976
The Journal of Pediatrics December 1978
Brief clinical and laboratory observations
8. Radel EO, and Schorr JB: Thrombocytopenic purpura with infectious mononucleosis, J PEDIATR 63:46, 1963. 9. Cohn J: Thrombocytopenia in childhood: an evaluation of 433 patients, Scand J HematoI16:226, 1976.
10. Lavelle KJ, Ransdell BA, and Kleet SA: THe influence of selective thrombocytopenia on nephrotoxic nephritis, J Lab Clin Med 87:967, 1976.
Iatrogenic hyperuricemia in children with cystic fibrosis G.P. Davidson, F. Morad Hassel, D. Crozier, M. Corey, and G.G. Forstner,* Toronto, Ont., Canada
PANCREATIC INSUFFICIENCY associated with cystic fibrosis has been treated with commercially prepared pancreatic extracts for many years with no apparent harmful effect. However, several recent reports have shown the presence of hyperuricosuria in children with CF and have related this to purine contamination of their pancreatic replacement therapy. J. 2 We report the frequent presence of hyperuricemia in a group of children with CF who were known to be consuming large dosages of pancreatic extract as part of their therapy. Hyperuricemia was more common in older patients who had been treated for a longer period of time.
50
x·_·_·x CONTROL o--oC.F.-
40 ~ V) ~
/;.
30
I
I
x
UJ
«
•
0; \
Z
~
e--ec.F.+
0
20
\
e \
•
c,
/
.~
60 mEq/l) on at least two occasions. All 97 patients had blood drawn for serum uric acid determinations following an overnight fast. From the The Hospital for Sick Children. 'Reprint address: The Hospital/or Sick Children, Toronto, Ont., MSG lX8 Canada.
0
2
3
4
5
6
7
8
9 10 11 12 13
URIC ACID (mgjdl)
Fig. I. Frequency distribution of serum uric acid levels in CF patients receiving pancreatic supplements (CF + l- CF patients not on pancreatic supplements (CF-). and controls.
A subgroup of 74 patients, consisting of 64 patients receiving pancreatic supplements, and ten patients not receiving supplements, was derived from the total group on the basis of their long-term inclusion in a study of pulmonary function over a period of five to seven years." Abbreviation used CF: cystic fibrosis FVC: forced vital capacity
Patients excluded from this subgroup had not had pulmonary function tested. In these patients simple correlations and multiple regressions were computed, using the recorded variables of serum uric acid, age, age at diagnosis, years since diagnosis, sex, Po., and changes in forced vital capacity, one-second FEY, mean forced expiratory flow rate during the middle half of the FYC, and one-second FEY as a percentage of FYC. Uric acid determinations were carried out using a direct colorimetric method with a uricase-catalase system. Control values for serum uric in children were obtained from measurements in 200 consecutive children in whom
0022-3476178/120976 + 03$00.30/0 © 1978 The C. V. Mosby Co.
Brie! clinical and laboratory observations
Volume 93
977
Number 6
12
•
11
• •
10
9 SERUM URIC ACID (mg/dl)
B
•
7
•••
6
o •
• •
5
e• • •
4
•
• •
3
• •
• •• • • • •• • •• • • • • •• • •• ••• ••• • • •• ·00 • •• • •
:.0
o •
o
0
oe
0 0
•
o{. I i
1
I
0 6
9
12
15
•
•
• I
I
i
18
21
24
1-
27
AGE (yeor s) Fig. 2. Correl ation o f seru m uric acid with age . • '" CF patients receiv ing pancreatic extract. 0 = CF patients not on pancreati c extract.
no renal or pancreatic disease was found. The mean value was 4.5 ± 1.3 (SD) mg/dl and was similar to that obtained by Harkness and Nicol.' Hyp eruricemia was defined as > 2 SO above the mean (i.e., > 7.1 mg/ dl). Simple correlations and multiple regressions of variables were computed using the SPSS statistical package . Group means were compared using the Student's t test.
RESULTS In the total CF group of 97 patients, the 15 patients not taking pancreatic extracts had a mean serum uric acid level of 4.9 ± 0.9 mgtdl ( ± SD), not significantly different from the controls. In contr ast, the mean serum uric acid concentration in the 82 patients receiving pancreatic enzymes was (6.2 ± 1.8 rng/d l (± SD), significantly higher than values in controls (P < 0.001), or in patients not taking pancreatic enzymes (P < 0.001). In Fig. 1 the percentage distribution of the individual values is shown for the con trols, CF patients receiving enzymes, and CF patients off enzymes; patients not taking enzymes had values which were distributed similarly to those in the control population. In contr ast, although some of the CF pat ients on pancreati c enzymes had values which were similar to those of the controls, many had values falling within a higher range, up to a maximum of 12.5 mg/dl, Twen ty-one of the 82 patients had hyperur icemia as defined in Methods. These results establish, therefore, that patients on high-dose pancreatic replacement therapy can develop elevated serum uric acid levels. To explore the factors which might precondition patients to hyperuricemia, serum uric acid levels were
correlated with a variety of factors (see Methods) common to a group of patients who had had repeated tests o f pulmonary function. In the 64 patients in th is group taking pancreatic enzymes. isex, age at diagnosis of CF. and indices reflecting the exten t of their pulmonary disease or its rate of progression were all unrelated to the serum uric acid level. In contrast, as shown in Fig. 2, high serum uric acid values were strongly correlated with the age of the patients (r = 0.46, P < 0.001). In these patients there was also a strong correlation with the years which had elapsed since diagnosis (r = 0.47, P < 0.001) (not shown). The correlation between age and years since diagnosis was extremely tight (r = 0.8). No relationship between serum uric acid concentration and age (Fig. 2), time since diagnosis, or any other factor was apparent in the patients not taking pancreatic replacement.
DISCUSSION These results indicate that hyperuricemia occurs in older CF patients with the grea ter lapse of time since diagnosis, Since pancreatic supplements were begun at or within a few months of the time of diagnosis, the patients with hyperuricemia are also those with the longest exposure to pancreatic supplements. Earlier studies in patients with CF I. 2 failed to describe hyp eruricemia, bu t this has developed in adults fed high-purine diets.' The additional purine load due to pancreatic supplementation in our pa tients was large, ranging from 150 to 585 mg/day, ' representing a two- to fivefold increase over their dietary intake. The strong age dependence of our findings could reflect increased ingestion of supplements in older
978
The Journal of Pediatrics December 1978
Brief clinicaland laboratory observations
patients. This seems unlikely, however, since most patients in this study who were older than 6 years were taking at least 100 capsules of pancreolipase or equivalent, and subsequent increases in intake appeared to be marginal. Other factors may therefore be involved. Stapleton et al" have recently reported that renal uric acid clearance is relatively elevated in childhood, falling to adult levels at approximately age 7. This is consistent with earlier evidence provided by Kaufman et al' that the urinary uric acid: creatinine ratio fell with age until age 10 before becoming stable, particularly since creatinine clearance reaches the adult range at age three." Younger patients may therefore have an increased capacity to clear uric acid, thus protecting themselves from hyperuricemia but exposing them to greater risks from hyperuricosuria. Hyperuricemia in older patients may also reflect renal tubular damage, since tubular secretion accounts for virtually all uric acid cleared by the kidney." With progression of their disease most of our patients are exposed repeatedly to arninoglycoside antibiotics, which also might damage tubular function. The absence of a relationship between pulmonary dysfunction and serum uric acid argues, however, that hyperuricemia is probably not related to a treatment reserved for pulmonary infections. Prolonged exposure to high-purine loads may itself constitute a threat to tubular function resulting in decreased uric acid clearance." We do not have information bearing on the renal function of all of our patients. In a sample of 22 patients, however, 15 of whom had hyperuricemia when tested, we found no abnormality in blood urea nitrogen, serum creatinine, creatinine clearance, urine osmolarity or urinary protein, and amino acid excretion. We have also examined postmortem specimens from six patients who had been receiving high-dose pancreatic supplementation and found no evidence of uric acid deposition, interstitial
fibrosis, or other renal pathology. These observations do not exclude the possibility of uric acid nephropathy in our older patients, but they do suggest that renal damage is likely to be rather mild in most of them. Clarification of the role of these and other factors in the production of hyperuricemia awaits a careful study of the relationship of purine load to urate excretion at various ages in these patien ts. REFERENCES I. Stapleton FB, Kennedy J, Nousia-Arvanitakis S, and
2.
3.
4. 5.
6.
7.
8.
9.
10.
Linshaw MA: Hyperuricosuria due to high dose pancreatic extract therapy in cystic fibrosis, N Engl J Med 295:246, 1976. Nousia-Arvanitakis S, Stapleton FB, Linshaw MA, and Kennedy J: Therapeutic approach to pancreatic extractinduced hyperuricosuria in cystic fibrosis, J PEDIATR 90:302, 1977. Corey M, Levison H, and Crozier D: Five- to seven-year course of pulmonary function in cystic fibrosis, Am Rev Resp Dis 114:1085, 1976. Harkness RA, and Nicol AD: Plasma uric acid levels in children, Arch Dis Child 44:773, 1969. Endozien JC, Udo UU, Young VR, and Scrimshaw NS: Effects of high levels of yeast feeding on uric acid metabolism of young men, Nature 228:180, 1970. Stapleton FB, Hassanein KM, and Linshaw MA: Renal uric acid clearance and excretion during childhood. Pediatr Res 11:558, 1977. Kaufman JM, Greene ML, and Seegmiller JE: Urine uric acid to creatinine ratio-a screening test for inherited disorders of purine metabolism, J PEDIATR 73:583, 1968. Winberg J: The 24-hour true endogenous creatinine clearance in infants and children without renal disease, Acta Paediatr Scand 48:443, 1959. Gutman AB, and Yu TF: A three-component system for regulation of renal excretion of uric acid in man, Trans Assoc Am Physicians 74:353, 1961. Klinenberg J, Kippen I, and Bluestone R: Hyperuricemic nephropathy: Pathologic features and factors influencing urate deposition, Nephron 14:88, 1975.
Thyroid storm following radioiodine for thyrotoxicosis Alberto Hayek, M.D., Albuquerque, N.M.
THYROID STORM, a rare complication ofjuvenile thyro-
toxicosis, has apparently been reported only five times in children.' Although the therapy of Graves disease remains controversial, there is increased acceptability of radioioFrom the Department of Pediatrics, University of New Mexico School of Medicine. Reprint address: Department af Pediatrtcs, University of New Mexic» School 01 Medicine, Albuquerque; NM 87131,
dine as a reasonable treatment for juvenile hyperthyroid3 Awareness of thyroid storm as a complication should be taken into account when radioiodine is used in children.
ism."
CASE REPORT At the age of to years, a girl with a known diagnosis of Down syndrome developed typical signs of juvenile hyperthyroidism.
0022·3476178/120978+03$00.30/0 © 1978 The C. Y, Mosby Co.
The Journal of Pediatrics December 1978
Brief clinical and laboratory observations
8. Radel EO, and Schorr JB: Thrombocytopenic purpura with infectious mononucleosis, J PEDIATR 63:46, 1963. 9. Cohn J: Thrombocytopenia in childhood: an evaluation of 433 patients, Scand J HematoI16:226, 1976.
10. Lavelle KJ, Ransdell BA, and Kleet SA: THe influence of selective thrombocytopenia on nephrotoxic nephritis, J Lab Clin Med 87:967, 1976.
Iatrogenic hyperuricemia in children with cystic fibrosis G.P. Davidson, F. Morad Hassel, D. Crozier, M. Corey, and G.G. Forstner,* Toronto, Ont., Canada
PANCREATIC INSUFFICIENCY associated with cystic fibrosis has been treated with commercially prepared pancreatic extracts for many years with no apparent harmful effect. However, several recent reports have shown the presence of hyperuricosuria in children with CF and have related this to purine contamination of their pancreatic replacement therapy. J. 2 We report the frequent presence of hyperuricemia in a group of children with CF who were known to be consuming large dosages of pancreatic extract as part of their therapy. Hyperuricemia was more common in older patients who had been treated for a longer period of time.
50
x·_·_·x CONTROL o--oC.F.-
40 ~ V) ~
/;.
30
I
I
x
UJ
«
•
0; \
Z
~
e--ec.F.+
0
20
\
e \
•
c,
/
.~
60 mEq/l) on at least two occasions. All 97 patients had blood drawn for serum uric acid determinations following an overnight fast. From the The Hospital for Sick Children. 'Reprint address: The Hospital/or Sick Children, Toronto, Ont., MSG lX8 Canada.
0
2
3
4
5
6
7
8
9 10 11 12 13
URIC ACID (mgjdl)
Fig. I. Frequency distribution of serum uric acid levels in CF patients receiving pancreatic supplements (CF + l- CF patients not on pancreatic supplements (CF-). and controls.
A subgroup of 74 patients, consisting of 64 patients receiving pancreatic supplements, and ten patients not receiving supplements, was derived from the total group on the basis of their long-term inclusion in a study of pulmonary function over a period of five to seven years." Abbreviation used CF: cystic fibrosis FVC: forced vital capacity
Patients excluded from this subgroup had not had pulmonary function tested. In these patients simple correlations and multiple regressions were computed, using the recorded variables of serum uric acid, age, age at diagnosis, years since diagnosis, sex, Po., and changes in forced vital capacity, one-second FEY, mean forced expiratory flow rate during the middle half of the FYC, and one-second FEY as a percentage of FYC. Uric acid determinations were carried out using a direct colorimetric method with a uricase-catalase system. Control values for serum uric in children were obtained from measurements in 200 consecutive children in whom
0022-3476178/120976 + 03$00.30/0 © 1978 The C. V. Mosby Co.
Brie! clinical and laboratory observations
Volume 93
977
Number 6
12
•
11
• •
10
9 SERUM URIC ACID (mg/dl)
B
•
7
•••
6
o •
• •
5
e• • •
4
•
• •
3
• •
• •• • • • •• • •• • • • • •• • •• ••• ••• • • •• ·00 • •• • •
:.0
o •
o
0
oe
0 0
•
o{. I i
1
I
0 6
9
12
15
•
•
• I
I
i
18
21
24
1-
27
AGE (yeor s) Fig. 2. Correl ation o f seru m uric acid with age . • '" CF patients receiv ing pancreatic extract. 0 = CF patients not on pancreati c extract.
no renal or pancreatic disease was found. The mean value was 4.5 ± 1.3 (SD) mg/dl and was similar to that obtained by Harkness and Nicol.' Hyp eruricemia was defined as > 2 SO above the mean (i.e., > 7.1 mg/ dl). Simple correlations and multiple regressions of variables were computed using the SPSS statistical package . Group means were compared using the Student's t test.
RESULTS In the total CF group of 97 patients, the 15 patients not taking pancreatic extracts had a mean serum uric acid level of 4.9 ± 0.9 mgtdl ( ± SD), not significantly different from the controls. In contr ast, the mean serum uric acid concentration in the 82 patients receiving pancreatic enzymes was (6.2 ± 1.8 rng/d l (± SD), significantly higher than values in controls (P < 0.001), or in patients not taking pancreatic enzymes (P < 0.001). In Fig. 1 the percentage distribution of the individual values is shown for the con trols, CF patients receiving enzymes, and CF patients off enzymes; patients not taking enzymes had values which were distributed similarly to those in the control population. In contr ast, although some of the CF pat ients on pancreati c enzymes had values which were similar to those of the controls, many had values falling within a higher range, up to a maximum of 12.5 mg/dl, Twen ty-one of the 82 patients had hyperur icemia as defined in Methods. These results establish, therefore, that patients on high-dose pancreatic replacement therapy can develop elevated serum uric acid levels. To explore the factors which might precondition patients to hyperuricemia, serum uric acid levels were
correlated with a variety of factors (see Methods) common to a group of patients who had had repeated tests o f pulmonary function. In the 64 patients in th is group taking pancreatic enzymes. isex, age at diagnosis of CF. and indices reflecting the exten t of their pulmonary disease or its rate of progression were all unrelated to the serum uric acid level. In contrast, as shown in Fig. 2, high serum uric acid values were strongly correlated with the age of the patients (r = 0.46, P < 0.001). In these patients there was also a strong correlation with the years which had elapsed since diagnosis (r = 0.47, P < 0.001) (not shown). The correlation between age and years since diagnosis was extremely tight (r = 0.8). No relationship between serum uric acid concentration and age (Fig. 2), time since diagnosis, or any other factor was apparent in the patients not taking pancreatic replacement.
DISCUSSION These results indicate that hyperuricemia occurs in older CF patients with the grea ter lapse of time since diagnosis, Since pancreatic supplements were begun at or within a few months of the time of diagnosis, the patients with hyperuricemia are also those with the longest exposure to pancreatic supplements. Earlier studies in patients with CF I. 2 failed to describe hyp eruricemia, bu t this has developed in adults fed high-purine diets.' The additional purine load due to pancreatic supplementation in our pa tients was large, ranging from 150 to 585 mg/day, ' representing a two- to fivefold increase over their dietary intake. The strong age dependence of our findings could reflect increased ingestion of supplements in older
978
The Journal of Pediatrics December 1978
Brief clinicaland laboratory observations
patients. This seems unlikely, however, since most patients in this study who were older than 6 years were taking at least 100 capsules of pancreolipase or equivalent, and subsequent increases in intake appeared to be marginal. Other factors may therefore be involved. Stapleton et al" have recently reported that renal uric acid clearance is relatively elevated in childhood, falling to adult levels at approximately age 7. This is consistent with earlier evidence provided by Kaufman et al' that the urinary uric acid: creatinine ratio fell with age until age 10 before becoming stable, particularly since creatinine clearance reaches the adult range at age three." Younger patients may therefore have an increased capacity to clear uric acid, thus protecting themselves from hyperuricemia but exposing them to greater risks from hyperuricosuria. Hyperuricemia in older patients may also reflect renal tubular damage, since tubular secretion accounts for virtually all uric acid cleared by the kidney." With progression of their disease most of our patients are exposed repeatedly to arninoglycoside antibiotics, which also might damage tubular function. The absence of a relationship between pulmonary dysfunction and serum uric acid argues, however, that hyperuricemia is probably not related to a treatment reserved for pulmonary infections. Prolonged exposure to high-purine loads may itself constitute a threat to tubular function resulting in decreased uric acid clearance." We do not have information bearing on the renal function of all of our patients. In a sample of 22 patients, however, 15 of whom had hyperuricemia when tested, we found no abnormality in blood urea nitrogen, serum creatinine, creatinine clearance, urine osmolarity or urinary protein, and amino acid excretion. We have also examined postmortem specimens from six patients who had been receiving high-dose pancreatic supplementation and found no evidence of uric acid deposition, interstitial
fibrosis, or other renal pathology. These observations do not exclude the possibility of uric acid nephropathy in our older patients, but they do suggest that renal damage is likely to be rather mild in most of them. Clarification of the role of these and other factors in the production of hyperuricemia awaits a careful study of the relationship of purine load to urate excretion at various ages in these patien ts. REFERENCES I. Stapleton FB, Kennedy J, Nousia-Arvanitakis S, and
2.
3.
4. 5.
6.
7.
8.
9.
10.
Linshaw MA: Hyperuricosuria due to high dose pancreatic extract therapy in cystic fibrosis, N Engl J Med 295:246, 1976. Nousia-Arvanitakis S, Stapleton FB, Linshaw MA, and Kennedy J: Therapeutic approach to pancreatic extractinduced hyperuricosuria in cystic fibrosis, J PEDIATR 90:302, 1977. Corey M, Levison H, and Crozier D: Five- to seven-year course of pulmonary function in cystic fibrosis, Am Rev Resp Dis 114:1085, 1976. Harkness RA, and Nicol AD: Plasma uric acid levels in children, Arch Dis Child 44:773, 1969. Endozien JC, Udo UU, Young VR, and Scrimshaw NS: Effects of high levels of yeast feeding on uric acid metabolism of young men, Nature 228:180, 1970. Stapleton FB, Hassanein KM, and Linshaw MA: Renal uric acid clearance and excretion during childhood. Pediatr Res 11:558, 1977. Kaufman JM, Greene ML, and Seegmiller JE: Urine uric acid to creatinine ratio-a screening test for inherited disorders of purine metabolism, J PEDIATR 73:583, 1968. Winberg J: The 24-hour true endogenous creatinine clearance in infants and children without renal disease, Acta Paediatr Scand 48:443, 1959. Gutman AB, and Yu TF: A three-component system for regulation of renal excretion of uric acid in man, Trans Assoc Am Physicians 74:353, 1961. Klinenberg J, Kippen I, and Bluestone R: Hyperuricemic nephropathy: Pathologic features and factors influencing urate deposition, Nephron 14:88, 1975.
Thyroid storm following radioiodine for thyrotoxicosis Alberto Hayek, M.D., Albuquerque, N.M.
THYROID STORM, a rare complication ofjuvenile thyro-
toxicosis, has apparently been reported only five times in children.' Although the therapy of Graves disease remains controversial, there is increased acceptability of radioioFrom the Department of Pediatrics, University of New Mexico School of Medicine. Reprint address: Department af Pediatrtcs, University of New Mexic» School 01 Medicine, Albuquerque; NM 87131,
dine as a reasonable treatment for juvenile hyperthyroid3 Awareness of thyroid storm as a complication should be taken into account when radioiodine is used in children.
ism."
CASE REPORT At the age of to years, a girl with a known diagnosis of Down syndrome developed typical signs of juvenile hyperthyroidism.
0022·3476178/120978+03$00.30/0 © 1978 The C. Y, Mosby Co.
