- Email: [email protected]
INDICATIONS FOR THYROID FUNCTION SCREENING
363 chloride is not a normal constituent of the diet and must be shown therefore to have no unwanted effects before its use can be advocated. Blood Pressure Unit,
Department of Medicine, Charing Cross Hospital Medical School, London W6 8RF
STEPHEN J. SMITH R. MARIE ROBERTS NIRMALA D. MARKANDU GRAHAM A. MACGREGOR
SIR,-Dr Henningsen and his colleagues are unduly optimistic in suggesting that a raised K+/Na+ ratio in the food would be beneficial "probably for overweight" as well as other conditions. They give reasons why abnormalities in the Na + - K pump might cause abnormally low energy requirements in obese people, and build their argument on this hypothesis. However, the energy requirements of groups of obese adults are on average higher than those of lean groups.I-4 Even the most enthusiastic supporters of the view that a defect in the thermogenic response to some stimulus contributes to the aetiology of obesity admit that their obese subjects had a higher daily energy expenditure than the lean controls.5 The hypothesis that an increase in K+/Na+ ratio in the food would cause a great increase in metabolic rate is one which would be easy to test by whole body calorimetry. If (surprisingly) this happened it might be a help to overweight people. However, no explanation (and treatment) is required for any postulated low energy requirements of obese adults: their energy output, and thus requirement for weight maintenance, is usually slightly higher than that of lean subjects of the same age, sex and height. Division of Clinical Sciences, Clinical Research Centre, Harrow, Middlesex HA1 3UJ
J. S. GARROW
METABOLIC CAUSES OF DEMENTIA
SIR,-I read with great interest the review the dementia syndrome
by Dr Small and Dr Jarvik (Dec. 25,
p. 1443). Dementia has also been described as a clinical manifestation in the genetically inherited sterol storage disease, cerebrotendinous xanthomatosis. The disease was first described in 19376and fifty-three cases have been reported. The disease is characterised by progressive neurological dysfunction (dementia, spinal cord paresis, and cerebellar ataxia), tendon xanthomas, cataracts, and premature atherosclerosis. Cholestanol (a saturated analogue of cholesterol) accumulates in almost every tissue, particularly in the nervous tissue and tendons. The plasma cholesterol is usually normal (117 to 220 mg/dl) while plasma cholestanol concentrations have ranged between 1 - 3 and 15 mg/dl (3 to 20 times the normal mean values).7 A deficiency ofa hepatic enzyme that catalyses the 24-hydroxylation of 5&bgr;-cholestan-3 a,7a,12a,25-tetrol, an intermediate in the bile acid synthetic pathway, has also been reported, which resulted in a marked decrease in chenodeoxycholic and cholic acid synthesis and excretion in bile.2 Salen and co-workers have treated patients with cerebrotendinous xanthomatosis with chenodeoxycholic acid, 1. Garrow
JS, Blaza SE, Warwick PM, Ashwell MA. Predisposition to obesity. Lancet 1980; i: 1103-04. 2. Blaza S, Garrow JS. Thermogenic response to temperature, exercise and food stimuli in lean and obese women, studied by 24-hour direct calorimetry. Br J Nutri (in press). 3 Jéquier E, Schutz Y. The contribution of BMR and physical activity to energy expenditure. In: Cioffi LA, James WPT, van Itallie TB, eds. The body weight regulatory system: Normal and disturbed mechanisms. New York: Raven Press, 1981: 89-96. E, Burnand B, Schutz Y, Jéquier E. Twenty-four-hour energy expenditure and resting metabolic rate in obese, moderately obese, and control subjects. Am J Clin Nutr 1982; 35: 566-573. 5 Shetty PS, Jung RT, James WPT, Barrand MA, Callingham BA Postprandial thermogenesis in obesity. Clin Sci 1981; 60: 519-25 6. van Bogaert L, Scherer HJ, Epstein E. Une forme cerebrale de la cholestérinose généralisée. Paris: Masson, 1973. 7 Sallen G, Shefer S, Bergmer VM. Familial diseases with storage of sterols other than cholesterol: Cerebrotendinous xanthomatosis and sitosterolemia with xanthomatosis. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS, eds. The metabolic basis of inherited disease. New York: McGraw-Hill, 1983: 713-30 4 Ravussin
acid synthesis and reduction resulting in inhibition of abnormal bile in plasma cholestanol concentration.22 Departments of Pathology and Physiology, Louisiana State University Medical Center, New Orleans, Louisiana, 70112, U.S.A.
ASHIM K. BHATTACHARYYA
INDICATIONS FOR THYROID FUNCTION SCREENING
SIR,-Editorials in The Lancet (Jan. 22) and the B.M.,’.1 have discussed two problems of using thyroid function tests to confirm or exclude thyroid disease-firstly, the exclusion of thyrotoxicosis in patients with atrial fibrillation and secondly, the interpretation of low free thyroxine (FT4) assay results in sick patients. To resolve these problems, a dynamic test of pituitary function, the thyrotropin releasing hormone (TRH) test, is recommended. Both editorials cite Forfar et al.2 who found that of 75 patients with atrial fibrillation 10 had impaired responses to TRH. 7 of these 10 had raised total thyroxine (TT4) and total triiodothyronine (TT3); 2 had a normal TT4, with raised TT3 in 1 case and a borderline TT3 in the other; only 1 had both TT4 and TT3 unequivocally in the normal range. Thus, the suggestion that thyrotoxicosis is underdiagnosed in atrial fibrillation depends upon a single case. Had a logical strategic approach been followed,3,4 involving FT4 or free thyroxine index (FTI) and TT3 corrected for thyroid hormone binding capacity variation,sall these cases except 1 would almost certainly have had laboratory evidence of thyrotoxicosis. In the context of the large numbers of thyroid function tests requested on patients with atrial fibrillation this strategic approach prevents overburdening the laboratory with TRH generated thyrotropin (TSH) requests. In the interpretation of low FT4 or FTI results in sick patients, the strategic approach4would require a TSH estimation, thus the distinction between non-thyroidal illness and primary hypothyroidism can usually be made on the initial sample. The TRH test is time consuming for all concerned, it is be difficult to sometimes unpleasant for the patient, and interpret in clinical practice(in elderly men, in patients on aspirin8 or steroid9 therapy, and in patients with diabetesl° or psychiatric illness, I for example), as your Jan. 22 editorial concedes. A thyroidal cause for a blunted TRH response not mentioned is, in our experience, prolonged pituitary suppression by a transient increase of thyroid hormones. Scientific and technical ingenuity have introduced direct free hormone measurements into clinical practice; FT4 has arrived and FT3 will follow. These tests are revealing new insights into thyroidal pathophysiology. Surely, the way forward is to welcome them so that patients may, wherever possible, have thyroid disease confirmed or excluded on single blood sample, and to keep the threshold for TRH testing high.
may
Departments of Nuclear Medicine and Chemical Pathology, Southampton General Hospital, Southampton SO9 4XY
R. MARDELL T. R. GAMLEN
1. Forfar
JC, Toft AD. Thyrotoxic atrial fibrillation: an underdiagnosed condition? Br Med J; 285: 909-10. 2. Forfar JC, Miller HC, Toft AD. Occult thyrotoxicosis: a correctable cause of "idiopathic" atrial fibrillation. Am J Cardiol 1979; 44: 9—12. 3. Britton KE, Quinn V, Brown BL, Ekins RP. A strategy for thyroid function tests. Br Med J 1975; iii: 350—52. 4. Mardell R. A strategy for in-vitro tests of thyroid function. Amersham: Radiochemical Centre, Amersham International, 1978. 5. Mardell R, Gerson M. A method of assessing serum triiodothyronine concentrations that is independent of subject’s age and variations in concentrations of binding proteins in serum. Clin Chem 1978; 24: 1792-96. 6. Hall R, Scanlon MF. Thyrotrophin-releasing hormone in clinical practice. J Clin Pathol 1976; 30: (Ass Clin Pathol suppl 7) 55-57. 7. Snyder PJ, Utiger RD. Response to thyrotrophin releasing hormone (TRH) in normal man. J Clin Endocrinol Metab 1972; 34: 380-85. 8. Dussault JH, Turcotte R, Guyda H. The effect of acetylsalicylic acid on TSH and PRL secretion after TRH stimulation in the human. J Clin Endocrinol Metab 1976; 43: 232-35. 9. Otsuki M, Dakoda M, Baba S. Influence of glucocorticoids on TRF induced TSH release in man. J Clin Endocrinol Metab 1973; 36: 95-102. 10. Naeije R, Golstein J, Clumeck N, Meinhold H, Wenzel KW, Vanhaelst L. A low T3 syndrome in diabetic ketoacidosis Clin Endocrinol 1978; 8: 467-72. 11. Spratt DI, Pont A, Miller MB, McDougall IR, Bayer MF, McLaughlin WT. Hyperthyroxinemia in patients with acute psychiatric disorders Am J Med 1982; 73: 41-48.
364
SlR,—You maintained (Jan. 22) that routine screening for thyroid disease is justified only in the elderly. This conclusion is based on a review of screening with serum thyroxine estimations. You rightly out that the best screening test for thyroid disease is the response of serum thyrotropin (TSH) to thryrotropin-releasing hormone (TRH). In borderline hypothyroidism, the cause of so much treatable morbidity, the problem is in deciding the normal range of response of TSH to TRH. 10% of one hospital population had thyroid antibodies,l and when we were selecting age and sex matched controls for a previous study, two out of twenty-two 2 subjects had to be rejected because they had thyroid antibodies.2 We have done TRH tests on nine Indian patients with buccal fibrosis. In selecting age and sex matched Indian controls, we have found one subject with unsuspected biochemical hypothyroidism and three with thyroid antibodies and an exaggerated response of TSH to TRH at 20 min (2 to 37,7 to 55, and 5 to 65 mU/1) out of the first fourteen persons screened. Certainly, autoimmune thyroiditis must be excluded when establishing a normal range of response of TSH to TRH in an Indian population.
pointed
Department of Endocrinology, Charing Cross Hospital, London W6 8RF
P. B. S. FOWLER P. DORRINGTON WARD P. HOOPER H. PARMAR
SIR,-Your Jan. 22 editorial pointed out the problems in interpreting serum T4 and free T4 index values in seriously ill patients. This is even more a problem in the elderly, in whom clinical features of hypothyroidism are so prevalent. In a recent survey we examined blood samples of 203 consecutive patients, aged 70 years or more, who had been referred for thyroid function tests because of clinical features of hypothyroidism. Serum thyroxine (T4) and thyrotropin (TSH) were measured on all samples. If T4 was low a free T4 index was calculated. 12 patients (5-9%) had definite hypothyroidism with low serum T4 and raised TSH levels. 19 patients (9 -3%) had low serum T4 and free T4 index but normal TSH values. Many of these were ill and on recovery serum T4 and free T4 index returned to normal. In patients with persistently low serum T4 and TSH levels a TRH test was done but found to be normal. We conclude that low serum T4 and free T4 index values are not uncommon in elderly patients. A diagnosis of hypothyroidism on the basis of these findings alone, even in patients with suggestive clinical features, will often be wrong. Department of Geriatric Medicine M. CROWE and Biochemistry, R. A. MOORE Radcliffe Infirmary, M. GALES Oxford OX2 6HE
SiR,—You suggest that a TRH test is the most valuable initial test a chronically sick patient with suspected thyroid disease and in geriatric patients. Basically, I agree. However, nobody would accept a blunted TSH response to TRH by itself as a reason for thyrostatic treatment, especially if concentrations of peripheral thyroid hormones are normal. There may be more explanations than Cushing’s syndrome or severe mental depression for a blunted TSH response in euthyroid patients. In an endemic goitre region such as ours a very important point is that patients with non-toxic (even small) nodular goitres do not respond normally to TRHand may even have no TSH response to TRH despite of apparently normal thyroid function. Moreover, non-thyroidal illness not only affects the concentrations of peripheral thyroid hormones but also in
1 Fowler
PBS, Swale J, Andrews H. Hypercholesterolaemia in borderline
hypothyroidism. Lancet 1970; ii· 488—91. Alaghband-Zadeh J, Carter GD, Daly JR, Fowler PBS, Greenwood TW. Association between exaggerated responsiveness to thyrotrophin-releasing hormone and hypercholesterolaemia. Lancet 1977; n: 998-1000. 3. Utiger RD. Tests ofthe hypothalamic-pituitary-thyroid axis. In: Werner S, Ingbar S, eds The thyroid: a fundamental and clinical text, 4th ed. New York: Harper & Row:
2
1978, 367-74.
blunts the TSH response to TRH. Patients with severe chronic renal insufficiency for example, exhibit no TSH reaction.’ An absent TSH response to TRH in a patient suspected of having hyperthyroidism does not, therefore, prove that clinically significant hyperthyroidism is present. Readers of your editorial might be tempted to accept a blunted TSH reaction as sufficient indication for treatment with thyrostatic drugs. In our experience there should be other indications, such as raised concentrations of free and/or total thyroid hormones or increased thyroid uptake or metabolic indices that support the diagnosis before treatment is started. However, in some chronically sick patients and in very old patients (where the TSH response is also blunted) the diagnosis of hyperthyroidism will still remain an enigma. 2nd
Department of Medicine, University of Vienna,
M. WEISSEL
A-1097 Vienna, Austria
ALDEHYDE DEHYDROGENASE AND ALCOHOLISM
SIR,-The letter by Dr Jenkins and colleagues (Dec. 4, p. 1275) in report of reduced cytosolic acetaldehyde dehydrogenase (AIdDH) activities in liver biopsy tissue from alcoholics contains several deficiencies. Furthermore their views 5 now seem to conflict with their previous suggestion. et al. used a novel method for Jenkins assaying AldDH6-namely, gas/liquid chromatographic assay of residual acetaldehyde after incubation with tissue extract. Enzyme assays in which a decrease of substrate is measured are liable to error. Acetaldehyde rapidly binds to, and forms adducts with, tissue constituents7and the method may in part be measuring tissue binding. Although Palmer and Jenkins claim that their assaycorrelates well with the standard spectrophotometric method it does give higher values, consistent response
to
our
with the suggestion that it also assays tissue binding. Alcoholics show a selective reduction in cytosolic enzyme activity, the principal site of acetaldehyde oxidation in man.8 Jenkins et al. seem to have assayed total hepatic activities, and their finding may relfect the mitochondrial damage of severe alcoholic liver disease. Jenkin et al. do not state the nature of the alcoholic liver disease of their patients. It is clearly important in sequential studies of this type only to investigate patients with hepatic hyperplasia or mild steatosis. Patients with alcoholic hepatitis and cirrhosis inevitably have more severe liver damage and it is therefore not possible in these cases to dissect out primary and secondary enzyme changes. More clinical details of their patients including details of liver function and any drugs, including disulfiram, taken by the patients are needed before their results can be fully interpreted. There is considerable interest in the possible role of acetaldehyde both in the underlying addiction and the pathogenesis of tissue damage in alcoholism. 9, 10 The finding of abnormal cytosolic isozymes of AldDH in alcoholics, alluded to by Jenkins and colleagues, is of considerable potential interest and further supports our suggestion that disorders of this enzyme play an important role in the pathogenesis and possibly the aetiology of alcoholism. M.R.C. Clinical Research Centre, Harrow, Middlesex HA 1 3UJ
T. J. PETERS
SIR,-It appears controversial that the lowered levels of liver
cytosolic aldehyde dehydrogenase (AldDH) observed in alcoholics by Professor Peters and co-workers (Nov. 13, p.1057) and by Dr 4. Weissel M, Stummvoll
5.
HK, Kolbe H, Höfer R. Basal and TRH-stimulated thyroid and pituitary hormones in various degrees of renal insufficiency. Acta Endocrinol (Kbh) 1979; 90: 23-32. Palmer KR, Jenkins WJ Impaired acetaldehyde oxidation in alcoholics Gut 1982: 23: 729-33.
KR, Jenkins WJ. An improved method for the determination of aldehyde dehydrogenase in human liver biopsies using gas chromatography. Clin Chim Acta
6. Palmer
1981; 115: 359-62. WJ, Stevens VJ, Peterson CM Reactions of biologic aldehydes with proteins. Diabetes 1982; 31(suppl 3) 15-21 8 Jenkins WJ, Peters TJ The subcellular localization of acetaldehyde dehydrogenases in 7 Fantl
human liver. Cell Biochem Fund
(in press)
Thomas M, Peters TJ. Acetaldehyde: its role in alcoholic toxicity and dependence Br J Addict 1981; 76: 375-8. 10. Enksson CJP. The role of acetaldehyde in drinking behaviour and tissue damage. Br J Alcohol Addict 1982, 17: 57-59. 9
Department of Medicine, Charing Cross Hospital Medical School, London W6 8RF
STEPHEN J. SMITH R. MARIE ROBERTS NIRMALA D. MARKANDU GRAHAM A. MACGREGOR
SIR,-Dr Henningsen and his colleagues are unduly optimistic in suggesting that a raised K+/Na+ ratio in the food would be beneficial "probably for overweight" as well as other conditions. They give reasons why abnormalities in the Na + - K pump might cause abnormally low energy requirements in obese people, and build their argument on this hypothesis. However, the energy requirements of groups of obese adults are on average higher than those of lean groups.I-4 Even the most enthusiastic supporters of the view that a defect in the thermogenic response to some stimulus contributes to the aetiology of obesity admit that their obese subjects had a higher daily energy expenditure than the lean controls.5 The hypothesis that an increase in K+/Na+ ratio in the food would cause a great increase in metabolic rate is one which would be easy to test by whole body calorimetry. If (surprisingly) this happened it might be a help to overweight people. However, no explanation (and treatment) is required for any postulated low energy requirements of obese adults: their energy output, and thus requirement for weight maintenance, is usually slightly higher than that of lean subjects of the same age, sex and height. Division of Clinical Sciences, Clinical Research Centre, Harrow, Middlesex HA1 3UJ
J. S. GARROW
METABOLIC CAUSES OF DEMENTIA
SIR,-I read with great interest the review the dementia syndrome
by Dr Small and Dr Jarvik (Dec. 25,
p. 1443). Dementia has also been described as a clinical manifestation in the genetically inherited sterol storage disease, cerebrotendinous xanthomatosis. The disease was first described in 19376and fifty-three cases have been reported. The disease is characterised by progressive neurological dysfunction (dementia, spinal cord paresis, and cerebellar ataxia), tendon xanthomas, cataracts, and premature atherosclerosis. Cholestanol (a saturated analogue of cholesterol) accumulates in almost every tissue, particularly in the nervous tissue and tendons. The plasma cholesterol is usually normal (117 to 220 mg/dl) while plasma cholestanol concentrations have ranged between 1 - 3 and 15 mg/dl (3 to 20 times the normal mean values).7 A deficiency ofa hepatic enzyme that catalyses the 24-hydroxylation of 5&bgr;-cholestan-3 a,7a,12a,25-tetrol, an intermediate in the bile acid synthetic pathway, has also been reported, which resulted in a marked decrease in chenodeoxycholic and cholic acid synthesis and excretion in bile.2 Salen and co-workers have treated patients with cerebrotendinous xanthomatosis with chenodeoxycholic acid, 1. Garrow
JS, Blaza SE, Warwick PM, Ashwell MA. Predisposition to obesity. Lancet 1980; i: 1103-04. 2. Blaza S, Garrow JS. Thermogenic response to temperature, exercise and food stimuli in lean and obese women, studied by 24-hour direct calorimetry. Br J Nutri (in press). 3 Jéquier E, Schutz Y. The contribution of BMR and physical activity to energy expenditure. In: Cioffi LA, James WPT, van Itallie TB, eds. The body weight regulatory system: Normal and disturbed mechanisms. New York: Raven Press, 1981: 89-96. E, Burnand B, Schutz Y, Jéquier E. Twenty-four-hour energy expenditure and resting metabolic rate in obese, moderately obese, and control subjects. Am J Clin Nutr 1982; 35: 566-573. 5 Shetty PS, Jung RT, James WPT, Barrand MA, Callingham BA Postprandial thermogenesis in obesity. Clin Sci 1981; 60: 519-25 6. van Bogaert L, Scherer HJ, Epstein E. Une forme cerebrale de la cholestérinose généralisée. Paris: Masson, 1973. 7 Sallen G, Shefer S, Bergmer VM. Familial diseases with storage of sterols other than cholesterol: Cerebrotendinous xanthomatosis and sitosterolemia with xanthomatosis. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS, eds. The metabolic basis of inherited disease. New York: McGraw-Hill, 1983: 713-30 4 Ravussin
acid synthesis and reduction resulting in inhibition of abnormal bile in plasma cholestanol concentration.22 Departments of Pathology and Physiology, Louisiana State University Medical Center, New Orleans, Louisiana, 70112, U.S.A.
ASHIM K. BHATTACHARYYA
INDICATIONS FOR THYROID FUNCTION SCREENING
SIR,-Editorials in The Lancet (Jan. 22) and the B.M.,’.1 have discussed two problems of using thyroid function tests to confirm or exclude thyroid disease-firstly, the exclusion of thyrotoxicosis in patients with atrial fibrillation and secondly, the interpretation of low free thyroxine (FT4) assay results in sick patients. To resolve these problems, a dynamic test of pituitary function, the thyrotropin releasing hormone (TRH) test, is recommended. Both editorials cite Forfar et al.2 who found that of 75 patients with atrial fibrillation 10 had impaired responses to TRH. 7 of these 10 had raised total thyroxine (TT4) and total triiodothyronine (TT3); 2 had a normal TT4, with raised TT3 in 1 case and a borderline TT3 in the other; only 1 had both TT4 and TT3 unequivocally in the normal range. Thus, the suggestion that thyrotoxicosis is underdiagnosed in atrial fibrillation depends upon a single case. Had a logical strategic approach been followed,3,4 involving FT4 or free thyroxine index (FTI) and TT3 corrected for thyroid hormone binding capacity variation,sall these cases except 1 would almost certainly have had laboratory evidence of thyrotoxicosis. In the context of the large numbers of thyroid function tests requested on patients with atrial fibrillation this strategic approach prevents overburdening the laboratory with TRH generated thyrotropin (TSH) requests. In the interpretation of low FT4 or FTI results in sick patients, the strategic approach4would require a TSH estimation, thus the distinction between non-thyroidal illness and primary hypothyroidism can usually be made on the initial sample. The TRH test is time consuming for all concerned, it is be difficult to sometimes unpleasant for the patient, and interpret in clinical practice(in elderly men, in patients on aspirin8 or steroid9 therapy, and in patients with diabetesl° or psychiatric illness, I for example), as your Jan. 22 editorial concedes. A thyroidal cause for a blunted TRH response not mentioned is, in our experience, prolonged pituitary suppression by a transient increase of thyroid hormones. Scientific and technical ingenuity have introduced direct free hormone measurements into clinical practice; FT4 has arrived and FT3 will follow. These tests are revealing new insights into thyroidal pathophysiology. Surely, the way forward is to welcome them so that patients may, wherever possible, have thyroid disease confirmed or excluded on single blood sample, and to keep the threshold for TRH testing high.
may
Departments of Nuclear Medicine and Chemical Pathology, Southampton General Hospital, Southampton SO9 4XY
R. MARDELL T. R. GAMLEN
1. Forfar
JC, Toft AD. Thyrotoxic atrial fibrillation: an underdiagnosed condition? Br Med J; 285: 909-10. 2. Forfar JC, Miller HC, Toft AD. Occult thyrotoxicosis: a correctable cause of "idiopathic" atrial fibrillation. Am J Cardiol 1979; 44: 9—12. 3. Britton KE, Quinn V, Brown BL, Ekins RP. A strategy for thyroid function tests. Br Med J 1975; iii: 350—52. 4. Mardell R. A strategy for in-vitro tests of thyroid function. Amersham: Radiochemical Centre, Amersham International, 1978. 5. Mardell R, Gerson M. A method of assessing serum triiodothyronine concentrations that is independent of subject’s age and variations in concentrations of binding proteins in serum. Clin Chem 1978; 24: 1792-96. 6. Hall R, Scanlon MF. Thyrotrophin-releasing hormone in clinical practice. J Clin Pathol 1976; 30: (Ass Clin Pathol suppl 7) 55-57. 7. Snyder PJ, Utiger RD. Response to thyrotrophin releasing hormone (TRH) in normal man. J Clin Endocrinol Metab 1972; 34: 380-85. 8. Dussault JH, Turcotte R, Guyda H. The effect of acetylsalicylic acid on TSH and PRL secretion after TRH stimulation in the human. J Clin Endocrinol Metab 1976; 43: 232-35. 9. Otsuki M, Dakoda M, Baba S. Influence of glucocorticoids on TRF induced TSH release in man. J Clin Endocrinol Metab 1973; 36: 95-102. 10. Naeije R, Golstein J, Clumeck N, Meinhold H, Wenzel KW, Vanhaelst L. A low T3 syndrome in diabetic ketoacidosis Clin Endocrinol 1978; 8: 467-72. 11. Spratt DI, Pont A, Miller MB, McDougall IR, Bayer MF, McLaughlin WT. Hyperthyroxinemia in patients with acute psychiatric disorders Am J Med 1982; 73: 41-48.
364
SlR,—You maintained (Jan. 22) that routine screening for thyroid disease is justified only in the elderly. This conclusion is based on a review of screening with serum thyroxine estimations. You rightly out that the best screening test for thyroid disease is the response of serum thyrotropin (TSH) to thryrotropin-releasing hormone (TRH). In borderline hypothyroidism, the cause of so much treatable morbidity, the problem is in deciding the normal range of response of TSH to TRH. 10% of one hospital population had thyroid antibodies,l and when we were selecting age and sex matched controls for a previous study, two out of twenty-two 2 subjects had to be rejected because they had thyroid antibodies.2 We have done TRH tests on nine Indian patients with buccal fibrosis. In selecting age and sex matched Indian controls, we have found one subject with unsuspected biochemical hypothyroidism and three with thyroid antibodies and an exaggerated response of TSH to TRH at 20 min (2 to 37,7 to 55, and 5 to 65 mU/1) out of the first fourteen persons screened. Certainly, autoimmune thyroiditis must be excluded when establishing a normal range of response of TSH to TRH in an Indian population.
pointed
Department of Endocrinology, Charing Cross Hospital, London W6 8RF
P. B. S. FOWLER P. DORRINGTON WARD P. HOOPER H. PARMAR
SIR,-Your Jan. 22 editorial pointed out the problems in interpreting serum T4 and free T4 index values in seriously ill patients. This is even more a problem in the elderly, in whom clinical features of hypothyroidism are so prevalent. In a recent survey we examined blood samples of 203 consecutive patients, aged 70 years or more, who had been referred for thyroid function tests because of clinical features of hypothyroidism. Serum thyroxine (T4) and thyrotropin (TSH) were measured on all samples. If T4 was low a free T4 index was calculated. 12 patients (5-9%) had definite hypothyroidism with low serum T4 and raised TSH levels. 19 patients (9 -3%) had low serum T4 and free T4 index but normal TSH values. Many of these were ill and on recovery serum T4 and free T4 index returned to normal. In patients with persistently low serum T4 and TSH levels a TRH test was done but found to be normal. We conclude that low serum T4 and free T4 index values are not uncommon in elderly patients. A diagnosis of hypothyroidism on the basis of these findings alone, even in patients with suggestive clinical features, will often be wrong. Department of Geriatric Medicine M. CROWE and Biochemistry, R. A. MOORE Radcliffe Infirmary, M. GALES Oxford OX2 6HE
SiR,—You suggest that a TRH test is the most valuable initial test a chronically sick patient with suspected thyroid disease and in geriatric patients. Basically, I agree. However, nobody would accept a blunted TSH response to TRH by itself as a reason for thyrostatic treatment, especially if concentrations of peripheral thyroid hormones are normal. There may be more explanations than Cushing’s syndrome or severe mental depression for a blunted TSH response in euthyroid patients. In an endemic goitre region such as ours a very important point is that patients with non-toxic (even small) nodular goitres do not respond normally to TRHand may even have no TSH response to TRH despite of apparently normal thyroid function. Moreover, non-thyroidal illness not only affects the concentrations of peripheral thyroid hormones but also in
1 Fowler
PBS, Swale J, Andrews H. Hypercholesterolaemia in borderline
hypothyroidism. Lancet 1970; ii· 488—91. Alaghband-Zadeh J, Carter GD, Daly JR, Fowler PBS, Greenwood TW. Association between exaggerated responsiveness to thyrotrophin-releasing hormone and hypercholesterolaemia. Lancet 1977; n: 998-1000. 3. Utiger RD. Tests ofthe hypothalamic-pituitary-thyroid axis. In: Werner S, Ingbar S, eds The thyroid: a fundamental and clinical text, 4th ed. New York: Harper & Row:
2
1978, 367-74.
blunts the TSH response to TRH. Patients with severe chronic renal insufficiency for example, exhibit no TSH reaction.’ An absent TSH response to TRH in a patient suspected of having hyperthyroidism does not, therefore, prove that clinically significant hyperthyroidism is present. Readers of your editorial might be tempted to accept a blunted TSH reaction as sufficient indication for treatment with thyrostatic drugs. In our experience there should be other indications, such as raised concentrations of free and/or total thyroid hormones or increased thyroid uptake or metabolic indices that support the diagnosis before treatment is started. However, in some chronically sick patients and in very old patients (where the TSH response is also blunted) the diagnosis of hyperthyroidism will still remain an enigma. 2nd
Department of Medicine, University of Vienna,
M. WEISSEL
A-1097 Vienna, Austria
ALDEHYDE DEHYDROGENASE AND ALCOHOLISM
SIR,-The letter by Dr Jenkins and colleagues (Dec. 4, p. 1275) in report of reduced cytosolic acetaldehyde dehydrogenase (AIdDH) activities in liver biopsy tissue from alcoholics contains several deficiencies. Furthermore their views 5 now seem to conflict with their previous suggestion. et al. used a novel method for Jenkins assaying AldDH6-namely, gas/liquid chromatographic assay of residual acetaldehyde after incubation with tissue extract. Enzyme assays in which a decrease of substrate is measured are liable to error. Acetaldehyde rapidly binds to, and forms adducts with, tissue constituents7and the method may in part be measuring tissue binding. Although Palmer and Jenkins claim that their assaycorrelates well with the standard spectrophotometric method it does give higher values, consistent response
to
our
with the suggestion that it also assays tissue binding. Alcoholics show a selective reduction in cytosolic enzyme activity, the principal site of acetaldehyde oxidation in man.8 Jenkins et al. seem to have assayed total hepatic activities, and their finding may relfect the mitochondrial damage of severe alcoholic liver disease. Jenkin et al. do not state the nature of the alcoholic liver disease of their patients. It is clearly important in sequential studies of this type only to investigate patients with hepatic hyperplasia or mild steatosis. Patients with alcoholic hepatitis and cirrhosis inevitably have more severe liver damage and it is therefore not possible in these cases to dissect out primary and secondary enzyme changes. More clinical details of their patients including details of liver function and any drugs, including disulfiram, taken by the patients are needed before their results can be fully interpreted. There is considerable interest in the possible role of acetaldehyde both in the underlying addiction and the pathogenesis of tissue damage in alcoholism. 9, 10 The finding of abnormal cytosolic isozymes of AldDH in alcoholics, alluded to by Jenkins and colleagues, is of considerable potential interest and further supports our suggestion that disorders of this enzyme play an important role in the pathogenesis and possibly the aetiology of alcoholism. M.R.C. Clinical Research Centre, Harrow, Middlesex HA 1 3UJ
T. J. PETERS
SIR,-It appears controversial that the lowered levels of liver
cytosolic aldehyde dehydrogenase (AldDH) observed in alcoholics by Professor Peters and co-workers (Nov. 13, p.1057) and by Dr 4. Weissel M, Stummvoll
5.
HK, Kolbe H, Höfer R. Basal and TRH-stimulated thyroid and pituitary hormones in various degrees of renal insufficiency. Acta Endocrinol (Kbh) 1979; 90: 23-32. Palmer KR, Jenkins WJ Impaired acetaldehyde oxidation in alcoholics Gut 1982: 23: 729-33.
KR, Jenkins WJ. An improved method for the determination of aldehyde dehydrogenase in human liver biopsies using gas chromatography. Clin Chim Acta
6. Palmer
1981; 115: 359-62. WJ, Stevens VJ, Peterson CM Reactions of biologic aldehydes with proteins. Diabetes 1982; 31(suppl 3) 15-21 8 Jenkins WJ, Peters TJ The subcellular localization of acetaldehyde dehydrogenases in 7 Fantl
human liver. Cell Biochem Fund
(in press)
Thomas M, Peters TJ. Acetaldehyde: its role in alcoholic toxicity and dependence Br J Addict 1981; 76: 375-8. 10. Enksson CJP. The role of acetaldehyde in drinking behaviour and tissue damage. Br J Alcohol Addict 1982, 17: 57-59. 9