research Council of Australia. BRYAN T. EMMERSON, M.D., F.R.A.C.P. : Reader in Medicine, University of Queensland at the Princess Alexandra Hospital, Brisbane, Australia; BRIAN R. KNOWLES, M.B., M.R.C.P.: Senior Lecturer in Therapeutics, University of Queensland at the Royal Brisbane Hospital, Brisbane, Australia. METABOLISM, VOL. 20, NO. 8 (AuGusT), 1971
721
722
EMMERSON AND KNOWLES
a n d that the a s s o c i a t i o n with h y p e r l i p i d e m i a is a s e c o n d a r y one, o r that the lipid a b n o r m a l i t y is the basic one a n d the disorders of u r a t e and c a r b o h y d r a t e m e t a b o l i s m are s e c o n d a r y to this. W h i l e the v a r i a b i l i t y of association b e t w e e n h y p e r u r i c e m i a a n d h y p e r l i p i d e m i a m a y b e a t t r i b u t e d in p a r t to this finding, it is also likely to be due in p a r t to the selection in the different studies of different types of gouty patients who exhibit widely v a r y i n g etiologies for their gout. 7 Thus, the same a b n o r m a l i t y of lipid m e t a b o l i s m might n o t be expected in an u n d e r e x c r e t o r of u r a t e as w o u l d b e e x p e c t e d in a gross o v e r p r o d u c e r of urate. A c u t e l e a d i n t o x i c a t i o n in c h i l d h o o d was c o m m o n in Q u e e n s l a n d b e t w e e n 1890 a n d 1930 a n d was a t t r i b u t e d to the l e a d p a i n t on the railings of open v e r a n d a s , which w o u l d p o w d e r a n d flake in the h o t s u m m e r s and was readily accessible to children, s T h e incidence of l e a d i n t o x i c a t i o n has steadily declined since the elimination of l e a d from p a i n t in areas accessible to children. H o w e v e r , up to 5 0 % of those seriously affected b y l e a d p o i s o n i n g d e v e l o p e d chronic renal failure some 1 5 - 4 0 y r later, 9 a n d half of these subjects with chronic lead n e p h r o p a t h y d e v e l o p e d acute gouty arthritis d u r i n g the course of their chronic r e n a l insufficiency. 1~ T h e gout in such patients has b e e n attributed to defective r e n a l excretion of urate. 1-~ T h e clinical features of this t y p e of " l e a d gout" differ from those seen in the m o r e usual g o u t y patients in the same c o m m u n i t y whose gout is n o t a t t r i b u t a b l e to antecedent l e a d intoxication, a n d for the p u r p o s e s of this c o m p a r i s o n they have been g r o u p e d and r e f e r r e d to as having " p r i m a r y gout. ''a3 This situation p r e s e n t e d an o p p o r t u n i t y to c o m p a r e lipid concentrations in patients with an a c q u i r e d form of gout with those in a group whose gout was of the intrinsic or i n h e r i t e d type. MATERIALS AND METHODS Criteria used for the diagnosis of gout were those established for population studies by a C.I.O.M.S. Symposium. 14 The lead gout group comprised 13 male patients with gout and chronic lead nephropathy, whose diagnostic criterial~ consisted of the presence of chronic bilateral renal disease not due to an alternative cause, together with a clear history of excessive past lead absorption, verified by an abnormal increase in the urinary excretion of lead after a standardized infusion of calcium EDTA.10 Nine of the 13 patients had themselves suffered recognized acute lead poisoning in childhood, and three had a sibling who had suffered from this condition. The primary gout group consisted of 27 male patients who had gout as defined above and who had either a normal urinary excretion of lead after the standardized infusion of calcium EDTA, thereby excluding excessive past lead absorption, or evidence of overproduction of urate in the form of a urinary uric acid excretion of greater than 590 mg/24 hr on a purine free diet. 15 Six patients satisfied the first criterion above (their mean urinary uric acid excretion not having been measured), five satisfied the second criterion above (their EDTA-induced lead excretion not having been measured), 12 had both normal EDTA-induced lead excretions and normal urinary uric acid excretions, and four had normal EDTA-induced lead excretions and elevated urinary uric acid excretions. In all, nine were known to be overproducers of urate. Patients were fully assessed clinically as part of a wider survey of the clinical features of the gout of chronic lead nephropathy, 13 and all patients who could be found to meet the above criteria prior to July 1970 were included in the study. Venous blood was taken after an overnight fast of at least 14 hr for estimation of the serum concentrations of urate,16 creatinine,17 triglycerides,18 and cholesterol. 19 Diets were otherwise unrestricted prior to blood sampling. Patients who were receiving allopurinol or uricosuric drugs (other than aspirin) continued to take them, but the representative urate concentration was taken
723
TRIGLYCERIDE CONCENTRATIONS
as the last recorded value prior to the institution of therapy. These values are marked * in Table 1. Desirable body weight was taken to be the average weight for height (without shoes) at ages 20-24 yr as found in the Build and Blood Pressure Study of the Society of Actuaries,20 and per cent desirable weight was calculated from the ratio of body weight to desirable weight. Per cent desirable weight correlates well (r=0.974) with per cent body fat.e1 RESULTS
Age Incidence The findings in the two groups are shown in Table 1. Despite the patients not being matched, the mean ages in the two groups were similar, although because of their more severe renal disease, lead gout patients do not usually survive as long as those with primary gout.
Fasting Serum Triglyceride Concentrations These were significantly higher in the primary gout group when compared by a t test (Table 1). This difference was not due to occasional high values because it persisted even when the two highest values were excluded (mean 224 __+ 98 m g / 1 0 0 ml; t = 3.95; p < 0.001). In view of the different variances of the lead and nonlead groups, the data was examined by the nonparametric Mann-Whitney U test 22 and a significant difference (p < 0.001) was again shown.
Fasting Serum Cholesterol Because of a misunderstanding, this estimation was omitted in three of the lead gout group. However, no significant differences were found between the serum cholesterol concentrations in the two groups.
Renal Function All of the lead gout patients had chronic renal disease as reflected by the serum creatinine concentrations. Only ten out of the 27 patients with primary gout demonstrated nitrogen retention (upper limit of normal serum creatinine 1.4 m g / 1 0 0 ml). Thus, as expected from the fact that renal disease was primary in the lead gout group, the serum creatinine concentrations were significantly greater in this group.
Height, Weight, and Per Cent Desirable Weight As shown in previous studies, 1~ patients with primary gout tend to be significantly taller and heavier than patients with lead gout. This is probably due to the primary gout subjects being overweight and the lead gout subjects being shorter in stature because of the presence of chronic illness. In the present patients, as shown in Table 1, the per cent desirable weight for the primary gout group was significantly greater than that for the lead gout group (p < 0.01 ).
Alcohol Consumption Because of the problems in assessing the extent of alcohol consumption, we attempted to grade it as shown in the footnote to Table 1. The first distinction was
724
E M M E R S O N AND KNOWLES
@
eq it3
od
G
t~
I. 1,1
@
TRIGLYCERIDE
725
CONCENTRATIONS
o
4 ,4 V
>
V
0 o~
~,~
+1
~r-i V ,,d ~,
~
~
~
~
+
~ ~V M '4 v
~ "4 ,.,.4
d
0'..~ 0
0
0
9
N
m~N
*
726
EMMERSON AND KNOWLES
between those who took alcohol only occasionally in small amounts or never (graded as nil) and those who took alcohol regularly (graded as mild, moderate, or heavy drinkers). There was a significantly greater number of regular drinkers in the primary gout group (exact test: p < 0.05). Similar conclusions were reached if the nil and mild drinkers were grouped and compared with the combination of moderate and heavy drinkers.
Relationship oJ Serum TrigIycerides to Serum Cholesterol Concentrations Significant correlations existed between triglycerides and cholesterol for both the primary gout group (r = 0.43, p < 0.05) and the lead gout group (r = 0.75, p < 0.02) whether considered singly or together (r == 0.45, p < 0.01).
Relationship o[ Serum Triglycerides to Serum Urate Concentrations No significant correlation was found.
Relationship of Serum Triglycerides to Renal Failure Chronic renal failure has been reported to induce hypertriglyceridemia,23,24 and our own experience with a patient who had a plasma triglyceride of 352 mg/100 ml when in advanced chronic renal failure, in whom the triglyceride fell to 81 rag/100 ml after renal transplantation, would support this. However, in the present data, no correlation can be shown between the plasma triglyceride and the serum creatinine concentration (or the logarithm of the serum creatinine concentration) in either the lead gout group or the primary gout group, viewed singly or together. In addition, exclusion of those cases with severe renal disease (serum creatinine greater than 7 rag/100 ml) did not appreciably alter the mean serum triglyceride in the lead gout group (115 rag/100 ml as opposed to 113 rag/100 ml). Actually, the greater degree of renal disease in the lead gout group should tend to increase the hypertriglyceridemia in that group, thereby tending to decrease rather than increase the difference between the serum triglycerides in the two groups. These factors, therefore, make it most unlikely that the greater hypertriglyceridemia in the primary gout group is related to the different degree of renal disease.
Relationship oJ TrigIycerides to Obesity Although the primary gout group showed greater hypertriglyceridemia and greater percentage average weight, and although hypertriglyceridemia may be a feature of obesity,21 no significant correlation was demonstrable between the serum triglyceride concentrations and the percentage average weight in the primary gout group (Spearman rank correlation coefficient = 0.28, N.S.). To assess the effect on the serum triglycerides of the different values for the percentage desirable weight in the two groups, a corrected value for the triglyceride of each subject was calculated according to the following relationship derived by Grace 25 in 46 normal subjects. Log triglyceride --- 1.387 + 0.00488% desirable weight. The corrected triglyceride concentration for each subject was calculated by multiplying the observed triglyceride value by the ratio of the calculated triglyceride concentration at 100% desirable weight to the calculated triglyceride concentration at the
727
TRIGLYCERIDE CONCENTRATIONS
observed per cent desirable weight. Comparison of the corrected triglyceride values in the two groups (each at the desirable weight for height) still showed significantly higher triglyceride concentrations in the primary gout group (209 • 135 rag/100 ml) as compared with the lead gout group (114 __ 44 rag/100 ml) (Mann-Whitney U test, p < 0.01).
Relationship o[ Serum Triglycerides to Alcohol Consumption Since both greater triglyceride concentration and significantly higher consumption of alcohol were found in the primary gout group and because hypertriglyceridemia may be a feature of alcoholism, the data was examined to see if there were any positive association between the two. However, no significant difference was found between the serum triglycerides and any of the different grades of alcohol consumption (Spearman rank correlation coefficient = 0.02, N.S.). Likewise, the presence of hypertriglyceridemia (serum triglyceride > 160 mg/100 ml) did not correlate with the presence or absence of alcohol consumption (X 2 = 0.29, N.S.). In addition, if only subjects with an alcohol consumption in the "nil" category were considered, the mean triglyceride concentration was still significantly greater in the primary gout group [mean primary gout (n = 7) = 261 • 119 rag/100 ml; mean lead gout (n = 8) = 123 --_+ 36 mg/100 ml]. If the triglycerides were compared by the Mann-Whitney test for nonparametric observations, the primary gout group still had significantly greater triglyceride concentrations than the lead gout group (p < 0.02). Thus, the present data provides no evidence of a relationship, either etiological or otherwise, between the hypertriglyceridemia in the primary gout group and their alcohol consumption.
Relationship of Urinary Urate Excretion to Triglyceride Concn in Primary Gout The criteria accepted for diagnosis tended to cause the inclusion in the primary gout group of a larger proportion of over-excretors than would be seen in the general population. Now, while all over-excretors of uric acid are accepted as being overproducers, not all overproducers demonstrate elevated urinary uric acid excretions (greater than 590 rag/24 hr on a purine free diet). Nonetheless, a correlation between urine uric acid and triglycerides was sought to see if the over-excretors in the primary gout group tended to be a hypertriglyceridemic group. No correlation was demonstrable, however, either in the primary gout group as a whole or when it was divided into over-excretors and normal excretors. The mean triglyceride for the over-excretors (296 ~ 121 mg/100 ml) was not significantly different from the normal excretors (268 +__ 193 mg/100 ml) and the mean for each was significantly different from that for the lead nephritics (113 ___ 34 mg/100 ml). This, therefore, does not support an association of overproduction of urate with hypertriglyceridemia, although it does not exclude such an association. DISCUSSION
It is becoming more widely appreciated that gout is a syndrome rather than a disease entity and that further understanding of it will depend upon the development of an etiologic classification. One definite variety of gout, which appears to
728
EMMERSON AND KNOWLES
be acquired, is that associated with chronic lead nephropathy. The present study was designed to reveal specific differences between this variety and the more common, and as yet undifferentiated type, usually designated as primary gout. It has established hypertriglyceridemia as a significant and frequent feature of primary gout, whereas its absence from patients with lead gout shows that it is not a regular association of hyperuricemia alone. Analysis of possible causes did not provide evidence that would allow the hypertriglyceridemia to be attributed to either renal disease, obesity, or alcohol consumption, although the clinical association of gout with hypertriglyceridemia, obesity, and regular alcohol consumption does suggest a distinct variety of gout. Such an association does not help in determining where the fundamental disorder lies and which features are secondary and nonessential. Had an association with urate overproduction been demonstrable, this might have provided a clue to the cause of the association by suggesting a common factor leading to overproduction of both urate and triglyceride. With the limited available data on this aspect, the absence of such a demonstration does not exclude such a possibility. Acute alcoholic excess has been associated with extreme hypertriglyceridemia, hypercholesterolemia, and hyperuricemia,26 and these have been shown to remit with abstinence from alcohol. It is notable however, that this association is not with hypertriglyceridemia alone, nor has it been demonstrated with regular mild or moderate consumption of alcohol. This is not to imply that the association of regular alcohol consumption with gout is not well established,27 or that it is not possible it may have a persistent effect on urate and lipids similar to repeated acute excesses. It merely indicates that such a mechanism has not yet been demonstrated and that, if alcohol is in fact the cause of the hyperlipemia and hyperuricemia in the primary gout group, it must be a more constantly operative factor in the etiology of primary gout than is presently accepted. Another important alternative to consider is whether the hypertriglyceridemic patients in the primary gout group might be suffering from carbohydrate induced hyperlipemia (Fredrickson Type IV) 2s in which alcohol is filling the inducing role of a carbohydrate. This condition is associated with hyperuricemia, and it may be that the hyperuricemia, becoming symptomatic, becomes the dominant presenting feature at a time when the hyperlipemia is asymptomatic. It is thus difficult to conclude on the evidence available that the hypertriglyceridemia is attributable to the greater alcohol consumption of the primary gout group. The present results might also throw light on the cause of the variable incidence of arterial disease in gout. The general clinical impression is that these are frequently associated? although this cannot be substantiated when viewed over the whole field of gout from the mortality statistics of life insurance companies. 29 This discrepancy might be explained, if there were one subtype of the syndrome of gout that was associated with hypertriglyceridemia and had an increased incidence of vascular disease, but that was not easily distinguished when combined with all the other subtypes of the gout syndrome not associated with hypertriglyceridemia and vascular disease. It would seem that further study should be directed toward the delineation of more characteristics of that Variety of gout that is associated with hypertriglyceridemia in the hope that this wiI1 elucidate the mechanism leading to the association.
729
TRIGLYCERIDE CONCENTRATIONS REFERENCES 1. Barlow, K. A.: Hyperlipidemia in primary gout. Metabolism 27:289, 1968. 2. Harris-Jones, J. N.: Hyperuricaemia and essential hypercholesterolaemia. Lancet 1:857, 1957. 3. Feldman, E. B., and Wallace, S. L.: Hypertriglyceridaemia in gout. Circulation 29:508, 1964. 4. Benedek, T. G.: Correlations of serum uric acid and lipid concentrations in normal, gouty and atherosclerotic men. Ann. Intern. Med. 66:851, 1967. 5. Kuntz, D., Roques, C., Paolaggi, F., and Ryckewaert, A.: l~tude comparative de la triglyc6ridfmie, de la lipid~mie, de la glyc6mie et de l'index pond6ral chez les hyperuric~miques et les normo-uric6miques. Patb. Biol. (Paris) 17:399, 1969. 6. Berkowitz, D.: Blood lipid and uric acid interrelationships. J A M A 190:856, 1964. 7. Kelley, W. N.: Recent progress in the pathogenesis and treatment of gout. Med. Times 97:230, 1969. 8. Nye, L. J. J.: Chronic Nephritis and Lead Poisoning. Sydney, Angus and Robertson, 1933, p. 87. 9. Henderson, D. A., and Inglis, J. A.: The lead content of bone in chronic Bright's Disease. Aust. Ann. Med. 6:145, 1957. 10. Emmerson, B. T.: Chronic lead nephropathy: The diagnostic use of calcium E D T A and the association with gout. Aust. Ann. Med. 12:310, 1963. 11. - - : Metals and the kidney. In Black, D. A. K . ((Ed.): Renal Disease (ed. 2). Oxford, Blackwell Scientific Publications, 1967, p. 565. 12. - - : The renal excretion of urate in chronic lead nephropathy. Aust. Ann. Med. 14:295, 1965. 13. - - : The clinical differentiation of lead gout from primary gout. Arthritis Rheum. 11:623, 1968. 14. Kellgren, J. H., Jeffrey, M. R., and Ball, J. (Eds.): The Epidemiology of Chronic Rheumatism. Oxford, Blackwell Scientific Publications, 1963, p. 295. 15. Wyngaarden, J. B.: Gout. In Stanbury, J. B., Wyngaarden, J. B., and Fredrickson, D. S. (Eds.): The Metabolic Basis of Inherited Disease (ed. 2). New York, Mc-
Graw-Hill, 1966, p. 691. 16. Liddle, L., Seegmiller, J. E., and Laster, L.: The enzymatic spectrophotometric method for determination of uric acid. J. Lab. Clin. Med. 54:903, 1959. 17. Edwards, K. D. G., and Whyte, H. M.: The measurement of creatinine in plasma and urine. Aust. J. Exp. Biol, Med. Sci. 36:383, 1958. 18. Carlson, L. A., and Wadstrom, L. B.: Determination of glycerides in blood serum. Clin. Chim. Acta 4: 197, 1959. 19. Liese, L., Abell, B., Levy, B., Brodie, B. B., and Kendall, F. E.: A simplified method for the estimation of total cholesterol in serum and demonstration of its specificity. J. Biol. Chem. 195:357, 1952. 20. Diem, K. (Ed.): Documenta Geigy Scientific Tables (ed. 6). St. Leonards, N. S. W., Geigy Pharmaceuticals Division of Geigy (Australia) Pty., 1962, p. 623. 21. Grace, C. S., and Goldrick, R. B.: Assessment of body composition in normal and obese subjects. Aust. Ann. Med. 18:26, 1969. 22. Siegal, S.: Nonparametric statistics for the behavioral sciences. New York, McGrawHill, 1956, p. 116. 23. Losowsky, M. S., and Kenward, D. H.: Lipid metabolism in acute and chronic renal failure. J. Lab. Clin. Med. 71:736, 1968. 24. Bagdade, J. D., Porte, D., and Bierman, E. L.: Hypertriglyceridemia : A metabolic consequence of chronic renal failure. New Eng. J. Med. 279: 181, 1968. 25. Grace, C. S.: Studies on fibrinolysis. M.D. Thesis, University of Sydney, t968. 26. Gebbie, T., and Prior, I. A. M.: Alcoholic hyperlipaemia. Med. J. Aust. 2:769, 1967. 27. Saker, B. M., Toiler, O. B., Burvill, M. J., and Reilly, K. A.: Alcohol consumption and gout. Med. J. Aust. 1:1213, 1967. 28. Frederickson, D. S., and Lees, R. S.: Familial hyperlipoproteinemia. In Stanbury, J. B., Wyngaarden, J. B., and Fredrickson, D. S. (Eds.): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1966, p. 467. 29. Talbott, J. H.: Gout (ed. 3). New York, Grune & Stratton, 1967, p. 214.
AUGUST, 1971
Triglyceride Concentrations in Primary Gout and Gout of Chronic Lead Nephropathy B y BRYAN T. EMMERSON AND BRIAN R. KNOWLES Serum cholesterol and triglyceride values were compared in two groups of patients with gouty arthritis, one in which the gout was associated with chronic lead nephropathy and another in which lead could be excluded and the gout be regarded as primary. Significant hypertriglyceridemia without hypercholesterolemia was found in the primary gout group. Comparison confirmed greater obesity and alcohol consumption in the primary gout group, but their presence did not correlate well with the hypertri-
glyceridemia. Analysis showed that the greater hypertriglyceridemia in the primary gout group persisted even when allowance was made for their greater weight and alcohol consumption. N o correlation was demonstrable between the degree of hypertriglyceridemia and the degree of overproduction of urate, as judged by the urinary excretion of uric acid. It is suggested that it is important to define the features of this type of gout associated with hypertriglyceridemia in order to elucidate its mechanism.
LTHOUGH ARTERIAL DISEASE HAS BEEN RECOGNIZED as a common feature of the syndrome of gout, reports of disorders of lipid metabolism in patients with gout have been remarkable chiefly for the inconstancy of the associated abnormality. Some report an association between hyperurieemia and both hypercholesterolemia and hypertriglyceridemia,1 while others find the association to be with hypercholesterolemia alone2 or with hypertriglyceridemia alone.3-5 Diminished carbohydrate tolerance has also been a frequent finding in gouty patients with hypertriglyceridemia.~ It is possible either that the primary association may be between gout and abnormalities of carbohydrate metabolism
A
From the Department of Medicine, University of Queensland, Brisbane, Australia. Received for publication March 17, 1971. Supported by grants from the Mayne Bequest Fund of the University of Queensland and the National Health and Medical Research Council of Australia. BRYAN T. EMMERSON, M.D., F.R.A.C.P. : Reader in Medicine, University of Queensland at the Princess Alexandra Hospital, Brisbane, Australia; BRIAN R. KNOWLES, M.B., M.R.C.P.: Senior Lecturer in Therapeutics, University of Queensland at the Royal Brisbane Hospital, Brisbane, Australia. METABOLISM, VOL. 20, NO. 8 (AuGusT), 1971
721
722
EMMERSON AND KNOWLES
a n d that the a s s o c i a t i o n with h y p e r l i p i d e m i a is a s e c o n d a r y one, o r that the lipid a b n o r m a l i t y is the basic one a n d the disorders of u r a t e and c a r b o h y d r a t e m e t a b o l i s m are s e c o n d a r y to this. W h i l e the v a r i a b i l i t y of association b e t w e e n h y p e r u r i c e m i a a n d h y p e r l i p i d e m i a m a y b e a t t r i b u t e d in p a r t to this finding, it is also likely to be due in p a r t to the selection in the different studies of different types of gouty patients who exhibit widely v a r y i n g etiologies for their gout. 7 Thus, the same a b n o r m a l i t y of lipid m e t a b o l i s m might n o t be expected in an u n d e r e x c r e t o r of u r a t e as w o u l d b e e x p e c t e d in a gross o v e r p r o d u c e r of urate. A c u t e l e a d i n t o x i c a t i o n in c h i l d h o o d was c o m m o n in Q u e e n s l a n d b e t w e e n 1890 a n d 1930 a n d was a t t r i b u t e d to the l e a d p a i n t on the railings of open v e r a n d a s , which w o u l d p o w d e r a n d flake in the h o t s u m m e r s and was readily accessible to children, s T h e incidence of l e a d i n t o x i c a t i o n has steadily declined since the elimination of l e a d from p a i n t in areas accessible to children. H o w e v e r , up to 5 0 % of those seriously affected b y l e a d p o i s o n i n g d e v e l o p e d chronic renal failure some 1 5 - 4 0 y r later, 9 a n d half of these subjects with chronic lead n e p h r o p a t h y d e v e l o p e d acute gouty arthritis d u r i n g the course of their chronic r e n a l insufficiency. 1~ T h e gout in such patients has b e e n attributed to defective r e n a l excretion of urate. 1-~ T h e clinical features of this t y p e of " l e a d gout" differ from those seen in the m o r e usual g o u t y patients in the same c o m m u n i t y whose gout is n o t a t t r i b u t a b l e to antecedent l e a d intoxication, a n d for the p u r p o s e s of this c o m p a r i s o n they have been g r o u p e d and r e f e r r e d to as having " p r i m a r y gout. ''a3 This situation p r e s e n t e d an o p p o r t u n i t y to c o m p a r e lipid concentrations in patients with an a c q u i r e d form of gout with those in a group whose gout was of the intrinsic or i n h e r i t e d type. MATERIALS AND METHODS Criteria used for the diagnosis of gout were those established for population studies by a C.I.O.M.S. Symposium. 14 The lead gout group comprised 13 male patients with gout and chronic lead nephropathy, whose diagnostic criterial~ consisted of the presence of chronic bilateral renal disease not due to an alternative cause, together with a clear history of excessive past lead absorption, verified by an abnormal increase in the urinary excretion of lead after a standardized infusion of calcium EDTA.10 Nine of the 13 patients had themselves suffered recognized acute lead poisoning in childhood, and three had a sibling who had suffered from this condition. The primary gout group consisted of 27 male patients who had gout as defined above and who had either a normal urinary excretion of lead after the standardized infusion of calcium EDTA, thereby excluding excessive past lead absorption, or evidence of overproduction of urate in the form of a urinary uric acid excretion of greater than 590 mg/24 hr on a purine free diet. 15 Six patients satisfied the first criterion above (their mean urinary uric acid excretion not having been measured), five satisfied the second criterion above (their EDTA-induced lead excretion not having been measured), 12 had both normal EDTA-induced lead excretions and normal urinary uric acid excretions, and four had normal EDTA-induced lead excretions and elevated urinary uric acid excretions. In all, nine were known to be overproducers of urate. Patients were fully assessed clinically as part of a wider survey of the clinical features of the gout of chronic lead nephropathy, 13 and all patients who could be found to meet the above criteria prior to July 1970 were included in the study. Venous blood was taken after an overnight fast of at least 14 hr for estimation of the serum concentrations of urate,16 creatinine,17 triglycerides,18 and cholesterol. 19 Diets were otherwise unrestricted prior to blood sampling. Patients who were receiving allopurinol or uricosuric drugs (other than aspirin) continued to take them, but the representative urate concentration was taken
723
TRIGLYCERIDE CONCENTRATIONS
as the last recorded value prior to the institution of therapy. These values are marked * in Table 1. Desirable body weight was taken to be the average weight for height (without shoes) at ages 20-24 yr as found in the Build and Blood Pressure Study of the Society of Actuaries,20 and per cent desirable weight was calculated from the ratio of body weight to desirable weight. Per cent desirable weight correlates well (r=0.974) with per cent body fat.e1 RESULTS
Age Incidence The findings in the two groups are shown in Table 1. Despite the patients not being matched, the mean ages in the two groups were similar, although because of their more severe renal disease, lead gout patients do not usually survive as long as those with primary gout.
Fasting Serum Triglyceride Concentrations These were significantly higher in the primary gout group when compared by a t test (Table 1). This difference was not due to occasional high values because it persisted even when the two highest values were excluded (mean 224 __+ 98 m g / 1 0 0 ml; t = 3.95; p < 0.001). In view of the different variances of the lead and nonlead groups, the data was examined by the nonparametric Mann-Whitney U test 22 and a significant difference (p < 0.001) was again shown.
Fasting Serum Cholesterol Because of a misunderstanding, this estimation was omitted in three of the lead gout group. However, no significant differences were found between the serum cholesterol concentrations in the two groups.
Renal Function All of the lead gout patients had chronic renal disease as reflected by the serum creatinine concentrations. Only ten out of the 27 patients with primary gout demonstrated nitrogen retention (upper limit of normal serum creatinine 1.4 m g / 1 0 0 ml). Thus, as expected from the fact that renal disease was primary in the lead gout group, the serum creatinine concentrations were significantly greater in this group.
Height, Weight, and Per Cent Desirable Weight As shown in previous studies, 1~ patients with primary gout tend to be significantly taller and heavier than patients with lead gout. This is probably due to the primary gout subjects being overweight and the lead gout subjects being shorter in stature because of the presence of chronic illness. In the present patients, as shown in Table 1, the per cent desirable weight for the primary gout group was significantly greater than that for the lead gout group (p < 0.01 ).
Alcohol Consumption Because of the problems in assessing the extent of alcohol consumption, we attempted to grade it as shown in the footnote to Table 1. The first distinction was
724
E M M E R S O N AND KNOWLES
@
eq it3
od
G
t~
I. 1,1
@
TRIGLYCERIDE
725
CONCENTRATIONS
o
4 ,4 V
>
V
0 o~
~,~
+1
~r-i V ,,d ~,
~
~
~
~
+
~ ~V M '4 v
~ "4 ,.,.4
d
0'..~ 0
0
0
9
N
m~N
*
726
EMMERSON AND KNOWLES
between those who took alcohol only occasionally in small amounts or never (graded as nil) and those who took alcohol regularly (graded as mild, moderate, or heavy drinkers). There was a significantly greater number of regular drinkers in the primary gout group (exact test: p < 0.05). Similar conclusions were reached if the nil and mild drinkers were grouped and compared with the combination of moderate and heavy drinkers.
Relationship oJ Serum TrigIycerides to Serum Cholesterol Concentrations Significant correlations existed between triglycerides and cholesterol for both the primary gout group (r = 0.43, p < 0.05) and the lead gout group (r = 0.75, p < 0.02) whether considered singly or together (r == 0.45, p < 0.01).
Relationship o[ Serum Triglycerides to Serum Urate Concentrations No significant correlation was found.
Relationship of Serum Triglycerides to Renal Failure Chronic renal failure has been reported to induce hypertriglyceridemia,23,24 and our own experience with a patient who had a plasma triglyceride of 352 mg/100 ml when in advanced chronic renal failure, in whom the triglyceride fell to 81 rag/100 ml after renal transplantation, would support this. However, in the present data, no correlation can be shown between the plasma triglyceride and the serum creatinine concentration (or the logarithm of the serum creatinine concentration) in either the lead gout group or the primary gout group, viewed singly or together. In addition, exclusion of those cases with severe renal disease (serum creatinine greater than 7 rag/100 ml) did not appreciably alter the mean serum triglyceride in the lead gout group (115 rag/100 ml as opposed to 113 rag/100 ml). Actually, the greater degree of renal disease in the lead gout group should tend to increase the hypertriglyceridemia in that group, thereby tending to decrease rather than increase the difference between the serum triglycerides in the two groups. These factors, therefore, make it most unlikely that the greater hypertriglyceridemia in the primary gout group is related to the different degree of renal disease.
Relationship oJ TrigIycerides to Obesity Although the primary gout group showed greater hypertriglyceridemia and greater percentage average weight, and although hypertriglyceridemia may be a feature of obesity,21 no significant correlation was demonstrable between the serum triglyceride concentrations and the percentage average weight in the primary gout group (Spearman rank correlation coefficient = 0.28, N.S.). To assess the effect on the serum triglycerides of the different values for the percentage desirable weight in the two groups, a corrected value for the triglyceride of each subject was calculated according to the following relationship derived by Grace 25 in 46 normal subjects. Log triglyceride --- 1.387 + 0.00488% desirable weight. The corrected triglyceride concentration for each subject was calculated by multiplying the observed triglyceride value by the ratio of the calculated triglyceride concentration at 100% desirable weight to the calculated triglyceride concentration at the
727
TRIGLYCERIDE CONCENTRATIONS
observed per cent desirable weight. Comparison of the corrected triglyceride values in the two groups (each at the desirable weight for height) still showed significantly higher triglyceride concentrations in the primary gout group (209 • 135 rag/100 ml) as compared with the lead gout group (114 __ 44 rag/100 ml) (Mann-Whitney U test, p < 0.01).
Relationship o[ Serum Triglycerides to Alcohol Consumption Since both greater triglyceride concentration and significantly higher consumption of alcohol were found in the primary gout group and because hypertriglyceridemia may be a feature of alcoholism, the data was examined to see if there were any positive association between the two. However, no significant difference was found between the serum triglycerides and any of the different grades of alcohol consumption (Spearman rank correlation coefficient = 0.02, N.S.). Likewise, the presence of hypertriglyceridemia (serum triglyceride > 160 mg/100 ml) did not correlate with the presence or absence of alcohol consumption (X 2 = 0.29, N.S.). In addition, if only subjects with an alcohol consumption in the "nil" category were considered, the mean triglyceride concentration was still significantly greater in the primary gout group [mean primary gout (n = 7) = 261 • 119 rag/100 ml; mean lead gout (n = 8) = 123 --_+ 36 mg/100 ml]. If the triglycerides were compared by the Mann-Whitney test for nonparametric observations, the primary gout group still had significantly greater triglyceride concentrations than the lead gout group (p < 0.02). Thus, the present data provides no evidence of a relationship, either etiological or otherwise, between the hypertriglyceridemia in the primary gout group and their alcohol consumption.
Relationship of Urinary Urate Excretion to Triglyceride Concn in Primary Gout The criteria accepted for diagnosis tended to cause the inclusion in the primary gout group of a larger proportion of over-excretors than would be seen in the general population. Now, while all over-excretors of uric acid are accepted as being overproducers, not all overproducers demonstrate elevated urinary uric acid excretions (greater than 590 rag/24 hr on a purine free diet). Nonetheless, a correlation between urine uric acid and triglycerides was sought to see if the over-excretors in the primary gout group tended to be a hypertriglyceridemic group. No correlation was demonstrable, however, either in the primary gout group as a whole or when it was divided into over-excretors and normal excretors. The mean triglyceride for the over-excretors (296 ~ 121 mg/100 ml) was not significantly different from the normal excretors (268 +__ 193 mg/100 ml) and the mean for each was significantly different from that for the lead nephritics (113 ___ 34 mg/100 ml). This, therefore, does not support an association of overproduction of urate with hypertriglyceridemia, although it does not exclude such an association. DISCUSSION
It is becoming more widely appreciated that gout is a syndrome rather than a disease entity and that further understanding of it will depend upon the development of an etiologic classification. One definite variety of gout, which appears to
728
EMMERSON AND KNOWLES
be acquired, is that associated with chronic lead nephropathy. The present study was designed to reveal specific differences between this variety and the more common, and as yet undifferentiated type, usually designated as primary gout. It has established hypertriglyceridemia as a significant and frequent feature of primary gout, whereas its absence from patients with lead gout shows that it is not a regular association of hyperuricemia alone. Analysis of possible causes did not provide evidence that would allow the hypertriglyceridemia to be attributed to either renal disease, obesity, or alcohol consumption, although the clinical association of gout with hypertriglyceridemia, obesity, and regular alcohol consumption does suggest a distinct variety of gout. Such an association does not help in determining where the fundamental disorder lies and which features are secondary and nonessential. Had an association with urate overproduction been demonstrable, this might have provided a clue to the cause of the association by suggesting a common factor leading to overproduction of both urate and triglyceride. With the limited available data on this aspect, the absence of such a demonstration does not exclude such a possibility. Acute alcoholic excess has been associated with extreme hypertriglyceridemia, hypercholesterolemia, and hyperuricemia,26 and these have been shown to remit with abstinence from alcohol. It is notable however, that this association is not with hypertriglyceridemia alone, nor has it been demonstrated with regular mild or moderate consumption of alcohol. This is not to imply that the association of regular alcohol consumption with gout is not well established,27 or that it is not possible it may have a persistent effect on urate and lipids similar to repeated acute excesses. It merely indicates that such a mechanism has not yet been demonstrated and that, if alcohol is in fact the cause of the hyperlipemia and hyperuricemia in the primary gout group, it must be a more constantly operative factor in the etiology of primary gout than is presently accepted. Another important alternative to consider is whether the hypertriglyceridemic patients in the primary gout group might be suffering from carbohydrate induced hyperlipemia (Fredrickson Type IV) 2s in which alcohol is filling the inducing role of a carbohydrate. This condition is associated with hyperuricemia, and it may be that the hyperuricemia, becoming symptomatic, becomes the dominant presenting feature at a time when the hyperlipemia is asymptomatic. It is thus difficult to conclude on the evidence available that the hypertriglyceridemia is attributable to the greater alcohol consumption of the primary gout group. The present results might also throw light on the cause of the variable incidence of arterial disease in gout. The general clinical impression is that these are frequently associated? although this cannot be substantiated when viewed over the whole field of gout from the mortality statistics of life insurance companies. 29 This discrepancy might be explained, if there were one subtype of the syndrome of gout that was associated with hypertriglyceridemia and had an increased incidence of vascular disease, but that was not easily distinguished when combined with all the other subtypes of the gout syndrome not associated with hypertriglyceridemia and vascular disease. It would seem that further study should be directed toward the delineation of more characteristics of that Variety of gout that is associated with hypertriglyceridemia in the hope that this wiI1 elucidate the mechanism leading to the association.
729
TRIGLYCERIDE CONCENTRATIONS REFERENCES 1. Barlow, K. A.: Hyperlipidemia in primary gout. Metabolism 27:289, 1968. 2. Harris-Jones, J. N.: Hyperuricaemia and essential hypercholesterolaemia. Lancet 1:857, 1957. 3. Feldman, E. B., and Wallace, S. L.: Hypertriglyceridaemia in gout. Circulation 29:508, 1964. 4. Benedek, T. G.: Correlations of serum uric acid and lipid concentrations in normal, gouty and atherosclerotic men. Ann. Intern. Med. 66:851, 1967. 5. Kuntz, D., Roques, C., Paolaggi, F., and Ryckewaert, A.: l~tude comparative de la triglyc6ridfmie, de la lipid~mie, de la glyc6mie et de l'index pond6ral chez les hyperuric~miques et les normo-uric6miques. Patb. Biol. (Paris) 17:399, 1969. 6. Berkowitz, D.: Blood lipid and uric acid interrelationships. J A M A 190:856, 1964. 7. Kelley, W. N.: Recent progress in the pathogenesis and treatment of gout. Med. Times 97:230, 1969. 8. Nye, L. J. J.: Chronic Nephritis and Lead Poisoning. Sydney, Angus and Robertson, 1933, p. 87. 9. Henderson, D. A., and Inglis, J. A.: The lead content of bone in chronic Bright's Disease. Aust. Ann. Med. 6:145, 1957. 10. Emmerson, B. T.: Chronic lead nephropathy: The diagnostic use of calcium E D T A and the association with gout. Aust. Ann. Med. 12:310, 1963. 11. - - : Metals and the kidney. In Black, D. A. K . ((Ed.): Renal Disease (ed. 2). Oxford, Blackwell Scientific Publications, 1967, p. 565. 12. - - : The renal excretion of urate in chronic lead nephropathy. Aust. Ann. Med. 14:295, 1965. 13. - - : The clinical differentiation of lead gout from primary gout. Arthritis Rheum. 11:623, 1968. 14. Kellgren, J. H., Jeffrey, M. R., and Ball, J. (Eds.): The Epidemiology of Chronic Rheumatism. Oxford, Blackwell Scientific Publications, 1963, p. 295. 15. Wyngaarden, J. B.: Gout. In Stanbury, J. B., Wyngaarden, J. B., and Fredrickson, D. S. (Eds.): The Metabolic Basis of Inherited Disease (ed. 2). New York, Mc-
Graw-Hill, 1966, p. 691. 16. Liddle, L., Seegmiller, J. E., and Laster, L.: The enzymatic spectrophotometric method for determination of uric acid. J. Lab. Clin. Med. 54:903, 1959. 17. Edwards, K. D. G., and Whyte, H. M.: The measurement of creatinine in plasma and urine. Aust. J. Exp. Biol, Med. Sci. 36:383, 1958. 18. Carlson, L. A., and Wadstrom, L. B.: Determination of glycerides in blood serum. Clin. Chim. Acta 4: 197, 1959. 19. Liese, L., Abell, B., Levy, B., Brodie, B. B., and Kendall, F. E.: A simplified method for the estimation of total cholesterol in serum and demonstration of its specificity. J. Biol. Chem. 195:357, 1952. 20. Diem, K. (Ed.): Documenta Geigy Scientific Tables (ed. 6). St. Leonards, N. S. W., Geigy Pharmaceuticals Division of Geigy (Australia) Pty., 1962, p. 623. 21. Grace, C. S., and Goldrick, R. B.: Assessment of body composition in normal and obese subjects. Aust. Ann. Med. 18:26, 1969. 22. Siegal, S.: Nonparametric statistics for the behavioral sciences. New York, McGrawHill, 1956, p. 116. 23. Losowsky, M. S., and Kenward, D. H.: Lipid metabolism in acute and chronic renal failure. J. Lab. Clin. Med. 71:736, 1968. 24. Bagdade, J. D., Porte, D., and Bierman, E. L.: Hypertriglyceridemia : A metabolic consequence of chronic renal failure. New Eng. J. Med. 279: 181, 1968. 25. Grace, C. S.: Studies on fibrinolysis. M.D. Thesis, University of Sydney, t968. 26. Gebbie, T., and Prior, I. A. M.: Alcoholic hyperlipaemia. Med. J. Aust. 2:769, 1967. 27. Saker, B. M., Toiler, O. B., Burvill, M. J., and Reilly, K. A.: Alcohol consumption and gout. Med. J. Aust. 1:1213, 1967. 28. Frederickson, D. S., and Lees, R. S.: Familial hyperlipoproteinemia. In Stanbury, J. B., Wyngaarden, J. B., and Fredrickson, D. S. (Eds.): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1966, p. 467. 29. Talbott, J. H.: Gout (ed. 3). New York, Grune & Stratton, 1967, p. 214.