- Email: [email protected]
Hormone replacement therapy and serum uric acid
showed identical patterns of functional recovery for Barthel index (and FAC). In addition, the difference of 3% in proportion of TACI between the arm and leg training groups does not explain the significant improvement reported in the leg-training group versus arm training on Barthel index and FAC 6 weeks after stroke. Second, if study groups were prognostically different, we would also expect significant differences in efficacy for Barthel index (and FAC) between the three study groups at 6 months. However, significant differences were not found. The differences at the baseline are not explanatory for the reported differences in efficacy. The difference in intensity of rehabilitation is the important factor. Third, by applying a generalised estimating equations (GEE) model (SPIDA version 6) from baseline to week 20 and from baseline to week 26 after stroke, we controlled for the differences at the baseline and multiple statistical testing. Prognostic factors were included in the GEE model to correct for differences at baseline. These covariates (ie, initial Barthel index, sitting balance, social support, Fugl-Meyer hand score, and myocardial infarction score of hemiplegic side) were established by forward multiple-regression analysis, which explained 42%, 56%, and 66% of FAC, Barthel index and Action Research Arm Test (ARA), respectively. Type of stroke (OCSP classification) showed high collinearity (eigenvalue of 0·015) with the motricity index, and was therefore not included in the GEE model. After adjustment for relevant covariates at the baseline, longitudinal analysis confirmed the effects revealed by cross-sectional analysis. Significant main effects between the leg-training group and the control group were also found for Barthel index (and FAC) from baseline to 26 weeks after stroke. McNaughton and colleagues claim that the organisational structure of inpatient stroke services and the coherence of the rehabilitation programme have a larger impact on outcome than specific elements needs further investigation.1 The impact of coherence of the rehabilitation programme may be one of the mechanisms that enhance the intensity of task-oriented rehabilitation programmes formulated by a rehabilitation team. In fact, coherence of a rehabilitation programme is highly structured in studies that investigate the effects of intensity of task-oriented rehabilitation programmes. Therefore,
THE LANCET • Vol 354 • November 6, 1999
we should be cautious in distinguishing between these aspects as separate, independent mechanisms for improving efficacy of stroke services.
colleagues, is that HRT increases insulin sensitivity, thereby reducing insulin concentrations, which in turn lead to increased renal uric acid excretion.
*Gert Kwakkel, Robert C Wagenaar
*Fernando Ovalle, David S H Bell
*Department of Physical Therapy and Research Institute for Fundamental and Clinical Human Movement Sciences, *University Hospital Vrije Universiteit, 1007 MB Amsterdam, Netherlands; and Department of Physical Therapy, Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, MA, USA (e-mail: [email protected])
Department of Medicine, University of Alabama at Birmingham, School of Medicine, Birmingham, AL 35233, USA
1
Mackey F, Louise Ada L, Heard R, Adams R. Stroke rehabilitation: are highly structured units more conductive to physical activity than less structured units? Arch Phys Med Rehabil 1996; 77: 1066–70.
Hormone replacement therapy and serum uric acid Sir—Hiroyuki Sumino and colleagues (Aug 21, p 650)1 show that hormone replacement therapy (HRT) in postmenopausal women is associated with a reduction of serum uric acid. However, the investigators have come to the wrong conclusion by ignoring two important issues: the effects of insulin on uric acid excretion, and the potential effects of HRT on insulin sensitivity. Moreover, although hyperuricaemia has been linked with an increased risk of cardiovascular disease, there is no evidence to support a causal relation. Data from the Framingham Heart Study indicate that uric acid does not have a causal role in the development of coronary artery disease (CAD) or death from CAD, and any apparent association between these outcomes is probably due to the association between uric acid concentrations and other risk factors (ie, insulin resistance or hyperinsulinaemia).2 Two studies3,4 have shown that the most likely explanation for the relation between hyperinsulinaemia and hyperuricaemia is the decrease in renal uric acid and sodium excretion caused by insulin’s effect on the kidney. Thus, the relation between hyperuricaemia and CAD seems to be a function of its relation with insulin resistance. In other words, hyperuricaemia is just a marker of hyperinsulinaemia. Several studies have shown that oestrogen replacement therapy increases insulin sensitivity (thereby reducing insulin concentrations), and although the evidence for the effects of combined HRT on insulin sensitivity are less clear, there is also evidence for a favourable effect that depends on the combination and doses used. 5 A more probable explanation for the decrease in uric acid concentrations seen by Sumino and
1
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. 2 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. 3 Facchini F, Chen I, Holenbeck CB, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and the plasma uric acid concentration. JAMA 1991; 266: 3008–11. 4 Quinones-Galvan A, Natali A, Baldi S, et al. Effect of insulin on uric acid excretion in humans. Am J Physiol 1995; 268: E1–5. 5 Brussard HE, Gevers JA, Frolich M, Kluft C, Krans HMJ. Short term estrogen replacement therapy improves insulin resistance, lipid and fibrinolysis in postmenopausal women with NIDDM. Diabetologia 1997; 40: 843–49.
Sir—Hiroyuki Sumino and colleagues1 state that “reducing the effect of hyperuricaemia by HRT could be beneficial to the cardiovascular systems” and “propose that the reduction of hyperuricaemia is one of the cardiovascular protective mechanisms by which HRT reduces the risk of cardiovascular disease”. Is hyperuricaemia really a risk factor for cardiovascular disease? This long-standing controversy has finally been resolved by the Framingham Heart Study investigators. 2 They found a strong association of raised uric acid concentrations with higher age-adjusted risk for coronary heart disease, death from cardiovascular disease, and death from all causes in women but not in men. But when adjustments were made for other cardiovascular disease risk factors, such as body-mass index, blood pressure, intake of antihypertensive drugs, diabetes, cholesterol, smoking, alcohol intake, left ventricular hypertrophy, and menopausal status, they found that there was no association between uric acid concentrations and any of the outcomes in men and women.2 Sumino and colleagues’ conclusion that reduction of hyperuricaemia by HRT is of benefit to cardiovascular systems is therefore no longer tenable. *A S Kashyap, Surekha Kashyap Departments of *Medicine and Hospital Administration, Armed Forces Medical College, Pune 411040, India (e-mail: [email protected])
1643
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
THE LANCET • Vol 354 • November 6, 1999
we should be cautious in distinguishing between these aspects as separate, independent mechanisms for improving efficacy of stroke services.
colleagues, is that HRT increases insulin sensitivity, thereby reducing insulin concentrations, which in turn lead to increased renal uric acid excretion.
*Gert Kwakkel, Robert C Wagenaar
*Fernando Ovalle, David S H Bell
*Department of Physical Therapy and Research Institute for Fundamental and Clinical Human Movement Sciences, *University Hospital Vrije Universiteit, 1007 MB Amsterdam, Netherlands; and Department of Physical Therapy, Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, MA, USA (e-mail: [email protected])
Department of Medicine, University of Alabama at Birmingham, School of Medicine, Birmingham, AL 35233, USA
1
Mackey F, Louise Ada L, Heard R, Adams R. Stroke rehabilitation: are highly structured units more conductive to physical activity than less structured units? Arch Phys Med Rehabil 1996; 77: 1066–70.
Hormone replacement therapy and serum uric acid Sir—Hiroyuki Sumino and colleagues (Aug 21, p 650)1 show that hormone replacement therapy (HRT) in postmenopausal women is associated with a reduction of serum uric acid. However, the investigators have come to the wrong conclusion by ignoring two important issues: the effects of insulin on uric acid excretion, and the potential effects of HRT on insulin sensitivity. Moreover, although hyperuricaemia has been linked with an increased risk of cardiovascular disease, there is no evidence to support a causal relation. Data from the Framingham Heart Study indicate that uric acid does not have a causal role in the development of coronary artery disease (CAD) or death from CAD, and any apparent association between these outcomes is probably due to the association between uric acid concentrations and other risk factors (ie, insulin resistance or hyperinsulinaemia).2 Two studies3,4 have shown that the most likely explanation for the relation between hyperinsulinaemia and hyperuricaemia is the decrease in renal uric acid and sodium excretion caused by insulin’s effect on the kidney. Thus, the relation between hyperuricaemia and CAD seems to be a function of its relation with insulin resistance. In other words, hyperuricaemia is just a marker of hyperinsulinaemia. Several studies have shown that oestrogen replacement therapy increases insulin sensitivity (thereby reducing insulin concentrations), and although the evidence for the effects of combined HRT on insulin sensitivity are less clear, there is also evidence for a favourable effect that depends on the combination and doses used. 5 A more probable explanation for the decrease in uric acid concentrations seen by Sumino and
1
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. 2 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. 3 Facchini F, Chen I, Holenbeck CB, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and the plasma uric acid concentration. JAMA 1991; 266: 3008–11. 4 Quinones-Galvan A, Natali A, Baldi S, et al. Effect of insulin on uric acid excretion in humans. Am J Physiol 1995; 268: E1–5. 5 Brussard HE, Gevers JA, Frolich M, Kluft C, Krans HMJ. Short term estrogen replacement therapy improves insulin resistance, lipid and fibrinolysis in postmenopausal women with NIDDM. Diabetologia 1997; 40: 843–49.
Sir—Hiroyuki Sumino and colleagues1 state that “reducing the effect of hyperuricaemia by HRT could be beneficial to the cardiovascular systems” and “propose that the reduction of hyperuricaemia is one of the cardiovascular protective mechanisms by which HRT reduces the risk of cardiovascular disease”. Is hyperuricaemia really a risk factor for cardiovascular disease? This long-standing controversy has finally been resolved by the Framingham Heart Study investigators. 2 They found a strong association of raised uric acid concentrations with higher age-adjusted risk for coronary heart disease, death from cardiovascular disease, and death from all causes in women but not in men. But when adjustments were made for other cardiovascular disease risk factors, such as body-mass index, blood pressure, intake of antihypertensive drugs, diabetes, cholesterol, smoking, alcohol intake, left ventricular hypertrophy, and menopausal status, they found that there was no association between uric acid concentrations and any of the outcomes in men and women.2 Sumino and colleagues’ conclusion that reduction of hyperuricaemia by HRT is of benefit to cardiovascular systems is therefore no longer tenable. *A S Kashyap, Surekha Kashyap Departments of *Medicine and Hospital Administration, Armed Forces Medical College, Pune 411040, India (e-mail: [email protected])
1643
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