Carbamazepine and false positive dexamethasone suppression tests for C
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《英国医生杂志》
1 Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, 2 Department of Medicine and Therapeutics, Chinese University of Hong Kong
Corresdondence to: R C W Ma rcwma@cuhk.edu.hk
Introduction
Cushing's syndrome arises from excess production of cortisol and has a high mortality if left untreated. The overnight 1 mg dexamethasone suppression test is widely used as a screening test for Cushing's syndrome, but it is not specific for this syndrome. The test has a false positive rate of 2-12%,1 2 which could be due to stress, weight loss,3 alcohol withdrawal,4 failure of ingestion of dexamethasone, or altered metabolism of the drug. Consequently, a positive overnight dexamethasone suppression test is usually followed by further endocrine testing, which usually includes low dose and high dose dexamethasone suppression. The dexamethasone suppression test is designed to assess the ability of exogenous dexamethasone to suppress endogenous corticotrophin and hence cortisol production. Dexamethasone is primarily metabolised by the cytochrome P450 system, by hepatic CYP3A4, an enzyme complex responsible for the metabolism of many xenobiotics.5 Considerable increases in cytochrome P450 enzymes can be seen in regular smokers and people who drink alcohol regularly.6 Several drugs such as phenobarbital, primidone, ethosuximide, carbamazepine, and rifampicin induce the activity of CYP3A4, and can lead to false positive dexamethasone suppression tests.7-9
Conversely, patients with adrenal insufficiency and taking steroid replacement may need increased doses of steroids if also taking these enzyme inducers.10 During endocrine testing, patients should ideally stop taking these interacting drugs. If this is not feasible, alternative strategies for evaluation include use of midnight cortisol,11 12 late night salivary cortisol,13 or hydrocortisone suppression tests.14 Measurement of urinary free cortisol may be helpful, although carbamazepine has also been reported to interfere with urinary cortisol measurements by high performance liquid chromatography.15 In screening patients for Cushing's syndrome, be aware of potential drug interactions with dexamethasone, which may lead to false positive results. Appropriate investigations and interpretation of results is necessary to avoid misdiagnosing Cushing's syndrome.
Drugs that induce metabolism of dexamethasone can lead to misdiagnosis of Cushing's syndrome
Contributors: RCWM collected the cases and initiated the project. All authors were actively involved with the care of the patients and participated in writing and critically reviewing the manuscript. RCWM is guarantor.
Funding: None.
Competing interests: None declared.
References
Cronin C, Igoe D, Duffy MJ, Cunningham SK, McKenna TJ. The overnight dexamethasone test is a worthwhile screening procedure. Clin Endocrinol (Oxf) 1990;33: 27-33.
Ness-Abramof R, Nabriski D, Apovian CM, Niven M, Weiss E, Shapiro MS, et al. Overnight dexamethasone suppression test: a reliable screen for Cushing's syndrome in the obese. Obes Res 2002;10: 1217-21.
Edelstein CK, Roy-Byrne P, Fawzy FI, Dornfeld L. Effects of weight loss on the dexamethasone suppression test. Am J Psychiatry 1983;140: 338-41.
Newsom G, Murray N. Reversal of dexamethasone suppression test non-suppression in alcohol abusers. Am J Psychiatry 1983;140: 353-4.
Guengerich FP. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 1999;39: 1-17.
Feierman DE, Melinkov Z, Nanji AA. Induction of CYP3A by ethanol in multiple in vitro and in vivo models. Alcohol Clin Exp Res 2003;27: 981-8.
Keitner GI, Fruzzetti AE, Miller IW, Norman WH, Brown WA. The effect of anticonvulsants on the dexamethasone suppression test. Can J Psychiatry 1989;34: 441-3.
Privitera MR, Greden JF, Gardner RW, Ritchie JC, Carroll BJ. Interference by carbamazepine with the dexamethasone suppression test. Biol Psychiatry 1982;17: 611-20.
Kyriazopoulou V, Vagenakis AG. Abnormal overnight dexamethasone suppression test in subjects receiving rifampicin therapy. J Clin Endocrinol Metab 1992;75: 315-7.
Putignano P, Kaltsas GA, Satta MA, Grossman AB. The effects of anti-convulsant drugs on adrenal function. Horm Metab Res 1998;30: 389-97.
Newell-Price J, Trainer P, Perry L, Wass J, Grossman A, Besser M. A single sleeping midnight cortisol has 100% sensitivity for the diagnosis of Cushing's syndrome. Clin Endocrinol (Oxf) 1995;43: 545-50.
Papanicolaou DA, Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. A single midnight serum cortisol measurement distinguishes Cushing's syndrome from pseudo-Cushing states. J Clin Endocrinol Metab 1998;83: 1163-7.
Papanicolaou DA, Mullen N, Kyrou I, Nieman LK. Nighttime salivary cortisol: a useful test for the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 2002;87: 4515-21.
Meikle AW, Stanchfield JB, West CD, Tyler FH. Hydrocortisone suppression test for Cushing syndrome: therapy with anticonvulsants. Arch Intern Med 1974;134: 1068-71.
Turpeinen U, Markkanen H, Valimaki M, Stenman UH. Determination of urinary free cortisol by HPLC. Clin Chem 1997;43: 1386-91.(Ronald C W Ma, resident specialist1, Win)
Corresdondence to: R C W Ma rcwma@cuhk.edu.hk
Introduction
Cushing's syndrome arises from excess production of cortisol and has a high mortality if left untreated. The overnight 1 mg dexamethasone suppression test is widely used as a screening test for Cushing's syndrome, but it is not specific for this syndrome. The test has a false positive rate of 2-12%,1 2 which could be due to stress, weight loss,3 alcohol withdrawal,4 failure of ingestion of dexamethasone, or altered metabolism of the drug. Consequently, a positive overnight dexamethasone suppression test is usually followed by further endocrine testing, which usually includes low dose and high dose dexamethasone suppression. The dexamethasone suppression test is designed to assess the ability of exogenous dexamethasone to suppress endogenous corticotrophin and hence cortisol production. Dexamethasone is primarily metabolised by the cytochrome P450 system, by hepatic CYP3A4, an enzyme complex responsible for the metabolism of many xenobiotics.5 Considerable increases in cytochrome P450 enzymes can be seen in regular smokers and people who drink alcohol regularly.6 Several drugs such as phenobarbital, primidone, ethosuximide, carbamazepine, and rifampicin induce the activity of CYP3A4, and can lead to false positive dexamethasone suppression tests.7-9
Conversely, patients with adrenal insufficiency and taking steroid replacement may need increased doses of steroids if also taking these enzyme inducers.10 During endocrine testing, patients should ideally stop taking these interacting drugs. If this is not feasible, alternative strategies for evaluation include use of midnight cortisol,11 12 late night salivary cortisol,13 or hydrocortisone suppression tests.14 Measurement of urinary free cortisol may be helpful, although carbamazepine has also been reported to interfere with urinary cortisol measurements by high performance liquid chromatography.15 In screening patients for Cushing's syndrome, be aware of potential drug interactions with dexamethasone, which may lead to false positive results. Appropriate investigations and interpretation of results is necessary to avoid misdiagnosing Cushing's syndrome.
Drugs that induce metabolism of dexamethasone can lead to misdiagnosis of Cushing's syndrome
Contributors: RCWM collected the cases and initiated the project. All authors were actively involved with the care of the patients and participated in writing and critically reviewing the manuscript. RCWM is guarantor.
Funding: None.
Competing interests: None declared.
References
Cronin C, Igoe D, Duffy MJ, Cunningham SK, McKenna TJ. The overnight dexamethasone test is a worthwhile screening procedure. Clin Endocrinol (Oxf) 1990;33: 27-33.
Ness-Abramof R, Nabriski D, Apovian CM, Niven M, Weiss E, Shapiro MS, et al. Overnight dexamethasone suppression test: a reliable screen for Cushing's syndrome in the obese. Obes Res 2002;10: 1217-21.
Edelstein CK, Roy-Byrne P, Fawzy FI, Dornfeld L. Effects of weight loss on the dexamethasone suppression test. Am J Psychiatry 1983;140: 338-41.
Newsom G, Murray N. Reversal of dexamethasone suppression test non-suppression in alcohol abusers. Am J Psychiatry 1983;140: 353-4.
Guengerich FP. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 1999;39: 1-17.
Feierman DE, Melinkov Z, Nanji AA. Induction of CYP3A by ethanol in multiple in vitro and in vivo models. Alcohol Clin Exp Res 2003;27: 981-8.
Keitner GI, Fruzzetti AE, Miller IW, Norman WH, Brown WA. The effect of anticonvulsants on the dexamethasone suppression test. Can J Psychiatry 1989;34: 441-3.
Privitera MR, Greden JF, Gardner RW, Ritchie JC, Carroll BJ. Interference by carbamazepine with the dexamethasone suppression test. Biol Psychiatry 1982;17: 611-20.
Kyriazopoulou V, Vagenakis AG. Abnormal overnight dexamethasone suppression test in subjects receiving rifampicin therapy. J Clin Endocrinol Metab 1992;75: 315-7.
Putignano P, Kaltsas GA, Satta MA, Grossman AB. The effects of anti-convulsant drugs on adrenal function. Horm Metab Res 1998;30: 389-97.
Newell-Price J, Trainer P, Perry L, Wass J, Grossman A, Besser M. A single sleeping midnight cortisol has 100% sensitivity for the diagnosis of Cushing's syndrome. Clin Endocrinol (Oxf) 1995;43: 545-50.
Papanicolaou DA, Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. A single midnight serum cortisol measurement distinguishes Cushing's syndrome from pseudo-Cushing states. J Clin Endocrinol Metab 1998;83: 1163-7.
Papanicolaou DA, Mullen N, Kyrou I, Nieman LK. Nighttime salivary cortisol: a useful test for the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 2002;87: 4515-21.
Meikle AW, Stanchfield JB, West CD, Tyler FH. Hydrocortisone suppression test for Cushing syndrome: therapy with anticonvulsants. Arch Intern Med 1974;134: 1068-71.
Turpeinen U, Markkanen H, Valimaki M, Stenman UH. Determination of urinary free cortisol by HPLC. Clin Chem 1997;43: 1386-91.(Ronald C W Ma, resident specialist1, Win)