- Email: [email protected]
Etiology of rickets in Nigerian children
692
Oginni et al.
pyruvate decarboxlase deficiency with profound lactic acidosis and hyperammonemia: responses to dichloroacetate and benzoate. Am J Med Genet 1985:22:291-9. 20. Kuroda Y, Ito M, Toshima K, et al. Treatment of congenital lactic acidosis by oral administrationof dichloroacetate. J Inherit Metab Dis 1986;9:244-52.
The Journal of Pedi, tric~ May 1996 21. Toth PP, EI-Shanti H, Eivens S, Rhead WJ, Klein JM. Transient improvementof congenital lactic acidosis in a male infant with pymvate decarboxylase deficiency treated with dichlon,acetate. J PEbIA'rR1993;123:427-30.
Etiology of rickets in Nigerian children L. M. O g i n n i , FMCS, M. Worsfold, PhD, 0 . A. O y e l a m i , FWACPaed, C, A. Sharp, PhD, D. E. Powell, BSc, a n d M. W. J. D a v i e , FRCP From the Departments of Orthopaedics and Paediatrics, Obafemi Awolowo University, IleIfe, Nigeria, and Charles Salt Research Centre, Robert Jones and Agnes Hunt Orthopaedic and District Hospital, Oswestry, Shropshire, United Kingdom
We studied 26 Nigerian children with active rickets (13 boys, 13 girls), aged I to 5 years, and compared results of biochemical studies with those of healthy control subjects. The plasma 1,25-dihydroxyvitamin D level was elevated (568 ± 317 pmol/L) and the 25-hydroxyvitamin D level was low (36 ± 28 nmol/L) in the children with rickets compared with the control subjects (369 ± 134 nmol/L and 69 ± 22 nmol/L, respectively). The results suggest that rickets in Nigeria is largely the result of calcium deficiency and that vitamin D deficiency and possibly end organ resistance may be contributory factors. (J Pediatr 1996; 128:692-4) Rickets is still common in Nigeria despite the abundant sunshine. Earlier reports had implicated deficiency of vitamin D 1-3, this hypothesis was supported by the good response to vitamin D supplementation, although this treatment was usually accompanied with calcium supplementation. However, a child in the tropics with adequate exposure to sunshine would not be expected to have vitamin D deficiency.4, 5 In 1990 we noticed in Ile-Ife that many of our patients with rickets who received vitamin D treatment had no improvement, in contrast to usual results with vitamin D deficiency rickets. Although there are many reports about tickets in Nigeria and Africa, the majority are epidemiologic and clinical studies. The only detailed biochemical study from Nigeria was by Okonofua et al.,6 whose findings in 11 patients with rickets suggest calcium deficiency as the main cause. These workers estimated calcium intake from the diet but did not measure urinary calcium excretion. Pettifor et al. 7 also reported calcium deficiency rickets in rural South Africa. Supported in part by the CommonwealthScholarship Commission and M. Davie Research Foundation. Submitted for publication Sept. 27, 1995; accepted Nov. 28, 1995. Reprint requests: L. M. Oginni, FMCS, Charles Salt Research Centre, Robert Jones & Agnes Hunt Orthopaedic & District Hospital, Oswestry, Shropshire, SY10 7AG, United Kingdom. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/22/70944
In this biochemical study, we compared 26 patients with rickets with healthy control subjects in an attempt to establish the cause of the condition in this environment.
METHODS Twenty-six patients with active rickets (13 boys, 13 girls), aged 1 to 5 years, seen in the orthopedic and pediatric clinics of the Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria, between January 1993 and September 1994, were studied and compared with 90 healthy control subjects
See commentary, p. 600.
iPTH Intact parathyroid hormone 25(OH)D 25-HydroxyvitaminD 1,25(OH)zD 1,25-DihydroxyvitaminD (55 boys, 35 girls) in the same age group and from the same community. The control subjects were children who had routine blood tests as part of a school entrance health survey or screening for sickle cell hemoglobinopathy. None of the children studied had sickle cell anemia. Only patients with clinical and radiologic features of rickets and who were not receiving any treatment were included in the study. Clinical criteria for the diagnosis of rickets included swollen wrists, rachitic rosaries, and angular deformities of
The Journal o f Pediatrics Volume 128, Number 5, Part 1
Oginni et al.
693
Table. Summary of biochemical data in patients and controls
Control subjects Patients with rickets
Reference (SI) Range (metric)
Albumin -corrected calcium (mmol/l.)
Phosphate (mmol/L)
Alkaline phosphatase (U/L)
iPTH (pmol/l.)
25(OH)D (mmol/L)
1,25(OH)2D (pmol/L)
2.35 + 0.14 (90) 2.06 _+0.23 (26) p <0.001 2.2-2.6 9-11 mg/dl
1.33 _+0.38 (84) 1.26 + 0.7 (26) p <0.03 0.6-1.3 1.8-4 mg/dl
160 -+ 55 (89) 492 + 214 (26) p <0.001 40-120 0.67-2 lakat/L
1.0 +- 1.2 (61) 5.9 -+ 6.9 (25) p <0.001 0.1-4.1 1-39 pg/ml
69 -+ 22 (20) 36 -+ 28 (22) p <0.0002 25-104 10-42 ng/ml
369 + 134 (23) 568 _+317 (26) p <0.01 60-108 25-45 pg/ml
iPTH, Intactparathyroidhormone;25(OH)D, 25-hydroxyvitaminD; 1,25(OH)2D:1,25-dihydroxyvitaminD.
Data reflect mean_+SD. The numberof controlsubjectsor patientswith rickets is listedin parentheses.
the knees. Roentgenographic criteria observed on anteroposterior x-ray views of both wrists and knees included widening and cupping of the metaphysis, fraying and thickening of the physis, and generalized rarefaction. In the control group only clinical assessment was used to rule out the existence of rickets, and x-ray studies were not done for ethical reasons. Informed consent was obtained from all parents and approval of the ethics committee was obtained. Blood samples were collected in lithium-heparin tubes and the plasma was separated into plain polypropylene tubes and stored at -20 ° C until transported frozen to the Charles Salt Research Centre, Oswestry, United Kingdom, where the biochemical analyses were performed. Blood samples were obtained at the time of initial diagnosis before any treatment was instituted. Serum electrolytes were analyzed with an Ektachem analyzer (Eastman Kodak Co., Rochester, N.Y.). The plasma albumin-corrected calcium value was calculated from the formula: Albumin-corrected calcium (measured in millimoles per liter) -- Total calcium + 0.03 (40 - plasma albumin [measured in grams per liter]). 8 Plasma 25-hydroxyvitamin D was measured by radioimmunoassay (ImmunoDiagnostic Systems Ltd., Boldon, United Kingdom); 1,25dihydroxyvitamin D and intact parathyroid hormone levels were measured by radioimmunoassay and immunoradiometric assay, respectively (INCSTAR Ltd., Wokingham, United Kingdom). All assays were done in duplicate. Many of the 1,25(OH)2D assays had to be repeated after dilution because the values were outside the usual range. Both interassay and intraassay coefficients of variation for all assays were between 0.5% and 7.5%. Not all the analytes were measured for every subject because of limited availability of plasma. Data were analyzed with Mann-Whitney U and Spearman tests for comparison and correlation respectively, where appropriate, with Statgraphics software (Statistical Graphics Corp., Inc., Rockville, Md.).
RESULTS A summary of the biochemical data for the two groups is shown in the Table. The plasma albumin-corrected calcium and phosphate levels were lower than in the control subjects, whereas the alkaline phosphate value was always elevated in children with rickets. The plasma 25(OH)D values in the healthy control subjects ranged from 32 to 140 nmot/L ( 13 to 56 ng/ml), whereas plasma 25(OH)D levels in the patients with rickets were between 7 and 147 nmol/L (3 to 59 ng/ml). Plasma 1,25(OH)2D levels in the healthy control subjects were between 173 and 592 pmol/L (72 to 247 ng/ml). These levels were significantly higher in children up to 3 years of age (391 _+ 120 pmol/L [163 ± 50 pg/ml]) than in older children (233 _ 144 pmol/L [97 -+ 60 pg/ml]) (p <0.004). Plasma 1,25(OH)2D levels were higher in the patients with rickets; values ranged from 146 to 1500 pmol/L (61 to 625 pg/ml). The ratios of plasma 1,25(OH)2D to 25(OH)D were from 2.5 to 10.8 pmol/nmol in the healthy control subjects, and the ratios in the patients with rickets were 9 to 60 pmol/nmol (p <0.001). Plasma iPTH levels in the healthy control subjects ranged from 0 to 4.1 pmol/L (0 to 39 pJml), and in the rickets group from 0 to 33.6 pmol/L (0 to 319 pg/ml), (p <0.001). There was no correlation between iPTH and plasma 1,25(OH)2D or calcium levels in either group. Three patients had values of analytes far beyond the mean. One patient had relatively low levels of 1,25(OH)2D (146 pmol/L [61 pg/ml]) and 25(OH)D (7 nmol/L [3 ng/ml]), but with a very high iPTH level of 33.6 pmol/L (319 pg/ml). Two other patients had elevated 1,25(OH)2D levels of 1500 and 1400 pmol/L (625 and 583 pg/ml). Their 25(OH)D levels were 25 and 147 nmol/L (10 and 59 ng/ml), whereas their il~l'H concentrations were 0 and 0.5 pmol/L (0 and 5 pg/ml), respectively. Urinary calcium was not detectable in most patients, but all but one of them had a value just above the detection limit (0.12 mmol/L). The mean urinary calcium/creatinineratio in
694
Oginni et al.
children with rickets was 0.07. The pediatric reference range is 0.32 to 0.48 for European children. 9" J0 DISCUSSION The maintenance of a normal plasma level of calcium is vital to the metabolic regulation of calcium homeostasis, and proper mineralization of bone depends on the availability of calcium in adequate amount and proportion. In most forms of rickets plasma calcium levels are usually low or normal, as was found in this study. Similarly, phosphate levels are usually low. In the absence of severe liver damage, plasma 25(OH)D levels are a reflection of the availability of vitamin D in the body, whereas circulating levels of its active metabolite, 1,25(OH)2D, depend on the metabolic demands. This study indicates that plasma levels of 1,25(OH)2D are higher in the first 3 years of life. In this study, rickets was associated in general with high plasma levels of 1,25(OH)2D, in agreement with the observations of Okonofua et al., 6 but in our study the 25(OH)D levels were tow compared with normal levels in their study. The low 25(OH)D levels might be related in part to the high rate of conversion to 1,25(OH)zD, perhaps aggravating an otherwise marginally adequate status. Decreased 25(OH)D levels may also be aggravated by calcium deficiency through increased production of more polar metabolites of vitamin D. II Nonetheless, the levels of 25(OH)D in all but one patient were adequate to maintain very high levels of 1,25(OH)2D, and therefore are unlikely to be the sole cause of rickets. High 1,25(OH)zD levels in the presence of normal calcium intake and normal absorbing capacity (e.g., primary hyperparathyroidism) would increase intestinal calcium absorption and also increase urinary calcium output. Urinary calcium levels were very low in the presence of high plasma levels of 1,25(OH)zD in the children with rickets. This finding and the presence of hypocalcemia and increased parathyroid activity further support the suggestion of dietary calcium deficiency by Okonofua et al. 6 Low consumption of dairy products and a high-fiber diet, which are common in Nigeria, may contribute to the calcium deficiency. The dietary calcium intake estimated by Okonofua et al. 6 for children with rickets in this area was less than 150 mg per day. In rickets, high levels of 1,25(OH)2D occur in calcium deficiency type rickets ~2 and in end organ resistance (vitamin D~lependent rickets type II). 13 This autosomal recessive condition is very rare and none of the patients had alopecia totalis, a clinical feature of the condition. 14 However, end organ resistance cannot be ruled out in the two patients with very high plasma 1,25(OH)2D levels of 1400 and 1500 pmol/L (583 and 625 pg/ml). The patient with low
The Journal of Pediatrics May 1996
levels of plasma 25(OH)D and 1,25(OH)2D is obviously vitamin D deficient. We conclude that rickets in Nigeria is in large part the result of dietary calcium deficiency; vitamin D deficiency and possibly end organ resistance may play contributory roles. Production of 1,25(OH)2D is enhanced in response to calcium deprivation, perhaps leading to some reduction in 25(OH)D. An ongoing therapeutic study should clarify the situation. We suggest that dietary calcium supplementation and clear advice on exposure to sunlight should be integral parts of preventive and therapeutic measures for rickets in the tropics.
We thank Drs. Ogunsuyi, Ogunlusi, and Adegbehingbe for their clinical assistance and Mr. Tony Sherlock for his laboratory assistance.
REFERENCES
1. Antia AU. Observations on nutritional tickets in childhood. West Afr J Med 1970;t9:169-72. 2. Laditan AAO, Adeniyi A. Rickets in Nigerian children-response to vitamin D. J Trop Med Hyg 1975;78:206-9. 3. Mariam TW, Sterky G. Severe rickets in infancy and childhood in Ethiopia. Tropical Paediatrics 1973;82:876-8. 4. Lawson DE, Paul AA, Black AE, et al. Relative contributions of diet and sunlight to vitamin D state in the elderly. Br Med J 1979;2:303-5. 5. Stamp TC, Haddad JG, Twigg CA. Comparison of oral 25-hydroxycholecalciferol, vitamin D and ultraviolet light as determinants of circulating 25-hydroxyvitamin D. Lancet 1977;1:1341-3. 6. Okonofua F, Gills DS, Alabi ZO, Thomas M, Bell JL, Dandona P. Rickets in Nigerian children--a consequence of calcium malnutrition. Metabolism 1991 ;40:209-13. 7. Pettifor JM, Ross FP, Wang J, et al. Rickets in children of rural origin in South Africa: Is low dietary calcium a factor? J Pediatr 1978;92:320-4. 8. Varley H, Gowenlock AN, Bell M. Practical clinical biochemistry; vol 1.5th ed. London: Heinemann, 1980:868-72. 9. Clark LC Jr, Thompson HL, Beck El, Jacobson W. Excretion of creatine and creatinine by children. Arch Pediatr Adolesc Med [Am J Dis Child] 1951;81:774-83. 10. Lentner C. Geigy scientific tables, vol 1.8th ed. Basel: CibaGeigy Ltd., 1981:59. 11. Clements MR, Johnson L, Fraser DR. A new mechanism for induced vitamin D deficiency in calcium deprivation. Nature 1987;325:62-5. 12. Pettifor JM, Ross FP, Travers R, et al. Dietary calcium deficiency: a syndrome associated with bone deformities and elevated serum 1,25dihydroxyvitamin D concentration. Metabolic Bone Disease and Related Research 1981 ;2:301-5. 13. Sockalosky JJ, Ulstrom RA, DeLuca HF, et al. Vitamin D-resistant rickets: end organ unresponsiveness to 1,25(OH)2D 3. J Pediatr 1980;96:701-3. 14. Rosen Jf, Fleischman AR, Finberg L, et al. Rickets with alopecia: an inborn error of vitamin D metabolism. J Pediatr 1979;94:729-35.
Oginni et al.
pyruvate decarboxlase deficiency with profound lactic acidosis and hyperammonemia: responses to dichloroacetate and benzoate. Am J Med Genet 1985:22:291-9. 20. Kuroda Y, Ito M, Toshima K, et al. Treatment of congenital lactic acidosis by oral administrationof dichloroacetate. J Inherit Metab Dis 1986;9:244-52.
The Journal of Pedi, tric~ May 1996 21. Toth PP, EI-Shanti H, Eivens S, Rhead WJ, Klein JM. Transient improvementof congenital lactic acidosis in a male infant with pymvate decarboxylase deficiency treated with dichlon,acetate. J PEbIA'rR1993;123:427-30.
Etiology of rickets in Nigerian children L. M. O g i n n i , FMCS, M. Worsfold, PhD, 0 . A. O y e l a m i , FWACPaed, C, A. Sharp, PhD, D. E. Powell, BSc, a n d M. W. J. D a v i e , FRCP From the Departments of Orthopaedics and Paediatrics, Obafemi Awolowo University, IleIfe, Nigeria, and Charles Salt Research Centre, Robert Jones and Agnes Hunt Orthopaedic and District Hospital, Oswestry, Shropshire, United Kingdom
We studied 26 Nigerian children with active rickets (13 boys, 13 girls), aged I to 5 years, and compared results of biochemical studies with those of healthy control subjects. The plasma 1,25-dihydroxyvitamin D level was elevated (568 ± 317 pmol/L) and the 25-hydroxyvitamin D level was low (36 ± 28 nmol/L) in the children with rickets compared with the control subjects (369 ± 134 nmol/L and 69 ± 22 nmol/L, respectively). The results suggest that rickets in Nigeria is largely the result of calcium deficiency and that vitamin D deficiency and possibly end organ resistance may be contributory factors. (J Pediatr 1996; 128:692-4) Rickets is still common in Nigeria despite the abundant sunshine. Earlier reports had implicated deficiency of vitamin D 1-3, this hypothesis was supported by the good response to vitamin D supplementation, although this treatment was usually accompanied with calcium supplementation. However, a child in the tropics with adequate exposure to sunshine would not be expected to have vitamin D deficiency.4, 5 In 1990 we noticed in Ile-Ife that many of our patients with rickets who received vitamin D treatment had no improvement, in contrast to usual results with vitamin D deficiency rickets. Although there are many reports about tickets in Nigeria and Africa, the majority are epidemiologic and clinical studies. The only detailed biochemical study from Nigeria was by Okonofua et al.,6 whose findings in 11 patients with rickets suggest calcium deficiency as the main cause. These workers estimated calcium intake from the diet but did not measure urinary calcium excretion. Pettifor et al. 7 also reported calcium deficiency rickets in rural South Africa. Supported in part by the CommonwealthScholarship Commission and M. Davie Research Foundation. Submitted for publication Sept. 27, 1995; accepted Nov. 28, 1995. Reprint requests: L. M. Oginni, FMCS, Charles Salt Research Centre, Robert Jones & Agnes Hunt Orthopaedic & District Hospital, Oswestry, Shropshire, SY10 7AG, United Kingdom. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/22/70944
In this biochemical study, we compared 26 patients with rickets with healthy control subjects in an attempt to establish the cause of the condition in this environment.
METHODS Twenty-six patients with active rickets (13 boys, 13 girls), aged 1 to 5 years, seen in the orthopedic and pediatric clinics of the Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria, between January 1993 and September 1994, were studied and compared with 90 healthy control subjects
See commentary, p. 600.
iPTH Intact parathyroid hormone 25(OH)D 25-HydroxyvitaminD 1,25(OH)zD 1,25-DihydroxyvitaminD (55 boys, 35 girls) in the same age group and from the same community. The control subjects were children who had routine blood tests as part of a school entrance health survey or screening for sickle cell hemoglobinopathy. None of the children studied had sickle cell anemia. Only patients with clinical and radiologic features of rickets and who were not receiving any treatment were included in the study. Clinical criteria for the diagnosis of rickets included swollen wrists, rachitic rosaries, and angular deformities of
The Journal o f Pediatrics Volume 128, Number 5, Part 1
Oginni et al.
693
Table. Summary of biochemical data in patients and controls
Control subjects Patients with rickets
Reference (SI) Range (metric)
Albumin -corrected calcium (mmol/l.)
Phosphate (mmol/L)
Alkaline phosphatase (U/L)
iPTH (pmol/l.)
25(OH)D (mmol/L)
1,25(OH)2D (pmol/L)
2.35 + 0.14 (90) 2.06 _+0.23 (26) p <0.001 2.2-2.6 9-11 mg/dl
1.33 _+0.38 (84) 1.26 + 0.7 (26) p <0.03 0.6-1.3 1.8-4 mg/dl
160 -+ 55 (89) 492 + 214 (26) p <0.001 40-120 0.67-2 lakat/L
1.0 +- 1.2 (61) 5.9 -+ 6.9 (25) p <0.001 0.1-4.1 1-39 pg/ml
69 -+ 22 (20) 36 -+ 28 (22) p <0.0002 25-104 10-42 ng/ml
369 + 134 (23) 568 _+317 (26) p <0.01 60-108 25-45 pg/ml
iPTH, Intactparathyroidhormone;25(OH)D, 25-hydroxyvitaminD; 1,25(OH)2D:1,25-dihydroxyvitaminD.
Data reflect mean_+SD. The numberof controlsubjectsor patientswith rickets is listedin parentheses.
the knees. Roentgenographic criteria observed on anteroposterior x-ray views of both wrists and knees included widening and cupping of the metaphysis, fraying and thickening of the physis, and generalized rarefaction. In the control group only clinical assessment was used to rule out the existence of rickets, and x-ray studies were not done for ethical reasons. Informed consent was obtained from all parents and approval of the ethics committee was obtained. Blood samples were collected in lithium-heparin tubes and the plasma was separated into plain polypropylene tubes and stored at -20 ° C until transported frozen to the Charles Salt Research Centre, Oswestry, United Kingdom, where the biochemical analyses were performed. Blood samples were obtained at the time of initial diagnosis before any treatment was instituted. Serum electrolytes were analyzed with an Ektachem analyzer (Eastman Kodak Co., Rochester, N.Y.). The plasma albumin-corrected calcium value was calculated from the formula: Albumin-corrected calcium (measured in millimoles per liter) -- Total calcium + 0.03 (40 - plasma albumin [measured in grams per liter]). 8 Plasma 25-hydroxyvitamin D was measured by radioimmunoassay (ImmunoDiagnostic Systems Ltd., Boldon, United Kingdom); 1,25dihydroxyvitamin D and intact parathyroid hormone levels were measured by radioimmunoassay and immunoradiometric assay, respectively (INCSTAR Ltd., Wokingham, United Kingdom). All assays were done in duplicate. Many of the 1,25(OH)2D assays had to be repeated after dilution because the values were outside the usual range. Both interassay and intraassay coefficients of variation for all assays were between 0.5% and 7.5%. Not all the analytes were measured for every subject because of limited availability of plasma. Data were analyzed with Mann-Whitney U and Spearman tests for comparison and correlation respectively, where appropriate, with Statgraphics software (Statistical Graphics Corp., Inc., Rockville, Md.).
RESULTS A summary of the biochemical data for the two groups is shown in the Table. The plasma albumin-corrected calcium and phosphate levels were lower than in the control subjects, whereas the alkaline phosphate value was always elevated in children with rickets. The plasma 25(OH)D values in the healthy control subjects ranged from 32 to 140 nmot/L ( 13 to 56 ng/ml), whereas plasma 25(OH)D levels in the patients with rickets were between 7 and 147 nmol/L (3 to 59 ng/ml). Plasma 1,25(OH)2D levels in the healthy control subjects were between 173 and 592 pmol/L (72 to 247 ng/ml). These levels were significantly higher in children up to 3 years of age (391 _+ 120 pmol/L [163 ± 50 pg/ml]) than in older children (233 _ 144 pmol/L [97 -+ 60 pg/ml]) (p <0.004). Plasma 1,25(OH)2D levels were higher in the patients with rickets; values ranged from 146 to 1500 pmol/L (61 to 625 pg/ml). The ratios of plasma 1,25(OH)2D to 25(OH)D were from 2.5 to 10.8 pmol/nmol in the healthy control subjects, and the ratios in the patients with rickets were 9 to 60 pmol/nmol (p <0.001). Plasma iPTH levels in the healthy control subjects ranged from 0 to 4.1 pmol/L (0 to 39 pJml), and in the rickets group from 0 to 33.6 pmol/L (0 to 319 pg/ml), (p <0.001). There was no correlation between iPTH and plasma 1,25(OH)2D or calcium levels in either group. Three patients had values of analytes far beyond the mean. One patient had relatively low levels of 1,25(OH)2D (146 pmol/L [61 pg/ml]) and 25(OH)D (7 nmol/L [3 ng/ml]), but with a very high iPTH level of 33.6 pmol/L (319 pg/ml). Two other patients had elevated 1,25(OH)2D levels of 1500 and 1400 pmol/L (625 and 583 pg/ml). Their 25(OH)D levels were 25 and 147 nmol/L (10 and 59 ng/ml), whereas their il~l'H concentrations were 0 and 0.5 pmol/L (0 and 5 pg/ml), respectively. Urinary calcium was not detectable in most patients, but all but one of them had a value just above the detection limit (0.12 mmol/L). The mean urinary calcium/creatinineratio in
694
Oginni et al.
children with rickets was 0.07. The pediatric reference range is 0.32 to 0.48 for European children. 9" J0 DISCUSSION The maintenance of a normal plasma level of calcium is vital to the metabolic regulation of calcium homeostasis, and proper mineralization of bone depends on the availability of calcium in adequate amount and proportion. In most forms of rickets plasma calcium levels are usually low or normal, as was found in this study. Similarly, phosphate levels are usually low. In the absence of severe liver damage, plasma 25(OH)D levels are a reflection of the availability of vitamin D in the body, whereas circulating levels of its active metabolite, 1,25(OH)2D, depend on the metabolic demands. This study indicates that plasma levels of 1,25(OH)2D are higher in the first 3 years of life. In this study, rickets was associated in general with high plasma levels of 1,25(OH)2D, in agreement with the observations of Okonofua et al., 6 but in our study the 25(OH)D levels were tow compared with normal levels in their study. The low 25(OH)D levels might be related in part to the high rate of conversion to 1,25(OH)zD, perhaps aggravating an otherwise marginally adequate status. Decreased 25(OH)D levels may also be aggravated by calcium deficiency through increased production of more polar metabolites of vitamin D. II Nonetheless, the levels of 25(OH)D in all but one patient were adequate to maintain very high levels of 1,25(OH)2D, and therefore are unlikely to be the sole cause of rickets. High 1,25(OH)zD levels in the presence of normal calcium intake and normal absorbing capacity (e.g., primary hyperparathyroidism) would increase intestinal calcium absorption and also increase urinary calcium output. Urinary calcium levels were very low in the presence of high plasma levels of 1,25(OH)zD in the children with rickets. This finding and the presence of hypocalcemia and increased parathyroid activity further support the suggestion of dietary calcium deficiency by Okonofua et al. 6 Low consumption of dairy products and a high-fiber diet, which are common in Nigeria, may contribute to the calcium deficiency. The dietary calcium intake estimated by Okonofua et al. 6 for children with rickets in this area was less than 150 mg per day. In rickets, high levels of 1,25(OH)2D occur in calcium deficiency type rickets ~2 and in end organ resistance (vitamin D~lependent rickets type II). 13 This autosomal recessive condition is very rare and none of the patients had alopecia totalis, a clinical feature of the condition. 14 However, end organ resistance cannot be ruled out in the two patients with very high plasma 1,25(OH)2D levels of 1400 and 1500 pmol/L (583 and 625 pg/ml). The patient with low
The Journal of Pediatrics May 1996
levels of plasma 25(OH)D and 1,25(OH)2D is obviously vitamin D deficient. We conclude that rickets in Nigeria is in large part the result of dietary calcium deficiency; vitamin D deficiency and possibly end organ resistance may play contributory roles. Production of 1,25(OH)2D is enhanced in response to calcium deprivation, perhaps leading to some reduction in 25(OH)D. An ongoing therapeutic study should clarify the situation. We suggest that dietary calcium supplementation and clear advice on exposure to sunlight should be integral parts of preventive and therapeutic measures for rickets in the tropics.
We thank Drs. Ogunsuyi, Ogunlusi, and Adegbehingbe for their clinical assistance and Mr. Tony Sherlock for his laboratory assistance.
REFERENCES
1. Antia AU. Observations on nutritional tickets in childhood. West Afr J Med 1970;t9:169-72. 2. Laditan AAO, Adeniyi A. Rickets in Nigerian children-response to vitamin D. J Trop Med Hyg 1975;78:206-9. 3. Mariam TW, Sterky G. Severe rickets in infancy and childhood in Ethiopia. Tropical Paediatrics 1973;82:876-8. 4. Lawson DE, Paul AA, Black AE, et al. Relative contributions of diet and sunlight to vitamin D state in the elderly. Br Med J 1979;2:303-5. 5. Stamp TC, Haddad JG, Twigg CA. Comparison of oral 25-hydroxycholecalciferol, vitamin D and ultraviolet light as determinants of circulating 25-hydroxyvitamin D. Lancet 1977;1:1341-3. 6. Okonofua F, Gills DS, Alabi ZO, Thomas M, Bell JL, Dandona P. Rickets in Nigerian children--a consequence of calcium malnutrition. Metabolism 1991 ;40:209-13. 7. Pettifor JM, Ross FP, Wang J, et al. Rickets in children of rural origin in South Africa: Is low dietary calcium a factor? J Pediatr 1978;92:320-4. 8. Varley H, Gowenlock AN, Bell M. Practical clinical biochemistry; vol 1.5th ed. London: Heinemann, 1980:868-72. 9. Clark LC Jr, Thompson HL, Beck El, Jacobson W. Excretion of creatine and creatinine by children. Arch Pediatr Adolesc Med [Am J Dis Child] 1951;81:774-83. 10. Lentner C. Geigy scientific tables, vol 1.8th ed. Basel: CibaGeigy Ltd., 1981:59. 11. Clements MR, Johnson L, Fraser DR. A new mechanism for induced vitamin D deficiency in calcium deprivation. Nature 1987;325:62-5. 12. Pettifor JM, Ross FP, Travers R, et al. Dietary calcium deficiency: a syndrome associated with bone deformities and elevated serum 1,25dihydroxyvitamin D concentration. Metabolic Bone Disease and Related Research 1981 ;2:301-5. 13. Sockalosky JJ, Ulstrom RA, DeLuca HF, et al. Vitamin D-resistant rickets: end organ unresponsiveness to 1,25(OH)2D 3. J Pediatr 1980;96:701-3. 14. Rosen Jf, Fleischman AR, Finberg L, et al. Rickets with alopecia: an inborn error of vitamin D metabolism. J Pediatr 1979;94:729-35.