- Email: [email protected]
First-line antihypertensive therapy
CORRESPONDENCE 5
Furberg CD, Herrington DM, Psaty BM. Are drugs within a class interchangeable? Lancet 1999; 354: 1202–04.
Author’s reply Sir—By definition all antihypertensive agents lower blood pressure. This reduction is achieved by haemodynamic, fluid volume, neuroendocrine, and endothelial mechanisms that vary greatly from one drug to the other. It seems, therefore, somewhat simplistic to expect that all beneficial effects of antihypertensive drugs (or absence thereof) are conferred by differences in mm Hg. For instance, like all antihypertensive drugs, -blockers lower blood pressure but have not been found to confer any morbidity and mortality benefits in the elderly.1 In the Medical Research Council trial, blood pressure was lowered by 14/6 mm Hg in the -blocker arm, yet morbidity and mortality were not different from placebo.2 In contrast, the exact same reduction in blood pressure with a diuretic resulted in a highly significant decrease in strokes and coronary events. In the NORDIL study,3 despite a 3 mm Hg difference in systolic blood pressure, no difference in primary outcome was noted. In fact, the risk of stroke was lower in the diltiazem arm than in the conventional therapy group, despite the higher systolic pressure. This divergence between the antihypertensive effect and the outcome in several studies makes it increasingly unlikely that impressive benefits in the HOPE study—ie, a reduction of death from cardiovascular cause by 26%—were solely the result of a fall of 2% in systolic and 0·7% in diastolic pressure, and could have been achieved by any other antihypertensive drug as well. It is similarly unlikely that a mere difference in systolic pressure of 1·5% (and no difference in diastolic pressure), as was seen between doxazosin and chlorthalidone in the ALLHAT study, would be responsible for a 104% increase in risk of congestive heart failure and a 25% increase in combined cardiovascular disease. The presence of diabetes has been shown to magnify the benefits of lowering blood pressure in patients with hypertension.4 As Lennart Hansson points out, in the HOT study, a small decrease in blood pressure resulted in a 50% increase in benefit in diabetic patients. In contrast, a similar difference in blood pressure conferred little if any benefit in nondiabetic hypertensive patients.5 Of note, patients with diabetes whose blood
THE LANCET • Vol 356 • August 5, 2000
pressure was titrated to the lowest treatment goal in the HOT study also more often received combination therapy—ie, angiotensin-converting enzyme inhibitors, which have been shown to be particularly beneficial in this patient group. Doxazosin is more expensive than chlorthalidone, and despite the overplayed potential of doxazosin to improve metabolic risk factors, in the ALLHAT study, it conferred significantly less morbidity and mortality benefits, lowered systolic blood pressure less well, and had a higher dropout rate. All taken together, these are clearly the characteristics of a second-class antihypertensive drug. If different morbidity and mortality data emerge for other formulations of doxazosin or other ␣-blockers, this issue could be revisited. Franz H Messerli Ochsner Clinic, New Orleans, LA 70121, USA (e-mail: [email protected]) 1
2
3
4
5
Messerli FH, Grossman E, Goldbourt U. Are -blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA 1998; 279: 1903–07. MRC Working Party: Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992; 304: 405–12. Hansson L, Hedner T, Lund-Johansen P, et al. Randomised trial of effects of calcium antagonists compared with diuretics and -blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000; 356: 359–65. Grossman E, Messerli FH, Goldbourt U. High blood pressure and diabetes mellitus— are all antihypertensive drugs created equal? Arch Intern Med (in press). Grossman E, Goldbourt U. Hypertension Optimal Treatment (HOT) trial. Lancet 1988; 352: 572.
Sir—Franz Messerli (March 11, p 863)1 had discussed the implications of the discontinuation of the doxazosin arm in a clinical trial, reminding us that the control of hypertension, although a very important endpoint, is still an intermediate endpoint en route to reduction in cardiovascular morbidity and mortality. He points out that several international guidelines recognise ␣-adrenergic receptor antagonists as “first-line antihypertensive drugs that have equal footing with angiotensinconverting-enzyme inhibitors, calcium antagonists, and angiotensin receptor inhibitors” and suggests that such guidelines, including ours,2 need to be amended. Although we agree that several organisations will need to revise their recommendations and review the basis on which they ascribe first line
therapy, the Canadian Task Force2 is not one of them. We have consistently maintained a systematic method of reviewing and grading evidence and have said that recommendations for first-line therapy should be made, wherever possible, “based on the identification of those therapies that not only effectively decrease blood pressure but also reduce the ultimate endpoints”.2 ␣-adrenergic antagonists have consistently been designated by us as alternate, not first-line therapy. Messerli’s commentary highlights the frailty of utilising non-systematic approaches in the evaluation of evidence which on occasion can result in recommendations reflecting undue bias from industry, government, and personal opinion. Thus, notwithstanding our objection to being “lumped in” with other sets of guidelines with which we differ, we do concur with Messerli’s message. As has been learned in the treatment of ventricular arrhythmias to avoid sudden death (class I antiarrhythmics), drugs that alter intermediate endpoints may demonstrate significant divergence in achieving “hard outcome” benefits. *Ross D Feldman, Norman Campbell, Pierre Larochelle, for the Task Force for the Development of the 1999 Canadian Recommendations for the Management of Hypertension Department of Medicine, Faculty of Medicine, The University of Western Ontario, London Health Sciences Centre, University Campus, London, ON N6A 5A5, Canada 1
2
Messerli FH. Implications of discontinuation of doxazosin arm of ALLHAT. Lancet 2000; 355: 863–64. Feldman RD, Campbell N, Larochelle P, et al for the Task Force for the Development of the 1999 Canadian Recommendations for the Management of Hypertension. Canadian recommendations for the management of hypertension. CMAJ 1999; 161 (suppl 12): S1–17.
Sir—In his March 11 commentary, Franz Messerli1 commented on the discontinuation of the doxazosin arm of ALLHAT. Doxazosin (an ␣1adrenoceptor blocker) as monotherapy in patients with hypertension and at least one other coronary heart disease risk factor conferred less overall cardiovascular benefits than did treatment with chlorthalidone. The treatement with doxazosin was associated with a significantly higher percentage of development of congestive heart failure compared with chlorthalidone. Messerli suggested “that a yet unknown powerful risk factor associated with doxazosin therapy counteracts the beneficial effect”. We would like to propose candidates for such putative risk factors
509
For personal use only. Not to be reproduced without permission of The Lancet.
CORRESPONDENCE
by considering possible consequences of blocking myocardial ␣1adrenoceptors by doxazosin in addition to the vascular ␣1-adrenoceptors. We found that norepinephrine in myocardial strips from explanted failing human hearts elicited an inotropic effect through ␣1-adrenoceptors with a mean value of about 90% above basal in the presence of -adrenoceptor blockade.2 The ␣1-adrenoceptors in failing human myocardium were located near the synaptic clefts indicating a functional role in vivo.3 In rabbit myocardium Hasenfuss and colleagues found that ␣1-adrenoceptor stimulation elicited an inotropic effect without decreasing the energetic economy in contrast to -adrenoceptor stimulation.4 Thus, stimulation of myocardial ␣1-adrenoceptors can elicit a moderate and energetically favourable inotropic effect. This effect may serve to counteract development of heart failure. Treatment with an ␣1adrenoceptor blocker may attenuate this low energy cost and supportive inotropic effect to an extent increasing the risk for developing heart failure in susceptible patients who are not concomitantly treated with a adrenoceptor blocker. We discovered that stimulation of myocardial ␣1-adrenoceptors activates a loop-diuretic sensitive Na/K/2Clcotransporter in the myocardium.5 This activation involved mechanisms unrelated to the inotropic effect. This cotransporter plays an important part in cell-volume regulation and maintenance of intracellular Cl⫺ and other electrolytes essential for proper cellular functions. Blockade of may myocardial ␣1-adrenoceptors disturb this regulation and increase the risk of developing heart failure in susceptible patients. ␣1-adrenoceptor stimulation is known to increase myocardial protein synthesis and gene expression. The compensatory myocardial hypertrophy is deleterious in the long run, eventually contributing to development of heart failure. In this sense it would be expected that blockade of myocardial ␣1-adrenoceptors would be beneficial. But the findings of the doxazosin arm of ALLHAT indicate that a benefit from reduction of myocardial hypertrophy by ␣1adrenoceptor blockade as monotherapy is counteracted by attenuation of ␣1adrenoceptor mediated beneficial effects, some of which may be coupled to the myocardial ␣1-adenoceptors, as discussed above. We suggest that blockade of the myocardial ␣1-adrenoceptors may be one risk factor associated with
510
doxazosin monotherapy in patients as those included in ALLHAT. *Jan-Bjørn Osnes, Halfdan Aass, Geir Øystein Andersen, Tor Skomedal *Department of Pharmacology, University of Oslo, P O Box 1057 Blindern, N-0316 Oslo, Norway; and Department of Cardiology and MSD Cardiovascular Research Centre, The National Hospital, Oslo (e-mail: [email protected]) 1
2
3
4
5
Messerli FH. Implications of discontinuation of doxazosin arm in ALLHAT. Lancet 2000; 355: 863–64. Skomedal T, Borthne K, Aass H, et al. Comparison between ␣1-adrenoceptor mediated and -adrenoceptor mediated inotropic components elicited by norepinephrine in failing human ventricular muscle. J Pharmacol Exp Therap 1997; 280: 721–29. Skomedal T, Dybvik T, Osnes J-B, et al. Location of myocardial ␣1- and adrenoceptors in relation to sympathetic nerve endings in failing human myocardium [suppl]. NaunynSchmiedeberg’s Arch Pharmacol 1998; 358 (2): R633. Hasenfuss G, Blanchard EM, Holubarsch C, et al. Influence of ␣- and -receptor stimulation on myocardial energetics in rabbit myocardium [suppl]. Circulation 1989; 80 (II): 153. Andersen GO, Enger M, Thoresen GH, et al, ␣1-Adrenergic activation of myocardial Na/K/2Cl-cotransport involving mitogen-activated protein kinase. Am J Physiol 1998; 275: H641–52.
Lactose intolerance and neuromuscular symptoms Sir—We found the case report by S B Matthews and A K Campbell (April 15, p 1330)1 on lactose intolerance confusing and uneducative. The investigators attributed all the symptoms of the case they describe, including raised serum creatine kinase (CK), to lactose intolerance, common in many adults of African, Asian, or Middle Eastern origin who are otherwise healthy. These people are not reported in the literature to suffer from the symptoms described by Matthews and Campbell or have raised CK with muscle pain, even after oral lactose challenge. The only support for their hypothesis comes from the improvement in symptoms when the patient went on a lactose-free diet although they describe improvement of symptoms amongst his family members as varying. Are Matthews and Campbell describing new neuromuscular features of lactose intolerance? Probably not. They have picked this patient and nine others (including three family members of the index case and six other similar cases)1 and have made the classical clinical error of attributing an abnormal
test result to the cause of the disease. They need to study hundreds of patients with lactose intolerance, those with symptoms as well as those without, before postulating this hypothesis. Alternatively, they should critically examine a large cohort of patients with symptoms similar to those seen in their index patient, to establish the causal link of lactose intolerance to the symptoms of muscle pain, orthostatic intolerance (tachycardia and labile hypertension), and raised serum CK. Does the diurnal pattern of the symptoms in the case (worse muscle pain in the morning) fit with their own hypothesis of sudden glucose overload of gut bacteria being responsible for the toxic metabolites (butane 2,3 diol,formate) released into the blood stream? Did they ever measure these putative metabolites in any of their patients and compare the results with other patients who have lactose intolerance but are free of neuromuscular symptoms? Since the reported patient’s symptoms began after a contact at a dairy farmhouse and he had positive Brucella antibody, could some of his symptoms be attributed to chronic brucellosis?2 I do not think so. Did anyone examine this patient’s muscles electrophysiologically or histologically at any time to see whether he could have had metabolic or mitochondrial muscle disease,3 which may present with identical neuromuscular symptoms and raised or normal resting serum CK? Did the investigators ever look for postural responses to norepinephrine release in their patient, since deficiencies in the norepinephrine transporter system are now known to present with identical orthostatic symptoms, tachycardia, and dizziness?4 I am not aware that lactose intolerance is one of the causes of raised serum CK, muscle pain, chronic fatigue, tachycardia, and labile hypertension in adults. Presumably, the investigators have never rechallenged their patients with lactose to see if the reported symptoms were reproducible. I believe that the suggestion made by Matthews and Campbell that there should be routine testing of lactose intolerance in patients with these symptoms is hardly appropriate. Abhijit Chaudhuri Department of Neurology, Institute of Neurological Sciences, University of Glasgow, Glasgow G51 4TF, UK (e-mail: [email protected]) 1 2
Matthews SB, Campbell AK. When sugar is not so sweet. Lancet 2000; 355: 1330. Ottenweller JE, Natelson BH, Gause WC, et al. Mouse running activity is lowered by Brucella abortus treatment: a potential model to study chronic fatigue. Physiol Behav 1998; 63: 795–801.
THE LANCET • Vol 356 • August 5, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
Furberg CD, Herrington DM, Psaty BM. Are drugs within a class interchangeable? Lancet 1999; 354: 1202–04.
Author’s reply Sir—By definition all antihypertensive agents lower blood pressure. This reduction is achieved by haemodynamic, fluid volume, neuroendocrine, and endothelial mechanisms that vary greatly from one drug to the other. It seems, therefore, somewhat simplistic to expect that all beneficial effects of antihypertensive drugs (or absence thereof) are conferred by differences in mm Hg. For instance, like all antihypertensive drugs, -blockers lower blood pressure but have not been found to confer any morbidity and mortality benefits in the elderly.1 In the Medical Research Council trial, blood pressure was lowered by 14/6 mm Hg in the -blocker arm, yet morbidity and mortality were not different from placebo.2 In contrast, the exact same reduction in blood pressure with a diuretic resulted in a highly significant decrease in strokes and coronary events. In the NORDIL study,3 despite a 3 mm Hg difference in systolic blood pressure, no difference in primary outcome was noted. In fact, the risk of stroke was lower in the diltiazem arm than in the conventional therapy group, despite the higher systolic pressure. This divergence between the antihypertensive effect and the outcome in several studies makes it increasingly unlikely that impressive benefits in the HOPE study—ie, a reduction of death from cardiovascular cause by 26%—were solely the result of a fall of 2% in systolic and 0·7% in diastolic pressure, and could have been achieved by any other antihypertensive drug as well. It is similarly unlikely that a mere difference in systolic pressure of 1·5% (and no difference in diastolic pressure), as was seen between doxazosin and chlorthalidone in the ALLHAT study, would be responsible for a 104% increase in risk of congestive heart failure and a 25% increase in combined cardiovascular disease. The presence of diabetes has been shown to magnify the benefits of lowering blood pressure in patients with hypertension.4 As Lennart Hansson points out, in the HOT study, a small decrease in blood pressure resulted in a 50% increase in benefit in diabetic patients. In contrast, a similar difference in blood pressure conferred little if any benefit in nondiabetic hypertensive patients.5 Of note, patients with diabetes whose blood
THE LANCET • Vol 356 • August 5, 2000
pressure was titrated to the lowest treatment goal in the HOT study also more often received combination therapy—ie, angiotensin-converting enzyme inhibitors, which have been shown to be particularly beneficial in this patient group. Doxazosin is more expensive than chlorthalidone, and despite the overplayed potential of doxazosin to improve metabolic risk factors, in the ALLHAT study, it conferred significantly less morbidity and mortality benefits, lowered systolic blood pressure less well, and had a higher dropout rate. All taken together, these are clearly the characteristics of a second-class antihypertensive drug. If different morbidity and mortality data emerge for other formulations of doxazosin or other ␣-blockers, this issue could be revisited. Franz H Messerli Ochsner Clinic, New Orleans, LA 70121, USA (e-mail: [email protected]) 1
2
3
4
5
Messerli FH, Grossman E, Goldbourt U. Are -blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA 1998; 279: 1903–07. MRC Working Party: Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992; 304: 405–12. Hansson L, Hedner T, Lund-Johansen P, et al. Randomised trial of effects of calcium antagonists compared with diuretics and -blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000; 356: 359–65. Grossman E, Messerli FH, Goldbourt U. High blood pressure and diabetes mellitus— are all antihypertensive drugs created equal? Arch Intern Med (in press). Grossman E, Goldbourt U. Hypertension Optimal Treatment (HOT) trial. Lancet 1988; 352: 572.
Sir—Franz Messerli (March 11, p 863)1 had discussed the implications of the discontinuation of the doxazosin arm in a clinical trial, reminding us that the control of hypertension, although a very important endpoint, is still an intermediate endpoint en route to reduction in cardiovascular morbidity and mortality. He points out that several international guidelines recognise ␣-adrenergic receptor antagonists as “first-line antihypertensive drugs that have equal footing with angiotensinconverting-enzyme inhibitors, calcium antagonists, and angiotensin receptor inhibitors” and suggests that such guidelines, including ours,2 need to be amended. Although we agree that several organisations will need to revise their recommendations and review the basis on which they ascribe first line
therapy, the Canadian Task Force2 is not one of them. We have consistently maintained a systematic method of reviewing and grading evidence and have said that recommendations for first-line therapy should be made, wherever possible, “based on the identification of those therapies that not only effectively decrease blood pressure but also reduce the ultimate endpoints”.2 ␣-adrenergic antagonists have consistently been designated by us as alternate, not first-line therapy. Messerli’s commentary highlights the frailty of utilising non-systematic approaches in the evaluation of evidence which on occasion can result in recommendations reflecting undue bias from industry, government, and personal opinion. Thus, notwithstanding our objection to being “lumped in” with other sets of guidelines with which we differ, we do concur with Messerli’s message. As has been learned in the treatment of ventricular arrhythmias to avoid sudden death (class I antiarrhythmics), drugs that alter intermediate endpoints may demonstrate significant divergence in achieving “hard outcome” benefits. *Ross D Feldman, Norman Campbell, Pierre Larochelle, for the Task Force for the Development of the 1999 Canadian Recommendations for the Management of Hypertension Department of Medicine, Faculty of Medicine, The University of Western Ontario, London Health Sciences Centre, University Campus, London, ON N6A 5A5, Canada 1
2
Messerli FH. Implications of discontinuation of doxazosin arm of ALLHAT. Lancet 2000; 355: 863–64. Feldman RD, Campbell N, Larochelle P, et al for the Task Force for the Development of the 1999 Canadian Recommendations for the Management of Hypertension. Canadian recommendations for the management of hypertension. CMAJ 1999; 161 (suppl 12): S1–17.
Sir—In his March 11 commentary, Franz Messerli1 commented on the discontinuation of the doxazosin arm of ALLHAT. Doxazosin (an ␣1adrenoceptor blocker) as monotherapy in patients with hypertension and at least one other coronary heart disease risk factor conferred less overall cardiovascular benefits than did treatment with chlorthalidone. The treatement with doxazosin was associated with a significantly higher percentage of development of congestive heart failure compared with chlorthalidone. Messerli suggested “that a yet unknown powerful risk factor associated with doxazosin therapy counteracts the beneficial effect”. We would like to propose candidates for such putative risk factors
509
For personal use only. Not to be reproduced without permission of The Lancet.
CORRESPONDENCE
by considering possible consequences of blocking myocardial ␣1adrenoceptors by doxazosin in addition to the vascular ␣1-adrenoceptors. We found that norepinephrine in myocardial strips from explanted failing human hearts elicited an inotropic effect through ␣1-adrenoceptors with a mean value of about 90% above basal in the presence of -adrenoceptor blockade.2 The ␣1-adrenoceptors in failing human myocardium were located near the synaptic clefts indicating a functional role in vivo.3 In rabbit myocardium Hasenfuss and colleagues found that ␣1-adrenoceptor stimulation elicited an inotropic effect without decreasing the energetic economy in contrast to -adrenoceptor stimulation.4 Thus, stimulation of myocardial ␣1-adrenoceptors can elicit a moderate and energetically favourable inotropic effect. This effect may serve to counteract development of heart failure. Treatment with an ␣1adrenoceptor blocker may attenuate this low energy cost and supportive inotropic effect to an extent increasing the risk for developing heart failure in susceptible patients who are not concomitantly treated with a adrenoceptor blocker. We discovered that stimulation of myocardial ␣1-adrenoceptors activates a loop-diuretic sensitive Na/K/2Clcotransporter in the myocardium.5 This activation involved mechanisms unrelated to the inotropic effect. This cotransporter plays an important part in cell-volume regulation and maintenance of intracellular Cl⫺ and other electrolytes essential for proper cellular functions. Blockade of may myocardial ␣1-adrenoceptors disturb this regulation and increase the risk of developing heart failure in susceptible patients. ␣1-adrenoceptor stimulation is known to increase myocardial protein synthesis and gene expression. The compensatory myocardial hypertrophy is deleterious in the long run, eventually contributing to development of heart failure. In this sense it would be expected that blockade of myocardial ␣1-adrenoceptors would be beneficial. But the findings of the doxazosin arm of ALLHAT indicate that a benefit from reduction of myocardial hypertrophy by ␣1adrenoceptor blockade as monotherapy is counteracted by attenuation of ␣1adrenoceptor mediated beneficial effects, some of which may be coupled to the myocardial ␣1-adenoceptors, as discussed above. We suggest that blockade of the myocardial ␣1-adrenoceptors may be one risk factor associated with
510
doxazosin monotherapy in patients as those included in ALLHAT. *Jan-Bjørn Osnes, Halfdan Aass, Geir Øystein Andersen, Tor Skomedal *Department of Pharmacology, University of Oslo, P O Box 1057 Blindern, N-0316 Oslo, Norway; and Department of Cardiology and MSD Cardiovascular Research Centre, The National Hospital, Oslo (e-mail: [email protected]) 1
2
3
4
5
Messerli FH. Implications of discontinuation of doxazosin arm in ALLHAT. Lancet 2000; 355: 863–64. Skomedal T, Borthne K, Aass H, et al. Comparison between ␣1-adrenoceptor mediated and -adrenoceptor mediated inotropic components elicited by norepinephrine in failing human ventricular muscle. J Pharmacol Exp Therap 1997; 280: 721–29. Skomedal T, Dybvik T, Osnes J-B, et al. Location of myocardial ␣1- and adrenoceptors in relation to sympathetic nerve endings in failing human myocardium [suppl]. NaunynSchmiedeberg’s Arch Pharmacol 1998; 358 (2): R633. Hasenfuss G, Blanchard EM, Holubarsch C, et al. Influence of ␣- and -receptor stimulation on myocardial energetics in rabbit myocardium [suppl]. Circulation 1989; 80 (II): 153. Andersen GO, Enger M, Thoresen GH, et al, ␣1-Adrenergic activation of myocardial Na/K/2Cl-cotransport involving mitogen-activated protein kinase. Am J Physiol 1998; 275: H641–52.
Lactose intolerance and neuromuscular symptoms Sir—We found the case report by S B Matthews and A K Campbell (April 15, p 1330)1 on lactose intolerance confusing and uneducative. The investigators attributed all the symptoms of the case they describe, including raised serum creatine kinase (CK), to lactose intolerance, common in many adults of African, Asian, or Middle Eastern origin who are otherwise healthy. These people are not reported in the literature to suffer from the symptoms described by Matthews and Campbell or have raised CK with muscle pain, even after oral lactose challenge. The only support for their hypothesis comes from the improvement in symptoms when the patient went on a lactose-free diet although they describe improvement of symptoms amongst his family members as varying. Are Matthews and Campbell describing new neuromuscular features of lactose intolerance? Probably not. They have picked this patient and nine others (including three family members of the index case and six other similar cases)1 and have made the classical clinical error of attributing an abnormal
test result to the cause of the disease. They need to study hundreds of patients with lactose intolerance, those with symptoms as well as those without, before postulating this hypothesis. Alternatively, they should critically examine a large cohort of patients with symptoms similar to those seen in their index patient, to establish the causal link of lactose intolerance to the symptoms of muscle pain, orthostatic intolerance (tachycardia and labile hypertension), and raised serum CK. Does the diurnal pattern of the symptoms in the case (worse muscle pain in the morning) fit with their own hypothesis of sudden glucose overload of gut bacteria being responsible for the toxic metabolites (butane 2,3 diol,formate) released into the blood stream? Did they ever measure these putative metabolites in any of their patients and compare the results with other patients who have lactose intolerance but are free of neuromuscular symptoms? Since the reported patient’s symptoms began after a contact at a dairy farmhouse and he had positive Brucella antibody, could some of his symptoms be attributed to chronic brucellosis?2 I do not think so. Did anyone examine this patient’s muscles electrophysiologically or histologically at any time to see whether he could have had metabolic or mitochondrial muscle disease,3 which may present with identical neuromuscular symptoms and raised or normal resting serum CK? Did the investigators ever look for postural responses to norepinephrine release in their patient, since deficiencies in the norepinephrine transporter system are now known to present with identical orthostatic symptoms, tachycardia, and dizziness?4 I am not aware that lactose intolerance is one of the causes of raised serum CK, muscle pain, chronic fatigue, tachycardia, and labile hypertension in adults. Presumably, the investigators have never rechallenged their patients with lactose to see if the reported symptoms were reproducible. I believe that the suggestion made by Matthews and Campbell that there should be routine testing of lactose intolerance in patients with these symptoms is hardly appropriate. Abhijit Chaudhuri Department of Neurology, Institute of Neurological Sciences, University of Glasgow, Glasgow G51 4TF, UK (e-mail: [email protected]) 1 2
Matthews SB, Campbell AK. When sugar is not so sweet. Lancet 2000; 355: 1330. Ottenweller JE, Natelson BH, Gause WC, et al. Mouse running activity is lowered by Brucella abortus treatment: a potential model to study chronic fatigue. Physiol Behav 1998; 63: 795–801.
THE LANCET • Vol 356 • August 5, 2000
For personal use only. Not to be reproduced without permission of The Lancet.