Impact of Availability of Oral Hydrocortisone on Growth of Children with CAH
http://www.100md.com
《美国医学杂志》
1 Jehangir Hospital, Deenanath Mangeshkar Hospital, Pune and Bombay Hospital, Bombay, India
2 Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, Pune, India
Abstract
Objectives: 1. To compare growth parameters of patients with Congenital Adrenal Hyperplasia (CAH) managed on Prednisolone (PR) before and on Hydrocortisone (HC) after its availability in India. 2. To compare growth parameters of patients with CAH who have been on treatment with HC since diagnosis with patients managed on PR. Methods : Growth parameters of twelve children (8 m, 4f) with congenital adrenal hyperplasia were retrospectively studied while on treatment with prednisolone (PR) earlier and then hydrocortisone (HC) after it became freely available in India. Results : Patients treated with PR had height Z score of - 0.42, weight Z score of - 0.45, and height velocity Z score of -2.06. On HC these scores were -0.27, +0.16 and + 2.27. Patients treated with HC from the begining had a height Z Score of + 0.08, weight Z score of +0.22, and height velocity Z score of +0.68. Conclusion : Hydrocortisone has a less growth effect than prednisolone and patients treated with HC from the beginning showed near normal growth.
Keywords: CAH; Hydrocortisone; Prednisolone, Growth
Congenital adrenal hyperplasia (CAH) is usually an autosomal recessive complex disorder where cortisol synthesis is affected. It may manifest with genital ambiguity, psedoprecocious puberty or Adrenal crisis in infancy. Lifelong therapy with synthetic corticosteroid is required in CAH to replace deficient cortisol and to suppress overproduction of Adrenocorticotrophic hormone (ACTH). The minimum dose of glucocorticoid to control virilization should be used so as not to interfere with growth. Prednisolone (PR) and dexamethasone (DX) have inhibitory effects on growth, and development of Cushingoid features is a major problem. Hence Hydrocortisone (HC) is the treatment of choice in growing children with CAH. The management of this complex condition was further complicated by the lack of consistent availability of oral HC in the Indian market until late 2001.[1] As such pediatricians and endocrinologists were forced to use alternatives like PR and DX. We started using HC to manage all our patients with CAH from December 2001. We present a comparative analysis of growth parameters of five patients (Group1) with CAH managed on PR before and on HC after December 2001 and of other seven children (Group 2) with CAH who have been on treatment with HC since diagnosis. We would like to present these observations as HC has now become available in India.
Materials and Methods
A retrospective study of 12 children diagnosed with CAH attending the Pediatric Endocrine Outpatient Department was undertaken. Five patients (Group 1-GR1) were initially treated with PR and then shifted to HC when it became available. Seven patients diagnosed after December 2001 were treated with HC from the beginning (Group 2-GR2). Patients were diagnosed on the basis of characteristic features of CAH including genital ambiguity, signs of hyperandrogenemia, adrenal crises, elevated levels of 17 hydroxyprogesterone (17 OHP), testosterone, and ACTH along with low serum cortisol. Detailed analysis of history, clinical examination, anthropometric and biochemical parameters was performed. Standard deviation (Z) scores for anthropometric parameters were calculated using Agarwal and Tanner standards.[2],[3],[4] Till December 2001 all patients were treated with oral PR (available as Wysolone by Wyeth Lederle 5,10 and 20 mg tablets and as Predon suspension by Cipla 5mg/5ml) in a dose of 4 mg/m2/day as single daily dose early in the morning. Fludrocortisone acetate was used as imported Florinef tablets (Squibb) till December 2001. Later oral fludrocortisone (available as Fludrocortisone acetate- Floricot- 100 Microgram tablets by Samarth Pharma) was used in a dose of 100 microgram/m2/day as a single daily dose early in the morning. Common salt in a dose of 2-5 gms/day was administered to the patients with salt losing CAH. GR2 (one female and six males) and the five previous patients (GR1) were treated with oral HC (available as Hisone 5, 10, 20 mg tablets by Samarth Pharma) in a dose of 12-15 mg/m2/day divided in 2-3 daily doses. Comparative data for one-year period on PR and one year on HC for GR1 and for 1 year on HC for GR2 is presented. Paired student t-test was applied to compare the difference between growth velocity means.
Results
Discussion
In patients with CAH normal growth is difficult to achieve and it is very important that growth is optimized from infancy and early childhood, as the loss of linear growth during this period cannot be made up later.[5] It has been shown that patients who were diagnosed by neonatal screening and then treated with age appropriate cortisol doses during the first year of life achieved a final height equal to or above the target height.[6] The use of appropriate steroid in accurate dose is thus vital. Studies suggest that glucocorticoids have a dose-dependent negative effect on growth in CAH patients and this effect on linear growth is most pronounced in the first year of life and between the ages of 8 and 14 yrs.[7] Steroids with long half-life elevate the level of circulating glucocorticoid for a prolonged period of time. This prolonged elevation of cortisol and thus lack of circadian rhythm leads to suppression of growth hormone axis leading to growth failure. HC remains the steroid of choice due to its physiological nature and biological half-life of up to 12 hours as compared to PR with a half-life of up to 36 hours.[5],[8] The growth suppressive relative potency of PR: HC has been reported to be 15:1.[9] The total daily dose of HC is usually administered two to three times daily with the largest portion given in the morning, thus mimicking the circadian rhythm and reducing the suppressive action on GH axis.[5] Growth velocity is considered to be a very sensitive parameter of growth hormone axis and is routinely used to assess the appropriateness of replacement dose; too slow velocity being indicative of overdose and too fast a sign of inadequacy.[10]
In India HC was not routinely available and the supply of imported medicine was inconsistent before Dec 2001.[1] Due to this PR and at times DX was used to manage this complex condition. The relative glucocorticoid potency of DX, PR and HC is 30:4:1.[11] PR being a potent long acting glucocorticoid, development of Cushingoid features and more importantly growth failure was a chronic problem faced by physicians involved in the management of CAH. We used PR and HC in equivalent doses. The 17 OHP levels were well controlled on both regimens and there were no cushingoid features in any of our patients suggesting adequate dose without overdosing. The growth suppression seen while on PR was however much more pronounced as compared to HC. Patients when shifted from PR to HC showed "catch up" growth in both height and weight, a sign of release from growth suppressive action of PR. Table 2 shows growth data of GR2 patients who were treated with HC from the beginning. All growth parameters of this group were within normal limits as shown by Z scores. These observations suggest that if HC is started from the beginning, it leads to near normal growth and should be the preferred modality of treatment especially during infancy and early childhood years when normal growth is an important priority. This has now become easier with the availability of HC in India.
References
1. Raghupathy P. Disorders of Adrenocortical Biosynthesis. In Desai MP, Bhatia V, Menon PS, eds. Pediatric Endocrine Disorders , 1st edn. Chennai, Orient Longman, 2001; 215-228.
2. Agarwal DK, Agarwal KN, Upadhyay SK, Mittal R, Prakash R, Rai S. Physical and sexual growth pattern of affluent Indian children from 5-18 years of age. Indian Pediatr 1992; 29: 1203-1282.
3. Agarwal DK, Agarwal KN. Physical growth in Indian affluent children (Birth - 6 years). Indian Pediatr 1994; 31: 377-413.
4. Tanner JM, Whitehouse RH, Takaishi M. Standards from birth to maturity for height, weight, height velocity and weight velocity: British children 1965. Arch Dis Child 1966; 41: 454-71.
5. Huma Z, Crawford C, New MI. Congenital Adrenal Hyperplasia . In Brook CGD, ed. Clinical Pediatric Endocrinology, 3rd edn. London, Blackwell Science, 1995; pp 536-557.
6. DiMartino-Nardi J, Stoner E, O'Connell A, New MI. The effect of treatment on final height in classical congenital adrenal hyperplasia. Acta Endocrinol Suppl 1986, 279: 305-314.
7. Stikkelbroeck NM, Van't Hof-Grootenboer, Hermus AR, Otten BJ, Van't Hof MA. Growth inhibition by glucocorticoid treatment in salt wasting 21-hydroxylase deficiency: in early infancy and (pre)puberty. J Clin Endocrinol Metab 2003; 88: 3525-3530.
8. Haynes RC, Murad F. Adrenocoticotrophic hormone, Adrenocortical steroids and their synthetic analogues, Inhibitors of Adrenocortical steroid biosynthesis. In Goodman LS, Gilman A, Mayer SE, Melmon LK, eds. The Pharmacological Basis of Therapeutics, 6th edn. New York, McMillan Publishing Co. Inc. 1975; 1466-1496.
9. Punthakee Z, Legault L, Polychronalos C. Prednisolone in the treatment of adrenal insufficiency: a re-evaluation of relative potency. J Pediatr 2003; 143 : 402-405.
10. Einaudi S, Lala R, Corrias A, Matarazzo P, Pagliardini S, Sanctis C. Auxological and biochemical parameters in assessing treatment of infants and toddlers with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Pediatr Endocrinol 1993; 6 : 173-178.
11. Adrenal cortex, corticotrophin, corticosteroids and antagonists. In Laurence DR, Benett PN, eds. Clinical Pharmacology, 6th edn. UK; Churchil Livingstone 1987; 647-663.(Khadilkar VV, Khadilkar A)
2 Hirabai Cowasji Jehangir Medical Research Institute, Jehangir Hospital, Pune, India
Abstract
Objectives: 1. To compare growth parameters of patients with Congenital Adrenal Hyperplasia (CAH) managed on Prednisolone (PR) before and on Hydrocortisone (HC) after its availability in India. 2. To compare growth parameters of patients with CAH who have been on treatment with HC since diagnosis with patients managed on PR. Methods : Growth parameters of twelve children (8 m, 4f) with congenital adrenal hyperplasia were retrospectively studied while on treatment with prednisolone (PR) earlier and then hydrocortisone (HC) after it became freely available in India. Results : Patients treated with PR had height Z score of - 0.42, weight Z score of - 0.45, and height velocity Z score of -2.06. On HC these scores were -0.27, +0.16 and + 2.27. Patients treated with HC from the begining had a height Z Score of + 0.08, weight Z score of +0.22, and height velocity Z score of +0.68. Conclusion : Hydrocortisone has a less growth effect than prednisolone and patients treated with HC from the beginning showed near normal growth.
Keywords: CAH; Hydrocortisone; Prednisolone, Growth
Congenital adrenal hyperplasia (CAH) is usually an autosomal recessive complex disorder where cortisol synthesis is affected. It may manifest with genital ambiguity, psedoprecocious puberty or Adrenal crisis in infancy. Lifelong therapy with synthetic corticosteroid is required in CAH to replace deficient cortisol and to suppress overproduction of Adrenocorticotrophic hormone (ACTH). The minimum dose of glucocorticoid to control virilization should be used so as not to interfere with growth. Prednisolone (PR) and dexamethasone (DX) have inhibitory effects on growth, and development of Cushingoid features is a major problem. Hence Hydrocortisone (HC) is the treatment of choice in growing children with CAH. The management of this complex condition was further complicated by the lack of consistent availability of oral HC in the Indian market until late 2001.[1] As such pediatricians and endocrinologists were forced to use alternatives like PR and DX. We started using HC to manage all our patients with CAH from December 2001. We present a comparative analysis of growth parameters of five patients (Group1) with CAH managed on PR before and on HC after December 2001 and of other seven children (Group 2) with CAH who have been on treatment with HC since diagnosis. We would like to present these observations as HC has now become available in India.
Materials and Methods
A retrospective study of 12 children diagnosed with CAH attending the Pediatric Endocrine Outpatient Department was undertaken. Five patients (Group 1-GR1) were initially treated with PR and then shifted to HC when it became available. Seven patients diagnosed after December 2001 were treated with HC from the beginning (Group 2-GR2). Patients were diagnosed on the basis of characteristic features of CAH including genital ambiguity, signs of hyperandrogenemia, adrenal crises, elevated levels of 17 hydroxyprogesterone (17 OHP), testosterone, and ACTH along with low serum cortisol. Detailed analysis of history, clinical examination, anthropometric and biochemical parameters was performed. Standard deviation (Z) scores for anthropometric parameters were calculated using Agarwal and Tanner standards.[2],[3],[4] Till December 2001 all patients were treated with oral PR (available as Wysolone by Wyeth Lederle 5,10 and 20 mg tablets and as Predon suspension by Cipla 5mg/5ml) in a dose of 4 mg/m2/day as single daily dose early in the morning. Fludrocortisone acetate was used as imported Florinef tablets (Squibb) till December 2001. Later oral fludrocortisone (available as Fludrocortisone acetate- Floricot- 100 Microgram tablets by Samarth Pharma) was used in a dose of 100 microgram/m2/day as a single daily dose early in the morning. Common salt in a dose of 2-5 gms/day was administered to the patients with salt losing CAH. GR2 (one female and six males) and the five previous patients (GR1) were treated with oral HC (available as Hisone 5, 10, 20 mg tablets by Samarth Pharma) in a dose of 12-15 mg/m2/day divided in 2-3 daily doses. Comparative data for one-year period on PR and one year on HC for GR1 and for 1 year on HC for GR2 is presented. Paired student t-test was applied to compare the difference between growth velocity means.
Results
Discussion
In patients with CAH normal growth is difficult to achieve and it is very important that growth is optimized from infancy and early childhood, as the loss of linear growth during this period cannot be made up later.[5] It has been shown that patients who were diagnosed by neonatal screening and then treated with age appropriate cortisol doses during the first year of life achieved a final height equal to or above the target height.[6] The use of appropriate steroid in accurate dose is thus vital. Studies suggest that glucocorticoids have a dose-dependent negative effect on growth in CAH patients and this effect on linear growth is most pronounced in the first year of life and between the ages of 8 and 14 yrs.[7] Steroids with long half-life elevate the level of circulating glucocorticoid for a prolonged period of time. This prolonged elevation of cortisol and thus lack of circadian rhythm leads to suppression of growth hormone axis leading to growth failure. HC remains the steroid of choice due to its physiological nature and biological half-life of up to 12 hours as compared to PR with a half-life of up to 36 hours.[5],[8] The growth suppressive relative potency of PR: HC has been reported to be 15:1.[9] The total daily dose of HC is usually administered two to three times daily with the largest portion given in the morning, thus mimicking the circadian rhythm and reducing the suppressive action on GH axis.[5] Growth velocity is considered to be a very sensitive parameter of growth hormone axis and is routinely used to assess the appropriateness of replacement dose; too slow velocity being indicative of overdose and too fast a sign of inadequacy.[10]
In India HC was not routinely available and the supply of imported medicine was inconsistent before Dec 2001.[1] Due to this PR and at times DX was used to manage this complex condition. The relative glucocorticoid potency of DX, PR and HC is 30:4:1.[11] PR being a potent long acting glucocorticoid, development of Cushingoid features and more importantly growth failure was a chronic problem faced by physicians involved in the management of CAH. We used PR and HC in equivalent doses. The 17 OHP levels were well controlled on both regimens and there were no cushingoid features in any of our patients suggesting adequate dose without overdosing. The growth suppression seen while on PR was however much more pronounced as compared to HC. Patients when shifted from PR to HC showed "catch up" growth in both height and weight, a sign of release from growth suppressive action of PR. Table 2 shows growth data of GR2 patients who were treated with HC from the beginning. All growth parameters of this group were within normal limits as shown by Z scores. These observations suggest that if HC is started from the beginning, it leads to near normal growth and should be the preferred modality of treatment especially during infancy and early childhood years when normal growth is an important priority. This has now become easier with the availability of HC in India.
References
1. Raghupathy P. Disorders of Adrenocortical Biosynthesis. In Desai MP, Bhatia V, Menon PS, eds. Pediatric Endocrine Disorders , 1st edn. Chennai, Orient Longman, 2001; 215-228.
2. Agarwal DK, Agarwal KN, Upadhyay SK, Mittal R, Prakash R, Rai S. Physical and sexual growth pattern of affluent Indian children from 5-18 years of age. Indian Pediatr 1992; 29: 1203-1282.
3. Agarwal DK, Agarwal KN. Physical growth in Indian affluent children (Birth - 6 years). Indian Pediatr 1994; 31: 377-413.
4. Tanner JM, Whitehouse RH, Takaishi M. Standards from birth to maturity for height, weight, height velocity and weight velocity: British children 1965. Arch Dis Child 1966; 41: 454-71.
5. Huma Z, Crawford C, New MI. Congenital Adrenal Hyperplasia . In Brook CGD, ed. Clinical Pediatric Endocrinology, 3rd edn. London, Blackwell Science, 1995; pp 536-557.
6. DiMartino-Nardi J, Stoner E, O'Connell A, New MI. The effect of treatment on final height in classical congenital adrenal hyperplasia. Acta Endocrinol Suppl 1986, 279: 305-314.
7. Stikkelbroeck NM, Van't Hof-Grootenboer, Hermus AR, Otten BJ, Van't Hof MA. Growth inhibition by glucocorticoid treatment in salt wasting 21-hydroxylase deficiency: in early infancy and (pre)puberty. J Clin Endocrinol Metab 2003; 88: 3525-3530.
8. Haynes RC, Murad F. Adrenocoticotrophic hormone, Adrenocortical steroids and their synthetic analogues, Inhibitors of Adrenocortical steroid biosynthesis. In Goodman LS, Gilman A, Mayer SE, Melmon LK, eds. The Pharmacological Basis of Therapeutics, 6th edn. New York, McMillan Publishing Co. Inc. 1975; 1466-1496.
9. Punthakee Z, Legault L, Polychronalos C. Prednisolone in the treatment of adrenal insufficiency: a re-evaluation of relative potency. J Pediatr 2003; 143 : 402-405.
10. Einaudi S, Lala R, Corrias A, Matarazzo P, Pagliardini S, Sanctis C. Auxological and biochemical parameters in assessing treatment of infants and toddlers with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Pediatr Endocrinol 1993; 6 : 173-178.
11. Adrenal cortex, corticotrophin, corticosteroids and antagonists. In Laurence DR, Benett PN, eds. Clinical Pharmacology, 6th edn. UK; Churchil Livingstone 1987; 647-663.(Khadilkar VV, Khadilkar A)