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Editorial: The skeletal effects of liver transplantation in children
EDITORIAL
The Skeletal Effects of Liver Transplantation in Children Juliet Compston
I
n recent years, there has been increasing recognition of the skeletal complications of solid organ transplantation, but the majority of studies have focused on adults, whereas children, who form a significant proportion of the transplant population, have received little attention in this respect. Therefore, the two articles in this issue that specifically address this topic are welcome and provide some reassurance that the deficit in bone mass frequently observed in children before liver transplantation is corrected postoperatively. Thus, in a cross-sectional study of 109 individuals who had undergone liver transplantation in childhood or adolescence a mean of 6 years previously, only 7.3% had a low bone mineral density (more than two standard deviations below the mean age- and gender-matched reference value).1 In the second study,2 prospective evaluation of bone mineral density changes in 30 children in whom preoperative bone mineral density was low showed a significant improvement after transplantation, with full recovery to normal values 2 years after surgery. A particularly interesting finding in the study of Okajima et al2 is that, in contrast to the rapid bone loss reported in adults, no reduction in bone mineral density occurred in the early postoperative phase. On the contrary, there was a significant increase in bone mineral density by 3 months after transplantation despite continuing immunosuppressive therapy. Associated with this increase there was a gain in bodyweight at 3 months, although a significant increase in height was not seen until 6 months after transplantation, coinciding with cessation of glucocorticoid therapy in the majority of patients. These observations would be consistent with two conclusions: first, that in these children the beneficial skeletal effects of restoring normal liver function can outweigh the adverse effects of immunosuppression and, secondly, that recovery in linear growth may occur only after glucocorticoid therapy is stopped. The reason for the different pattern of change in bone mineral density after transplantation in adults and children is likely to be associated with age-related differences in bone cell activity and, in particular, the much greater potential for bone accretion and modeling in the younger age group. Thus, increased bone growth by modeling is a physiologic process in childhood, whereas in adults the predominant activity is
bone remodeling with no change in bone size except that caused by slow apposition at the periosteal surfaces. Because the assessment of bone mineral density by dualenergy X-ray absorptiometry provides an areal rather than a volumetric value, these measurements are critically dependent on bone size and, hence, in childhood and adolescence, largely reflect linear growth.3 Conversely, in adults, alterations in bone mineral density reflect changes in volumetric density to a much greater extent, and the capacity for increase in bone size in response to mechanical or pharmacologic agents is limited. Determinants of posttransplantation bone disease in children, other than pre-existing bone disease, have not been defined clearly, but exposure to glucocorticoids is likely to be an important factor. Thus, in the study of Guthery et al,1 lumbar spine bone mineral density was associated negatively with cumulative glucocorticoid dose, and subjects with reduced bone mineral density were more likely to have been treated for graft rejection on at least one occasion. Boot et al,4 in a cross-sectional study of young adults who had undergone renal transplantation during childhood, also reported an inverse correlation between bone mineral density and glucocorticoid exposure.4 These observations emphasize the importance of keeping the dose and duration of glucocorticoid therapy to a minimum and are consistent with evidence for a similar pathogenetic role of glucocorticoids in adults undergoing organ transplantation. The incidence of fractures after transplantation in children is not well documented, although in one study, 16.2% of a large cohort of children were reported to develop fractures after liver transplantation.5 No fracture data were available in the study of Guthery et al,1 whereas in that of Okajima et al,2 no children had From the Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. Address reprint requests to Juliet Compston, MD, Dept of Medicine, Box 157, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom. Telephone: 44-122-333-6867; FAX: 44-122-333-6846; E-mail: [email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0904-0008$30.00/0 doi:10.1053/jlts.2003.50084
Liver Transplantation, Vol 9, No 4 (April), 2003: pp 371-372
371
372
Juliet Compston
fractures in the first 2 years after transplantation, although 3 had sustained fractures preoperatively. The relationship between bone mineral density and fracture risk, although well documented in older women and, to a lesser extent, men, has not been established in children, and, hence, the clinical significance of low bone mineral density in this age group is uncertain. Nevertheless, it is likely that failure to attain a normal peak bone mass is associated with increased fracture risk later in life. Overall, the emerging data provide grounds for optimism in regard to bone health in children undergoing liver transplantation. In contrast to the situation in adults, in which severe bone disease before surgery has been regarded as a contraindication to transplantation because of the risk of postoperative exacerbation, liver transplantation may be seen as having rapid beneficial skeletal effects in children. Nevertheless, measures should be taken to optimize bone health before transplantation (for example prevention of vitamin D deficiency and maintenance of good nutrition), and the use
of glucocorticoids should be kept to a minimum. Finally, there is need for more information about the long-term skeletal effects of transplantation in children and adolescents, particularly in regard to fracture risk.
References 1. Guthery SL, Pohl JF, Bucuvalas JC, Alonso MH, Ryckman FC, Balistreri WF, et al. Bone mineral density in long-term survivors following pediatric liver transplantation. Liver Transpl 2003;9: 365-370. 2. Okajima H, Shigeno C, Inomata Y, Egawa H, Uemoto S, Asonuma K, et al. Long-term effects of liver transplantation on bone mineral density in children with end-stage liver disease: A two-year prospective study. Liver Transpl 2003;9:360-364. 3. Compston JE. Bone mineral density: BMC, BMD or corrected BMD? Bone 1995;16:5-7. 4. Boot AM, Nauta J, Hokken-Koelega ACS, Pols HAP, de Ridder MAJ, de Muinck Keizer-Schrama SMPF. Renal transplantation and osteoporosis. Arch Dis Child 1995;72:502-506. 5. Hill SA, Kelly DA, John PR. Bone fractures in children undergoing orthotopic liver transplantation. Pediatr Radiol 1995; 25(Suppl 1):S112-S117.
The Skeletal Effects of Liver Transplantation in Children Juliet Compston
I
n recent years, there has been increasing recognition of the skeletal complications of solid organ transplantation, but the majority of studies have focused on adults, whereas children, who form a significant proportion of the transplant population, have received little attention in this respect. Therefore, the two articles in this issue that specifically address this topic are welcome and provide some reassurance that the deficit in bone mass frequently observed in children before liver transplantation is corrected postoperatively. Thus, in a cross-sectional study of 109 individuals who had undergone liver transplantation in childhood or adolescence a mean of 6 years previously, only 7.3% had a low bone mineral density (more than two standard deviations below the mean age- and gender-matched reference value).1 In the second study,2 prospective evaluation of bone mineral density changes in 30 children in whom preoperative bone mineral density was low showed a significant improvement after transplantation, with full recovery to normal values 2 years after surgery. A particularly interesting finding in the study of Okajima et al2 is that, in contrast to the rapid bone loss reported in adults, no reduction in bone mineral density occurred in the early postoperative phase. On the contrary, there was a significant increase in bone mineral density by 3 months after transplantation despite continuing immunosuppressive therapy. Associated with this increase there was a gain in bodyweight at 3 months, although a significant increase in height was not seen until 6 months after transplantation, coinciding with cessation of glucocorticoid therapy in the majority of patients. These observations would be consistent with two conclusions: first, that in these children the beneficial skeletal effects of restoring normal liver function can outweigh the adverse effects of immunosuppression and, secondly, that recovery in linear growth may occur only after glucocorticoid therapy is stopped. The reason for the different pattern of change in bone mineral density after transplantation in adults and children is likely to be associated with age-related differences in bone cell activity and, in particular, the much greater potential for bone accretion and modeling in the younger age group. Thus, increased bone growth by modeling is a physiologic process in childhood, whereas in adults the predominant activity is
bone remodeling with no change in bone size except that caused by slow apposition at the periosteal surfaces. Because the assessment of bone mineral density by dualenergy X-ray absorptiometry provides an areal rather than a volumetric value, these measurements are critically dependent on bone size and, hence, in childhood and adolescence, largely reflect linear growth.3 Conversely, in adults, alterations in bone mineral density reflect changes in volumetric density to a much greater extent, and the capacity for increase in bone size in response to mechanical or pharmacologic agents is limited. Determinants of posttransplantation bone disease in children, other than pre-existing bone disease, have not been defined clearly, but exposure to glucocorticoids is likely to be an important factor. Thus, in the study of Guthery et al,1 lumbar spine bone mineral density was associated negatively with cumulative glucocorticoid dose, and subjects with reduced bone mineral density were more likely to have been treated for graft rejection on at least one occasion. Boot et al,4 in a cross-sectional study of young adults who had undergone renal transplantation during childhood, also reported an inverse correlation between bone mineral density and glucocorticoid exposure.4 These observations emphasize the importance of keeping the dose and duration of glucocorticoid therapy to a minimum and are consistent with evidence for a similar pathogenetic role of glucocorticoids in adults undergoing organ transplantation. The incidence of fractures after transplantation in children is not well documented, although in one study, 16.2% of a large cohort of children were reported to develop fractures after liver transplantation.5 No fracture data were available in the study of Guthery et al,1 whereas in that of Okajima et al,2 no children had From the Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. Address reprint requests to Juliet Compston, MD, Dept of Medicine, Box 157, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom. Telephone: 44-122-333-6867; FAX: 44-122-333-6846; E-mail: [email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0904-0008$30.00/0 doi:10.1053/jlts.2003.50084
Liver Transplantation, Vol 9, No 4 (April), 2003: pp 371-372
371
372
Juliet Compston
fractures in the first 2 years after transplantation, although 3 had sustained fractures preoperatively. The relationship between bone mineral density and fracture risk, although well documented in older women and, to a lesser extent, men, has not been established in children, and, hence, the clinical significance of low bone mineral density in this age group is uncertain. Nevertheless, it is likely that failure to attain a normal peak bone mass is associated with increased fracture risk later in life. Overall, the emerging data provide grounds for optimism in regard to bone health in children undergoing liver transplantation. In contrast to the situation in adults, in which severe bone disease before surgery has been regarded as a contraindication to transplantation because of the risk of postoperative exacerbation, liver transplantation may be seen as having rapid beneficial skeletal effects in children. Nevertheless, measures should be taken to optimize bone health before transplantation (for example prevention of vitamin D deficiency and maintenance of good nutrition), and the use
of glucocorticoids should be kept to a minimum. Finally, there is need for more information about the long-term skeletal effects of transplantation in children and adolescents, particularly in regard to fracture risk.
References 1. Guthery SL, Pohl JF, Bucuvalas JC, Alonso MH, Ryckman FC, Balistreri WF, et al. Bone mineral density in long-term survivors following pediatric liver transplantation. Liver Transpl 2003;9: 365-370. 2. Okajima H, Shigeno C, Inomata Y, Egawa H, Uemoto S, Asonuma K, et al. Long-term effects of liver transplantation on bone mineral density in children with end-stage liver disease: A two-year prospective study. Liver Transpl 2003;9:360-364. 3. Compston JE. Bone mineral density: BMC, BMD or corrected BMD? Bone 1995;16:5-7. 4. Boot AM, Nauta J, Hokken-Koelega ACS, Pols HAP, de Ridder MAJ, de Muinck Keizer-Schrama SMPF. Renal transplantation and osteoporosis. Arch Dis Child 1995;72:502-506. 5. Hill SA, Kelly DA, John PR. Bone fractures in children undergoing orthotopic liver transplantation. Pediatr Radiol 1995; 25(Suppl 1):S112-S117.