- Email: [email protected]
Effects of fenofibrate and gemfibrozil on plasma homocysteine
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Effects of fenofibrate and gemfibrozil on plasma homocysteine Sir—Sabine Westphal and colleagues (July 7, p 39)1 report an increase in plasma homocysteine in patients with hypertriglyceridaemia who were given fenofibrate, but not gemfibrozil after 6 weeks. They state that gemfibrozil should be the preferred fibrate for cardioprotection in hypertriglyceridaemic patients. We disagree with their conclusion, which they base on a study of small sample size (n=22) that used changes of one risk factor as the outcome measure. Although raised plasma homocysteine is an independent risk factor for coronary heart disease, they did not assess the effects of the two fibrates on other homoeostatic factors. Among such factors, fibrinogen has a pivotal role in thrombogenesis. Workers in several studies have assessed effects of different fibrates on fibrinogen concentrations and have consistently shown that gemfibrozil raises plasma concentrations, whereas fenofibrate, ciprofibrate, and bezafibrate lower them. The duration of those trials ranged from 8 weeks to 2 years in dyslipidaemic patients.2–4 The mechanism by which fibrinogen undergoes fibrin-induced reduction is thought to be mediated through peroxisome proliferator-activated receptor-␣ (PPAR␣).5 Gemfibrozil does not bind and activate the PPAR␣ and, hence, does not lead to a reduction in fibrinogen concentration. The mechanism of gemfibrozilinduced hyperfibrinogenaemia is, however, unknown. Thus, this unfavourable effect of gemfibrozil on fibrinogen concentration could theoretically counterbalance its beneficial effects on homocysteine. There is a tendency for researchers to use changes in individual coronary heart disease risk factors as secondary (surrogate) endpoints in the assessment of efficacy of lipid-lowering drugs. Clearly, the only way to assess the relative efficacy of different fibrates is by doing large-scale placebocontrolled randomised trials that use hard clinical endpoints. *N Norman Chan, Francis C C Chow Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, Hong Kong (e-mail: [email protected])
THE LANCET • Vol 358 • November 24, 2001
1
2
3
4
5
Westphal S, Dierkes J, Luley C. Effects of fenofibrate and gemfibrozil on plasma homocysteine. Lancet 2001; 358: 39–40. Branchi A, Rovellini A, Sommariva D, Gugliandolo AG, Fasoli A. Effect of three fibrate derivatives and of two HMG-CoA reductase inhibitors on plasma fibrinogen level in patients with primary hypercholesterolaemia. Thromb Haemost 1993; 70: 241–43. Durrington PN, Mackness MI, Bhatnagar D, et al. Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipidaemia. Atherosclerosis 1998; 138: 217–25. de la Serna G, Cadarso C. Fenofibrate decreases plasma fibrinogen, improves lipid profile, and reduces uricemia. Clin Pharmacol Ther 1999; 66: 166–72. Kockx M, Gervois PP, Poulain P, et al. Fibrates suppress fibrinogen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-␣. Blood 1999; 9: 2991–98.
Sir—Sabine Westphal and colleagues’ findings1 lack internal validity because of a failed randomisation scheme. Specifically, the median pretreatment total homocysteine concentrations at the start of the gemfibrozil treatment period were 21% greater than those at the start of the fenofibrate treatment period. Starkly contrasting data have been described from a much larger study with a more valid design.2 In the VAHIT trial2 6 months of gemfibrozil treatment raised mean total homocysteine concentrations by 22%, from 11·0 mol/L to 13·4 mol/L, compared with a 1·7% change, from 12·0 mol/L to 11·8 mol/L in the gemfibrozil placebo group. Moreover, Westphal and colleagues do not acknowledge critically relevant findings which show that although fenofibrate treatment may indeed raise serum creatinine concentrations, simultaneous measurement of insulin clearance reveals that true glomerular filtration rate remains unchanged.3 As reported earlier by Hottelart and colleagues,3 after 2 weeks of treatment with 200 mg fenofibrate daily in 13 hyperlipidaemic patients whose baseline renal function ranged from slightly reduced to normal (baseline
creatinine clearance 30–110 mL/min), serum creatinine increased by 16%. However, directly measured glomerular filtration rate by insulin clearance did not change. Those findings clearly do not support the hypothesis of Westphal and colleagues that fenofibrate raises total homocysteine concentrations by reducing true glomerular filtration rate. Andrew G Bostom Division of Renal Diseases, Rhode Island Hospital, 593 Eddy Street Providence, RI 02903, USA (e-mail: [email protected]) 1
2
3
Westphal S, Dierkes J, Luley C. Effects of fenofibrate and gemfibrozil on plasma homocysteine. Lancet 2001; 358: 39–40. Schaefer EJ, MacNamara JR, Selhub J, et al. Gemfibrozil treatment raised homocysteine concentrations in VA-HIT. Circulation 2000; 102: II–847 (abstr 4067). Hottelart C, el Esper N, Achard JM, Pruna A, Fournier A. Fenofibrate increases blood creatinine, but does not change the glomerular filtration rate in patients with mild renal insufficiency. Nephrologie 1999; 20: 41–44.
Author’s reply Sir—Norman Chan and Francis Chow question our recommendation to prefer gemfibrozil because it reportedly raises fibrinogen. This side-effect, however, is not unanimously described. No change in fibrinogen1 or even a significant were reported after decrease2 gemfibrozil, which is in line with our experience. Moreover, two large intervention studies (Helsinki Heart and VA-HIT) have proven gemfibrozil’s positive effect on clinical outcome, which suggests that, even if this side-effect occurred, it was outweighed by the clinical profit of treatment with gemfibrozil. Andrew Bostom focuses on differing pretreatment homocysteine concentrations in the treatment groups. We tested the comparability of the groups for all relevant parameters and, since they did not differ statistically, we conclude that the study design is valid. Bostom’s main criticism concerns opposing data from the VA-HIT trial showing that
1811
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
homocysteine increased after 6 months of treatment with gemfibrozil. Presently we cannot comment since that report has not yet been published in full. If confirmed, there would be a long-term effect reversing the finding of our short-term study, which would be difficult to explain without further studies. Bostom finally questions the hypothesis that a fibrate-induced deterioration of the glomerular filtration rate is causative for the increase of homocysteine. He quotes Hottelart, who did not note a lowering of insulin clearance in 13 patients after 2 weeks of fenofibrate. Hottelart’s finding, however, contrasts with our earlier observation in 22 patients who were treated for 6 weeks with bezafibrate, which, like fenofibrate, raises homocysteine.3 We recorded a significant lowering of the glomerular filtration rate from 69 mL per min to 62 mL per min after bezafibrate (unpublished data). In addition, other workers suggest that drug-induced falls in the glomerular filtration rate might be associated with increases of homocysteine. Respective reports mention rises in homocysteine concentrations in patients treated with or antiepileptic antihypertensive4 drugs,5 some of which raise creatinine. If confirmed, drug-induced hyperhomocysteinaemia might be substantially more frequent than is presently acknowledged by the medical community. Sabine Westphal Faculty of Medicine, Otto-Von-GuerickeUniversität Magdeburg, Institut fur Klinische Chemie und Pathobiochemie, Universitätsklinikum, D-39120 Magdeburg, Germany (e-mail: [email protected])
1
2
3
4
5
Mussoni L, Mannucci L, Sirtori C, et al. Effects of gemfibrozil on insulin sensitivity and on haemostatic variables in hypertriglyceridaemic patients. Atherosclerosis 2000; 148: 397–406. Avellone G, di Garbo V, Cordovo R, et al. Improvement of fibrinolysis and plasma lipoprotein levels induced by gemfibrozil in hypertriglyceridemia. Blood Coagul Fibrinolysis 1995; 354: 543–48. Dierkes J, Westphal S, Luley C. Serum homocysteine increases after therapy with fenofibrate or bezafibrate. Lancet 1999; 354: 219–20. Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 2001; 73: 613–21. Schwaninger M, Ringleb P, Winter R, et al. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia 1999; 40: 345–50.
1812
Hypopituitarism after head injury Sir—In their case report (June 9, p 1848),1 Jackie Springer and Annette Chollet seek a causal connection between hypopituitarism and head injury sustained 2 years earlier, in a depressed man aged 47 years. The purported association with trauma may have been incidental. Springer and Chollet base their diagnosis of brain injury first on a neuropsychological examination that showed widely disparate results more consistent with depression than mild brain trauma; and second, on the findings of a positron emission tomography scan displaying frontallobe hypometabolism, a non-specific finding encountered in neuropsychiatric states.2 That brain injury was sustained is improbable according to the more reliable yardstick of clinical injury characteristics.3 I assume a cause for the described hypopituitarism other than trauma. Peter Rees Department of Neurology, Burnaby Hospital, Burnaby, BC V5G 2X6, Canada 1 2
3
Springer J, Chollet A. A traumatic car crash. Lancet 2001; 357: 1848. Mayberg IIS. Frontal lobe dysfunction in secondary depression. J Neuropsychiatry Clin Neurosci 1994; 6: 438–42. Alexander MP. Mild traumatic brain injury. Neurology 1995; 45: 1253–60.
Author’s reply Sir—The neurologist made the diagnosis of brain injury 2 years before presentation to our office. The neuropsychological testing was done as part of a head-injury rehabilitation programme and was done 1·5 years before our assessment. Subsequent to the patient’s first visit in our office, we reviewed all available medical records, including those that predated the automobile accident. There was no mention of previous depression or pituitary dysfunction in any record. The duration and severity of our patient’s symptoms since the accident caused us to consider whether endocrine function had been compromised. The neurologist had established that the patient’s behavioural and cognitive symptoms, including getting lost in public places, were the result of a traumatic brain injury. In addition, the patient had completed an outpatient rehabilitation programme but was still unable to work, drive, or be at home alone. Given the
prevalence of traumatic head injuries (220 per 100 000 people), the incidence of poor functional outcome, and the high cost of rehabilitation,1,2 investigation of a neuroendocrine cause for this patient’s symptoms seemed prudent. Some of the metabolic deficiencies on the patient’s positron emission tomography scan were indeed indicative of depression. However, his abnormalities also included a substantial degree of cortical asymmetry with the frontal lobe hypometabolism that the radiologist attributed to post-traumatic encephalopathy. This patient’s pituitary function was also abnormal across every measure and has responed well to replacement therapy. We would have been surprised if our patient had not been depressed given the loss of function and cognition. Furthermore, the most common persistent psychological dysfunction of traumatic brain injury is depression and anxiety;3 thus, we believe the depression to be a result of the traumatic brain injury. Peter Rees references Alexander’s review of mild traumatic brain injury. Alexander comments “There are probably many factors about the injury that are poorly recognized”. This feature is precisely what we were trying to point out with our report— pituitary failure can occur even in minor head injuries and is poorly recognised. Alexander further states “There is no direct treatment of these mild residual states beyond treatment of somatic symptoms and advice about stress management”. In our report, we suggest that one such treatment is recombinant human growth hormone for even mild traumatic brain injury and pituitary dysfunction. We attempted to call attention to this entity, which is frequently not recognised and, as yet, not treated adequately by endocrinologists. Jackie Springer American Association of Clinical Endocrinologists, Overland Park, KS 66210, USA (e-mail: [email protected]) 1
2
3
Centers for Disease Control and Prevention. Traumatic brain injury: Colorado, Missouri, Oklahoma and Utah, 1990–1993. MMWR Morb Mortal Wkly Rep 1997; 46: 8–11. Katz DI, Alexander MP. Traumatic brain injury: predicting course of recovery and outcome for patients admitted to rehabilitation. Arch Neurol 1994; 51: 661–70. Lieberman SA, Oberoi AL, Gilkison CR, Masel BE, Urban RJ. Prevalence of neuroendocrine dysfunction in patients recovering from traumatic brain injury. J Clin Endocrinol Metab 2001; 86: 2752–56.
THE LANCET • Vol 358 • November 24, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Effects of fenofibrate and gemfibrozil on plasma homocysteine Sir—Sabine Westphal and colleagues (July 7, p 39)1 report an increase in plasma homocysteine in patients with hypertriglyceridaemia who were given fenofibrate, but not gemfibrozil after 6 weeks. They state that gemfibrozil should be the preferred fibrate for cardioprotection in hypertriglyceridaemic patients. We disagree with their conclusion, which they base on a study of small sample size (n=22) that used changes of one risk factor as the outcome measure. Although raised plasma homocysteine is an independent risk factor for coronary heart disease, they did not assess the effects of the two fibrates on other homoeostatic factors. Among such factors, fibrinogen has a pivotal role in thrombogenesis. Workers in several studies have assessed effects of different fibrates on fibrinogen concentrations and have consistently shown that gemfibrozil raises plasma concentrations, whereas fenofibrate, ciprofibrate, and bezafibrate lower them. The duration of those trials ranged from 8 weeks to 2 years in dyslipidaemic patients.2–4 The mechanism by which fibrinogen undergoes fibrin-induced reduction is thought to be mediated through peroxisome proliferator-activated receptor-␣ (PPAR␣).5 Gemfibrozil does not bind and activate the PPAR␣ and, hence, does not lead to a reduction in fibrinogen concentration. The mechanism of gemfibrozilinduced hyperfibrinogenaemia is, however, unknown. Thus, this unfavourable effect of gemfibrozil on fibrinogen concentration could theoretically counterbalance its beneficial effects on homocysteine. There is a tendency for researchers to use changes in individual coronary heart disease risk factors as secondary (surrogate) endpoints in the assessment of efficacy of lipid-lowering drugs. Clearly, the only way to assess the relative efficacy of different fibrates is by doing large-scale placebocontrolled randomised trials that use hard clinical endpoints. *N Norman Chan, Francis C C Chow Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, Hong Kong (e-mail: [email protected])
THE LANCET • Vol 358 • November 24, 2001
1
2
3
4
5
Westphal S, Dierkes J, Luley C. Effects of fenofibrate and gemfibrozil on plasma homocysteine. Lancet 2001; 358: 39–40. Branchi A, Rovellini A, Sommariva D, Gugliandolo AG, Fasoli A. Effect of three fibrate derivatives and of two HMG-CoA reductase inhibitors on plasma fibrinogen level in patients with primary hypercholesterolaemia. Thromb Haemost 1993; 70: 241–43. Durrington PN, Mackness MI, Bhatnagar D, et al. Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipidaemia. Atherosclerosis 1998; 138: 217–25. de la Serna G, Cadarso C. Fenofibrate decreases plasma fibrinogen, improves lipid profile, and reduces uricemia. Clin Pharmacol Ther 1999; 66: 166–72. Kockx M, Gervois PP, Poulain P, et al. Fibrates suppress fibrinogen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-␣. Blood 1999; 9: 2991–98.
Sir—Sabine Westphal and colleagues’ findings1 lack internal validity because of a failed randomisation scheme. Specifically, the median pretreatment total homocysteine concentrations at the start of the gemfibrozil treatment period were 21% greater than those at the start of the fenofibrate treatment period. Starkly contrasting data have been described from a much larger study with a more valid design.2 In the VAHIT trial2 6 months of gemfibrozil treatment raised mean total homocysteine concentrations by 22%, from 11·0 mol/L to 13·4 mol/L, compared with a 1·7% change, from 12·0 mol/L to 11·8 mol/L in the gemfibrozil placebo group. Moreover, Westphal and colleagues do not acknowledge critically relevant findings which show that although fenofibrate treatment may indeed raise serum creatinine concentrations, simultaneous measurement of insulin clearance reveals that true glomerular filtration rate remains unchanged.3 As reported earlier by Hottelart and colleagues,3 after 2 weeks of treatment with 200 mg fenofibrate daily in 13 hyperlipidaemic patients whose baseline renal function ranged from slightly reduced to normal (baseline
creatinine clearance 30–110 mL/min), serum creatinine increased by 16%. However, directly measured glomerular filtration rate by insulin clearance did not change. Those findings clearly do not support the hypothesis of Westphal and colleagues that fenofibrate raises total homocysteine concentrations by reducing true glomerular filtration rate. Andrew G Bostom Division of Renal Diseases, Rhode Island Hospital, 593 Eddy Street Providence, RI 02903, USA (e-mail: [email protected]) 1
2
3
Westphal S, Dierkes J, Luley C. Effects of fenofibrate and gemfibrozil on plasma homocysteine. Lancet 2001; 358: 39–40. Schaefer EJ, MacNamara JR, Selhub J, et al. Gemfibrozil treatment raised homocysteine concentrations in VA-HIT. Circulation 2000; 102: II–847 (abstr 4067). Hottelart C, el Esper N, Achard JM, Pruna A, Fournier A. Fenofibrate increases blood creatinine, but does not change the glomerular filtration rate in patients with mild renal insufficiency. Nephrologie 1999; 20: 41–44.
Author’s reply Sir—Norman Chan and Francis Chow question our recommendation to prefer gemfibrozil because it reportedly raises fibrinogen. This side-effect, however, is not unanimously described. No change in fibrinogen1 or even a significant were reported after decrease2 gemfibrozil, which is in line with our experience. Moreover, two large intervention studies (Helsinki Heart and VA-HIT) have proven gemfibrozil’s positive effect on clinical outcome, which suggests that, even if this side-effect occurred, it was outweighed by the clinical profit of treatment with gemfibrozil. Andrew Bostom focuses on differing pretreatment homocysteine concentrations in the treatment groups. We tested the comparability of the groups for all relevant parameters and, since they did not differ statistically, we conclude that the study design is valid. Bostom’s main criticism concerns opposing data from the VA-HIT trial showing that
1811
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
homocysteine increased after 6 months of treatment with gemfibrozil. Presently we cannot comment since that report has not yet been published in full. If confirmed, there would be a long-term effect reversing the finding of our short-term study, which would be difficult to explain without further studies. Bostom finally questions the hypothesis that a fibrate-induced deterioration of the glomerular filtration rate is causative for the increase of homocysteine. He quotes Hottelart, who did not note a lowering of insulin clearance in 13 patients after 2 weeks of fenofibrate. Hottelart’s finding, however, contrasts with our earlier observation in 22 patients who were treated for 6 weeks with bezafibrate, which, like fenofibrate, raises homocysteine.3 We recorded a significant lowering of the glomerular filtration rate from 69 mL per min to 62 mL per min after bezafibrate (unpublished data). In addition, other workers suggest that drug-induced falls in the glomerular filtration rate might be associated with increases of homocysteine. Respective reports mention rises in homocysteine concentrations in patients treated with or antiepileptic antihypertensive4 drugs,5 some of which raise creatinine. If confirmed, drug-induced hyperhomocysteinaemia might be substantially more frequent than is presently acknowledged by the medical community. Sabine Westphal Faculty of Medicine, Otto-Von-GuerickeUniversität Magdeburg, Institut fur Klinische Chemie und Pathobiochemie, Universitätsklinikum, D-39120 Magdeburg, Germany (e-mail: [email protected])
1
2
3
4
5
Mussoni L, Mannucci L, Sirtori C, et al. Effects of gemfibrozil on insulin sensitivity and on haemostatic variables in hypertriglyceridaemic patients. Atherosclerosis 2000; 148: 397–406. Avellone G, di Garbo V, Cordovo R, et al. Improvement of fibrinolysis and plasma lipoprotein levels induced by gemfibrozil in hypertriglyceridemia. Blood Coagul Fibrinolysis 1995; 354: 543–48. Dierkes J, Westphal S, Luley C. Serum homocysteine increases after therapy with fenofibrate or bezafibrate. Lancet 1999; 354: 219–20. Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 2001; 73: 613–21. Schwaninger M, Ringleb P, Winter R, et al. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia 1999; 40: 345–50.
1812
Hypopituitarism after head injury Sir—In their case report (June 9, p 1848),1 Jackie Springer and Annette Chollet seek a causal connection between hypopituitarism and head injury sustained 2 years earlier, in a depressed man aged 47 years. The purported association with trauma may have been incidental. Springer and Chollet base their diagnosis of brain injury first on a neuropsychological examination that showed widely disparate results more consistent with depression than mild brain trauma; and second, on the findings of a positron emission tomography scan displaying frontallobe hypometabolism, a non-specific finding encountered in neuropsychiatric states.2 That brain injury was sustained is improbable according to the more reliable yardstick of clinical injury characteristics.3 I assume a cause for the described hypopituitarism other than trauma. Peter Rees Department of Neurology, Burnaby Hospital, Burnaby, BC V5G 2X6, Canada 1 2
3
Springer J, Chollet A. A traumatic car crash. Lancet 2001; 357: 1848. Mayberg IIS. Frontal lobe dysfunction in secondary depression. J Neuropsychiatry Clin Neurosci 1994; 6: 438–42. Alexander MP. Mild traumatic brain injury. Neurology 1995; 45: 1253–60.
Author’s reply Sir—The neurologist made the diagnosis of brain injury 2 years before presentation to our office. The neuropsychological testing was done as part of a head-injury rehabilitation programme and was done 1·5 years before our assessment. Subsequent to the patient’s first visit in our office, we reviewed all available medical records, including those that predated the automobile accident. There was no mention of previous depression or pituitary dysfunction in any record. The duration and severity of our patient’s symptoms since the accident caused us to consider whether endocrine function had been compromised. The neurologist had established that the patient’s behavioural and cognitive symptoms, including getting lost in public places, were the result of a traumatic brain injury. In addition, the patient had completed an outpatient rehabilitation programme but was still unable to work, drive, or be at home alone. Given the
prevalence of traumatic head injuries (220 per 100 000 people), the incidence of poor functional outcome, and the high cost of rehabilitation,1,2 investigation of a neuroendocrine cause for this patient’s symptoms seemed prudent. Some of the metabolic deficiencies on the patient’s positron emission tomography scan were indeed indicative of depression. However, his abnormalities also included a substantial degree of cortical asymmetry with the frontal lobe hypometabolism that the radiologist attributed to post-traumatic encephalopathy. This patient’s pituitary function was also abnormal across every measure and has responed well to replacement therapy. We would have been surprised if our patient had not been depressed given the loss of function and cognition. Furthermore, the most common persistent psychological dysfunction of traumatic brain injury is depression and anxiety;3 thus, we believe the depression to be a result of the traumatic brain injury. Peter Rees references Alexander’s review of mild traumatic brain injury. Alexander comments “There are probably many factors about the injury that are poorly recognized”. This feature is precisely what we were trying to point out with our report— pituitary failure can occur even in minor head injuries and is poorly recognised. Alexander further states “There is no direct treatment of these mild residual states beyond treatment of somatic symptoms and advice about stress management”. In our report, we suggest that one such treatment is recombinant human growth hormone for even mild traumatic brain injury and pituitary dysfunction. We attempted to call attention to this entity, which is frequently not recognised and, as yet, not treated adequately by endocrinologists. Jackie Springer American Association of Clinical Endocrinologists, Overland Park, KS 66210, USA (e-mail: [email protected]) 1
2
3
Centers for Disease Control and Prevention. Traumatic brain injury: Colorado, Missouri, Oklahoma and Utah, 1990–1993. MMWR Morb Mortal Wkly Rep 1997; 46: 8–11. Katz DI, Alexander MP. Traumatic brain injury: predicting course of recovery and outcome for patients admitted to rehabilitation. Arch Neurol 1994; 51: 661–70. Lieberman SA, Oberoi AL, Gilkison CR, Masel BE, Urban RJ. Prevalence of neuroendocrine dysfunction in patients recovering from traumatic brain injury. J Clin Endocrinol Metab 2001; 86: 2752–56.
THE LANCET • Vol 358 • November 24, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.