- Email: [email protected]
Hormone replacement therapy and serum uric acid
1
2
Sumino H, Ichikawa S, Kanda T, Nakamura T, Sakamaki T. Reduction of serum uric acid by hormone replacement therapy in postmenopausal women with hyperuricaemia. Lancet 1999; 354: 650. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999; 131: 7–13.
Authors’ reply Sir—We thank Fernando Ovalle and David Bell, and A S Kashyap and Surekha Kashyap for their comments, and we take note of their criticisms about the controversial question of whether hyperuricaemia is a risk factor for cardiovascular disease. At almost the same time as our paper was published, the Framingham Heart Study1 reported that uric acid did not have a causal role in the development of coronary heart disease, death from cardiovascular disease, or death from all causes. Although we acknowledge these findings, the main point of our report is that HRT reduced serum uric acid in postmenopausal women with hyperuricaemia, which presents a health problem irrespective of the effects on cardiovascular disease. Ovalle and Bell raise interesting points related to the mechanism of the lowering effect of HRT on hyperuricaemia, which was not referred to in our study. We measured insulin resistance using Matthews and in 40 colleagues’ method2 postmenopausal women with normal serum uric acid and 12 postmenopausal women with hyperuricaemia before and 6 months after combined HRT. The treatment significantly decreased fasting insulin concentrations (p<0·05) and insulin resistance (p<0·01) in postmenopausal women with normal serum uric acid (table). However, HRT significantly decreased serum uric acid in postmenopausal women with hyperuricaemia (p<0·01), but did not affect fasting insulin concentrations or insulin resistance (table). Interestingly, in the hyperuricaemic group, fasting insulin concentrations and the insulin resistance marker showed a significantly positive correlation with serum uric acid Fasting insulin concentration (mU/L)
Insulin resistance (HOMA index)
Serum uric acid (mol/L)
Women with normal serum uric acid Baseline 5·5 (2·5) 1·30 (0·65) 6 months 4·7 (2·3)* 1·08 (0·57)
256 (42) 256 (48)
Women with hyperuricaemia Baseline 5·9 (2·5) 1·42 (0·62) 6 months 5·0 (1·6) 1·13 (0·42)
381 (36) 351 (60)†
Data are means (SD). HOMA=homeostasis model assessment *p<0·05. †p<0·01 compared with baseline (paired t test).
Effect of HRT on postmenopausal women
1644
concentration before HRT (p<0·01 and p<0·05, respectively). By contrast, the correlation between fasting insulin concentration/insulin resistance and serum uric acid was lost after HRT. As a result, hyperuricaemia before HRT could be a marker of hyperuricaemia as suggested by Ovalle and Bell. However, in postmenopausal women with hyperuricaemia, HRT reduced serum uric acid concentrations with a slight, but not significant reduction of insulin resistance. Although the reasons why the effect of HRT on insulin resistance differed between women with normal serum uric acid and women with hyperuricaemia is not known, the lowering of serum uric acid by HRT in women with hyperuricaemia could not be explained by insulin resistance alone. We used combined HRT in these studies and the evidence for a favourable effect of combined HRT on insulin resistance or sensitivity is less clear than oestrogen replacement therapy, as mentioned by Ovalle and Bell. *Hiroyuki Sumino, Shuichi Ichikawa, Tsugiyasu Kanda, Tetsuya Nakamura, Tetsuo Sakamaki *Second Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Gunma 371-8571, Japan; Department of Laboratory Medicine, and Medical Informatics and Decision Sciences, Gunma University School of Medicine, Maebashi; and Cardiovascular Hospital of Central Japan, Seta-gun, Gunma (e-mail: [email protected]) 1
Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999; 131: 7–13. 2 Matthews DR, Hosker JP, Rundenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–19.
Stem-cell transplantation Sir—I am grateful for the comments of the European Group for Blood and Marrow Transplantation (EBMT) working party (Aug 28, p 788),1 and welcome the chance for further discussion on late sequelae after haemopoietic stem-cell transplantation. As a member of the bone-marrow transplant working group of the UK Children’s Cancer Study Group (UKCCSG), I am well aware of the difficult dilemmas and challenges facing transplantation physicians, and of the excellent work done by the EBMT working party on late effects. Indeed, our own data from the UKCCSG database is automatically available to the EBMT, through joint
registration of UK patients to both organisations. However, I feel that the EBMT may have misinterpreted the observations that I made in my May 8 commentary. 2 I mentioned Cerveri and colleagues’ findings that pulmonary sequelae were greater when transplantation for malignant haematological disorders had taken place after second or third r e m i s s i o n . 3 The commentary as a whole, and especially my comments about the good selection of patients, were directed at salvage therapy by stem-cell transplantation, of patients with repeated relapse. I am well aware of the efforts that the EBMT and others have directed towards formulation of guidelines to encourage good selection of patients. 4 Nonetheless, with the increased availability of unrelated donors, coupled with parental pressure and advancement of transplantation medicine, it is now possible to transplant children after repeated relapse of their malignant disease. Some children may even undergo a second stem-cell transplant procedure. Although this procedure gives a patient a last chance of survival, those surviving may have a plethora of late sequelae and a high risk of secondary cancers. The risk is related to high cumulative doses of chemotherapy and radiation, and to young age at transplantation. Curtis and colleagues5 evaluated almost 20 000 bone marrow recipients and found that occurrence of solid secondary neoplasms in patients less than 10 years old at transplantation, was 36·6 times higher than expected, mainly due to excess tumours of brain and thyroid. In our own cohort of 83 survivors (>3 years) of transplantation for acute leukaemia, done at a median age of 6·5 years, five patients developed secondary solid malignant neoplasms and two developed secondary myelodysplasia at a median age of 8·6 years from transplantation. We have not yet seen a plateau. In the UK, oncologists who specialise in late effects are not isolated from their colleagues in transplant units. There is commonly a seamless continuum in the treatment of patients with malignant disease from diagnosis, through the pre-transplantation phase, to regular follow-up. I have the advantage of working in this system. Therefore, far from being obstructive or unsupportive of our transplant colleagues, favourable discussion and mutual education is the norm. Nonetheless, we cannot avoid the unpalatable fact that the incidence of
THE LANCET • Vol 354 • November 6, 1999
2
Sumino H, Ichikawa S, Kanda T, Nakamura T, Sakamaki T. Reduction of serum uric acid by hormone replacement therapy in postmenopausal women with hyperuricaemia. Lancet 1999; 354: 650. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999; 131: 7–13.
Authors’ reply Sir—We thank Fernando Ovalle and David Bell, and A S Kashyap and Surekha Kashyap for their comments, and we take note of their criticisms about the controversial question of whether hyperuricaemia is a risk factor for cardiovascular disease. At almost the same time as our paper was published, the Framingham Heart Study1 reported that uric acid did not have a causal role in the development of coronary heart disease, death from cardiovascular disease, or death from all causes. Although we acknowledge these findings, the main point of our report is that HRT reduced serum uric acid in postmenopausal women with hyperuricaemia, which presents a health problem irrespective of the effects on cardiovascular disease. Ovalle and Bell raise interesting points related to the mechanism of the lowering effect of HRT on hyperuricaemia, which was not referred to in our study. We measured insulin resistance using Matthews and in 40 colleagues’ method2 postmenopausal women with normal serum uric acid and 12 postmenopausal women with hyperuricaemia before and 6 months after combined HRT. The treatment significantly decreased fasting insulin concentrations (p<0·05) and insulin resistance (p<0·01) in postmenopausal women with normal serum uric acid (table). However, HRT significantly decreased serum uric acid in postmenopausal women with hyperuricaemia (p<0·01), but did not affect fasting insulin concentrations or insulin resistance (table). Interestingly, in the hyperuricaemic group, fasting insulin concentrations and the insulin resistance marker showed a significantly positive correlation with serum uric acid Fasting insulin concentration (mU/L)
Insulin resistance (HOMA index)
Serum uric acid (mol/L)
Women with normal serum uric acid Baseline 5·5 (2·5) 1·30 (0·65) 6 months 4·7 (2·3)* 1·08 (0·57)
256 (42) 256 (48)
Women with hyperuricaemia Baseline 5·9 (2·5) 1·42 (0·62) 6 months 5·0 (1·6) 1·13 (0·42)
381 (36) 351 (60)†
Data are means (SD). HOMA=homeostasis model assessment *p<0·05. †p<0·01 compared with baseline (paired t test).
Effect of HRT on postmenopausal women
1644
concentration before HRT (p<0·01 and p<0·05, respectively). By contrast, the correlation between fasting insulin concentration/insulin resistance and serum uric acid was lost after HRT. As a result, hyperuricaemia before HRT could be a marker of hyperuricaemia as suggested by Ovalle and Bell. However, in postmenopausal women with hyperuricaemia, HRT reduced serum uric acid concentrations with a slight, but not significant reduction of insulin resistance. Although the reasons why the effect of HRT on insulin resistance differed between women with normal serum uric acid and women with hyperuricaemia is not known, the lowering of serum uric acid by HRT in women with hyperuricaemia could not be explained by insulin resistance alone. We used combined HRT in these studies and the evidence for a favourable effect of combined HRT on insulin resistance or sensitivity is less clear than oestrogen replacement therapy, as mentioned by Ovalle and Bell. *Hiroyuki Sumino, Shuichi Ichikawa, Tsugiyasu Kanda, Tetsuya Nakamura, Tetsuo Sakamaki *Second Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Gunma 371-8571, Japan; Department of Laboratory Medicine, and Medical Informatics and Decision Sciences, Gunma University School of Medicine, Maebashi; and Cardiovascular Hospital of Central Japan, Seta-gun, Gunma (e-mail: [email protected]) 1
Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999; 131: 7–13. 2 Matthews DR, Hosker JP, Rundenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–19.
Stem-cell transplantation Sir—I am grateful for the comments of the European Group for Blood and Marrow Transplantation (EBMT) working party (Aug 28, p 788),1 and welcome the chance for further discussion on late sequelae after haemopoietic stem-cell transplantation. As a member of the bone-marrow transplant working group of the UK Children’s Cancer Study Group (UKCCSG), I am well aware of the difficult dilemmas and challenges facing transplantation physicians, and of the excellent work done by the EBMT working party on late effects. Indeed, our own data from the UKCCSG database is automatically available to the EBMT, through joint
registration of UK patients to both organisations. However, I feel that the EBMT may have misinterpreted the observations that I made in my May 8 commentary. 2 I mentioned Cerveri and colleagues’ findings that pulmonary sequelae were greater when transplantation for malignant haematological disorders had taken place after second or third r e m i s s i o n . 3 The commentary as a whole, and especially my comments about the good selection of patients, were directed at salvage therapy by stem-cell transplantation, of patients with repeated relapse. I am well aware of the efforts that the EBMT and others have directed towards formulation of guidelines to encourage good selection of patients. 4 Nonetheless, with the increased availability of unrelated donors, coupled with parental pressure and advancement of transplantation medicine, it is now possible to transplant children after repeated relapse of their malignant disease. Some children may even undergo a second stem-cell transplant procedure. Although this procedure gives a patient a last chance of survival, those surviving may have a plethora of late sequelae and a high risk of secondary cancers. The risk is related to high cumulative doses of chemotherapy and radiation, and to young age at transplantation. Curtis and colleagues5 evaluated almost 20 000 bone marrow recipients and found that occurrence of solid secondary neoplasms in patients less than 10 years old at transplantation, was 36·6 times higher than expected, mainly due to excess tumours of brain and thyroid. In our own cohort of 83 survivors (>3 years) of transplantation for acute leukaemia, done at a median age of 6·5 years, five patients developed secondary solid malignant neoplasms and two developed secondary myelodysplasia at a median age of 8·6 years from transplantation. We have not yet seen a plateau. In the UK, oncologists who specialise in late effects are not isolated from their colleagues in transplant units. There is commonly a seamless continuum in the treatment of patients with malignant disease from diagnosis, through the pre-transplantation phase, to regular follow-up. I have the advantage of working in this system. Therefore, far from being obstructive or unsupportive of our transplant colleagues, favourable discussion and mutual education is the norm. Nonetheless, we cannot avoid the unpalatable fact that the incidence of
THE LANCET • Vol 354 • November 6, 1999