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HYPERCHOLESTEROLÆMIA IN BORDERLINE HYPOTHYROIDISM STAGE OF PREMYXŒDEMA
488
HYPERCHOLESTEROLÆMIA IN BORDERLINE HYPOTHYROIDISM STAGE OF PREMYXŒDEMA
P. B. S. FOWLER J. SWALE HILARY ANDREWS
Charing Cross Hospital, London W.C.2
Hypercholesterolæmia precedes all evidence of thyroid failure in patients with autoimmune thyroiditis. This stage of autoimmune thyroiditis has been called premyxœdema. Fifty euthyroid patients are described in whom hypercholesSum ary
terolæmia
was
considered
to
be due
thyroiditis. Coronary-artery disease these patients and their relatives.
to
autoimmune in
was common
Introduction
THYROID antibodies are often the sole finding in autoimmune thyroiditis. These -antibodies may be present in hyperthyroidism, but it is more usual for autoimmune thyroiditis at first to be associated with normal thyroid function. This euthyroid stage of latent hypothyroidism may persist or develop into myxoedema. Fowler and Swale1 described a family in which hypercholesterolaemia preceded by many years all evidence of hypothyroidism. This stage of autoimmune thyroiditis, characterised by hypercholesterolaemia alone, has been called " premyxoedema ". We report here premyxoedema in fifty more patients. Thyroid antibodies may be detected in about 10% of the population. The presence of thyroid antibodies in apparently healthy people has been correlated with changes in the thyroid gland.2 The pathological condition can be described as asymptomatic, focal, atrophic thyroiditis, and corresponds to the clinical state of latent hypothyroidism. Autoimmune thyroiditis embraces focal thyroiditis, diffuse thyroiditis, and Hashimoto’s disease. The difference between focal and diffuse thyroiditis is a matter of degree which may dictate whether myxoedema develops or no. Diffuse atrophic thyroiditis and Hashimoto’s disease differ mainly in the degree of DR. NORRIS AND OTHERS: REFERENCES
Billings, F. T., Jr., Kalstone, B. M., Spencer, J. L., Ball, C. O. T., Meneeley, G. R. Am. J. Med. 1949, 7, 356. 2. Doscher, N., Poindexter, C. A. ibid. 1950, 8, 623. 3. Beard, O. W., Hipp, H. R., Robins, M., Taylor, J. S., Ebert, R. V., Beran, L. G. ibid. 1960, 28, 871. 4. Restieaux, N., Bray, C., Bullard, H., Murray, M., Robinson, J., Brigden, W., McDonald, L. Lancet, 1967, i, 1285. 5. Sloman, G., Stannard, M., Goble, A. J. Am. Heart J. 1968, 75, 1.
140.
6. Norris, R. M., Brandt, P. W. T., Lee, A. J. Lancet, 1969, i, 278. 7. Norris, R. M., Brandt, P. W. T., Caughey, D. E., Lee, A. J., Scott, P. J. ibid. p. 274. 8. Kendall, M., Stuart, A. The Advanced Theory of Statistics; vol. III, p. 317. London, 1966. 9. Honey, G. E., Truelove, S. C. Lancet, 1957, i, 1155. 10. Rosenberg, B. A., Malack, M. Am. J. Cardiol. 1961, 8, 799. 11. Cole, D. R., Singian, E. B., Katz, L. N. Circulation, 1954, 9, 321. 12. Pell, S., D’Alonzo, C. A. New Engl. J. Med. 1964, 270, 915. 13. Bjorck, G., Sievers, J., Blomquist, G. Acta. med. scand. 1958,
162, 81. 14. Second Report of the
Working Party on Anticoagulant Therapy in Coronary Thrombosis to the Medical Research Council. Br. med. J. 1964, ii, 837. 15. Leven, P. Acta med. scand. 1966, suppl. no. 466. 16. Report of a Research Committee to the Medical Research Council. Lancet, 1968, ii, 693. 17. Favaloro, R. G. J. thorac. cardiovasc. Surg. 1969, 58, 178.
lymphocytic infiltration, but in both conditions functional impairment eventually develops. The functional stages through which autoimmune thyroiditis may pass can be summarised as follows: (1) a thyrotoxic person or a healthy individual enters a state of latent hypothyroidism in which tests of thyroid function are all normal 3; (2) this latent state proceeds to premyxoedema, in which hypercholesterolaemia is the only abnormality 1; (3) eventually, a state of myxcedema may be reached, and here thyroid function is impaired. Serum-cholesterol may increase before the thyroid fails for reasons other than autoimmune thyroiditis (e.g., gradual obliteration of the gland by irradiation). Although we show here that the serum-cholesterol may rise years before hypothyroidism develops, hypercholesterolsemia is a poor index of hypothyroidism. It is found in other disorders such as nephrosis, obstructive jaundice, diabetes mellitus, and, more important, as an idiopathic familial disorder with or without xanthomatosis. The serum-cholesterol may be lowered by anxmia,4 inanition,5and inflammation.6 Thus, there is a fall after a myocardial infarction with a rise to the preinfarction levels that corresponds to the return of the erythrocyte-sedimentation rate to normal.’7 Thirdly, the serum-cholesterol varies unpredictably in some patients depending to some extent on the method of estimation. Although these are three valid reasons for mistrusting the serum-cholesterol as a diagnostic test of hypothyroidism, we have found that a rising serum-cholesterol is often the first evidence that autoimmune thyroiditis is passing from the latent stage towards hypothyroidism. When other tests of thyroid function are normal, this hypercholesterolaemia may be thought to be unrelated to thyroid disease. We describe here fifty patients, euthyroid by objective tests, who had hypercholesterolaemia related to thyroid disease. Patients and Methods Examples of premyxoedema had been found in one family, but was this family unique ? To answer this question, we investigated patients attending one of us (P. B. S. F.). Tests for thyroid antibodies were done on patients with ischasmic heart-disease associated with hypercholesterolaemia. Other patients who were screened included those with goitres, past or family history of thyroid disease and those with other specific autoimmune diseases such as pernicious anxmia. This group of fifty patients, although they were followed up for longer periods, were mostly collected in one year.
A serum-cholesterol of 300 mg. per 100 ml. or more was accepted as hypercholesterolaemia. Patients were investigated if, besides hypercholesterolasmia, thyroid antibodies were present (or the thyroid had been ablated) at a time when the patient was clinically and objectively euthyroid. Tests for thyroid antibodies were often negative after thyroid ablation even when there was histological proof of autoimmune thyroiditis. Since the association of antibodies with hypercholesterolaemia could be fortuitous, other signs of thyroid disease such as the eventual development of overt hypothyroidism or evidence of diminished thyroid reserve by stimulation with thyrotrophin (T.S.H.) were looked for. Methods
Although patients were euthyroid at first, a number later developed definite hypothyroidism when signs rather than symptoms were significant. Symptoms developed so
489
insidiously that it was only their disappearance on treatment that made the patient aware of their previous presence. Objective tests of thyroid function were done on all
patients. The duration of the ankle reflex was measured with an electromagnetic device or, later, by a photoelectric method.8 It was the best single measurement of thyroid function. Fogel et al. give the normal range by this method as 230400 milliseconds from the blow to half-relaxation. We find that recordings in most normal persons fall between 240 and 320 milliseconds. Some patients with premyxoedema developing hypothyroidism were found with consistent recordings around 360 milliseconds before there was other evidence of thyroid failure. Protein-bound iodine (P.B.I.) and serum-cholesterol estimations were done in parallel. Cholesterol estimations were repeated after a period on L-thyroxine. Hobbs et al. accord significance to a cholesTABLE I-SERUM-P.B.I.
AND/OR
NORMAL
3-DAY 131r
UPTAKE
terol fall of 60 mg. per 100 ml. on oral L-thyroxine as an objective test of thyroid function. Radioactive-iodine-uptake studies were done in many patients, and correlated well with the P.B.I. estimation and ankle-reflex recordings. Early on, we did a T.s.H.-stimulation test using 10 I.U. of T.S.H. daily for 3 successive days. This test was helpful only in confirming that an athyreotic patient had no thyroid reserve at all or that the condition of the thyroid was primary and not secondary to pituitary insufficiency. The test is superstimulatory and not without danger, and we have known it to cause decubital angina and to precipitate heart-failure and adrenal insufficiency. A discriminatory test is needed for patients with premyxoedema to demonstrate a diminished thyroid reserve. The 4-hour uptake of iodine-132 before and 22 hours after stimulation with 2-5 l.U. of T.S.H.9 was helpful in demonstrating a diminished thyroid reserve in patients who
(N.I.U.),
CHOLESTEROL
VALUES,
PRESENTATION AND COMMENTS IN
FIFTY PATIENTS WITH PREMYXOIDEMA
t With thyroid disease. T4=On L-thyroxine, dose in mg. A.J.T.=Ankle-jerk test in milliseconds. Cholesterol= Serum-cholesterol in mg. per 100 ml. P.B.I. = Serum-protein-bound-iodine in µg. per 100 ml. Hobbs= Hobbs-test results shown as % uptake, at 4 hours, of iodine-132 before and after T.s.H.
*Follow-up.
490
euthyroid by other objective tests. In this " Hobbs test ", the figures refer to the percentage uptake at 4 hours
were
of
a dose of iodine-132 before and after T.s.H. We accept " normal " if, after stimulation, more than response as 35% of the dose is taken up at 4 hours; "no thyroid reserve " if only 3% or less of the dose is taken up after T.S.H. ; and " diminished reserve ", as between normal and no thyroid reserve (i.e., 3-35% of the dose taken up after
a
T.S.H.). Basal metabolic rates and thyroid biopsies were rarely done. The P.B.I. was estimated using a Technicon’AutoAnalyzer’. 3-8 µg. per 100 ml. serum is the lower limit of normal for our laboratory. The cholesterol was estimated by the method of Abell et a1.10 Antibodies to thyroglobulin were estimated by the tanned red-blood-cell technique using Wellcome thyroglobulin-sensitised sheep cells as described,’.’ modified for the microtitre apparatus. Serum diluted 1/10 was screened by the immunofluorescent technique for antibodies to thyroid epithelial-cell cytoplasm,12 except that tissues were frozen and stored in liquid nitrogen
(-196°C). Fifty patients in the surgical wards were paired with the premyxmdematous patients for sex and age. They all seemed to be euthyroid and had no past or family history of thyroid disease and no history of coronary-artery disease (C.A.D.). The same technique in the controls and the patients with premyxcedema were used for the P.B.I., cholesterol, and thyroid antibodies. Results
There were sixteen men and thirty-four women in the premyxcedema group (average age 51, range 24-72). Cholesterol and P.B.I.
Table i shows simultaneous cholesterol and P.B.I. levels in the fifty patients. There were no patients with a serum-p.B.I. of less than 40 µg. per 100 ml. There was no correlation between the serum-cholesterol and P.B.I. levels, but the serum-cholesterol rose further as the P.B.I. fell in those patients with autoimmune thyroiditis who became hypothyroid. The serum-cholesterol levels in these patients fell dramatically with L-thyroxine. For example, case 8 had a serum-cholesterol of 430 mg. per 100 ml. when her iodine-131 uptake was normal in 1961. She was investigated at this time because of a strong family history of autoimmune thyroiditis. Her serum-cholesterol was 570 mg. per 100 ml. in 1965 when she had definite hypothyroidism and the level fell to 260 mg. per 100 ml. on replacement therapy. The serum-cholesterol of case 24 was 446 mg. per 100 ml. at the stage of premyxoedema and fell to 195 mg. per 100 ml. on L-thyroxine 0-2 mg. daily, while the level of case 9 fell from 500 mg. per 100 ml. at the stage of premyxcedema to 250 mg. per 100 ml. on 0-3 mg. Thyroid Antibodies
L-thyroxine
daily.
Forty-four out of the fifty patients with premyxoedema had thyroid antibodies. The thyroid had been ablated in all six of the fifty with premyxcedema who had no thyroid antibodies. Two had thyroidectomy, three had therapeutic iodine-131, one had both forms of treatment. There were no thyroid antibodies in case 13 after thyroid ablation although the gland showed the changes of thyroiditis. Thyroid antibodies have waned in the sisters of cases 8 and 20 as they developed myxcedema, in contrast to the large amount found in a nephew and
niece with latent hypothyroidism. (Removal of the antigenic stimulus of the thyroid gland accounts for the frequent disappearance of antibodies in patients with gross myxoedema and in those who have had
thyroid ablation.) Controls Four (8%) of the controls had a serum-cholesterol above 300 mg. per 100 ml. and five (10%) had thyroid antibodies. All five controls with thyroid antibodies
Three of the five merely had low titres to antibodies of thyroglobulin. Only two (4%) had antibodies and one of these patients died microsomal after mitral-valve soon replacement. Necropsy revealed a severe atrophic thyroiditis despite the absence of signs or symptoms during life.
were women.
Other Evidence of
Thyroid Disease
Evidence of thyroid disease other than the presence of thyroid antibodies was sought in these patients.
Twenty-two (group A) (44%) progressed to hypothyroidism ; twenty-one (group B) (42%) had a diminished thyroid reserve, notable fall of cholesterol on thyroxine therapy, or an ankle reflex recording of 360 milliseconds; and seven (group C) (14%), excluding the above, had a history of thyroid disease. Group D (extra to the fifty patients described in this paper) constituted those who had no definite evidence of thyroid disease other than the presence of thyroid antibodies and hypercholesterolaemia. There were many in group D in whom the association of
thyroid antibodies to hypercholesterolsemia could be fortuitous. For example, a man with Addison’s disease had thyroid antibodies present in high titre; serum365 mg. per 100 ml. It was not felt justifiable to do a " Hobbs test " to demonstrate a diminished thyroid reserve in case it precipitated
cholesterol
was
adrenal insufficiency. Presentation
The fifty patients presented in the following ways: with thyroid disease when first seen (thirty), screening (nine), coronary-artery disease (ten), and hypertension
(one). Complications
Twenty-six (52%) of the fifty patients had degenerative arterial disease. This was due in part to selection since ten presented with C.A.D. and one with hypertension. Excluding the ten patients who presented with C.A.D., sixteen (40%) out of forty had degenerative arterial disease. Family History The familial tendency in autoimmune thyroiditis is well shown in cases 8, 20, and 30, three of eight sisters all with autoimmune thyroiditis. There was a striking tendency to c.A.D. in some families. This is best shown in the family tree of case 37 (table II). Carbimazole-induced Temporary
Premyxœdema Temporary premyxoedema characterised by hypercholesterolaemia in a euthyroid patient can be induced with antithyroid drugs. One woman (not in this series) presented with thyrotoxicosis in April, 1968. At this time the P.B.I. was 13-1 µg. per 100 ml. and the serum-cholesterol was 227 mg. per 100 ml. In July, 1969, on a maintenance dose of carbimazole 7-5 mg. daily, she was clinically euthyroid. The P.B.I. was normal at 4-4 µg. per 100
491 TABLE II--CAUSE OF DEATH
(OR
PRESENT CASE 37
HEALTH)
IN FAMILY OF
Morris et al.15 pointed out that C.A.D. is not found in communities with a serum-cholesterol under 180 mg. per 100 ml. In affluent societies with a serumcholesterol varying between 200 and 300 mg. per 100 ml. the incidence of C.A.D. is high. Furthermore, the incidence is directly proportional to the cholesterol level. There is the enigma that in a society with all at risk some are singled out to have higher cholesterol levels with an increased risk of C.A.D. Since thyroid antibodies are present in 10% of the population in affluent countries, further study is needed to assess the importance of the hypercholesterolaemia of premyxoedema as a cause of C.A.D. Fluorescein-conjugated anti-human IgG was kindly supplied by Dr. T. T. B. Phillips of the Lister Institute. We are grateful for the technical assistance given by Miss E. Ferguson, Miss R. Hurter, Miss P. Thome, and the department of radiotherapy. Requests for reprints should be addressed to P. B. S. F. REFERENCES
Fowler, P. B. S., Swale, J. Lancet, 1967, i, 1077. Goudie, R. B., Anderson, J. R., Gray, K. G. J. Path. Bact. 1959, 77, 389. 3. Bastenie, P. A., Neve, P., Bonnyns, M., Vanhaelst, L., Chailly, M. Lancet, 1967, i, 915. 4. Rifkind, B. M., Gale, M. ibid. 1967, ii, 640. 5. Adlersberg, D., Sobotka, H. in Cholesterol (edited by R. P. Cook); p. 397. New York, 1958. 6. London, M. G., Muirden, K. D., Hewitt, J. V. Br. med. J. 1963, i, 1. 2.
ml. with Another
a
serum-cholesterol of 375 mg. per 100 ml.
woman
previously thyrotoxic
was
clinically
carbimazole 10 mg. b.d. Her P.B.1. was 3-8 µg, per 100 ml. and the duration of her ankle reflex to half relaxation was within the normal range at the time when her serum-cholesterol was 400 mg. per 100 ml. The corollary of drug-induced premyxcedema is the hypercholesterolaemia of inadequately treated myxcedema. The serum-cholesterol was often high when less than 0-3 mg. of L-thyroxine as a replacement dose for myxcedema kept the patient symptom-free.
euthyroid
on
Discussion
If autoimmune thyroiditis is not associated with a goitre, the latent stage is asymptomatic and only likely to manifest itself when degenerative arterial disease related to the hypercholesterolsemia produces symp-
Patients with Hashimoto’s disease are treated with L-thyroxine both because these patients are known to develop hypothyroidism and because L-thyroxine makes the gland smaller. C.A.D. in these patients, when untreated, and the effect of L-thyroxine in correcting the hypercholesterolæmia suggests that prevention of C.A.D. is another important reason for giving these
1380.
7. Watson, W. C., Buchanan, K. D., Dickson, C. ibid. 1963, ii, 709. 8. Fogel, R. L., Epstein, J. A., Stopak, J. H., Kupperman, H. S. N.Y. State J. Med. 1962, 62, 1159. 9. Hobbs, J. R., Bayliss, R. I. S., Maclagan, N. F. Lancet, 1963, i, 8. 10. Abell, L. L., Levy, B. B., Brodie, B. B., Kendall, F. E. J. biol. Chem. 1952, 195, 357. 11. Fulthorpe, A. J., Roitt, I. M., Doniach, D., Couchman, K. J. clin. Path. 1961, 14, 654. 12. Balfour, B. M., Doniach, D., Roitt, I. M., Couchman, K. G. Br. J. exp. Path. 1961, 42, 307. 13. Bastenie, P. A., Vanhaelst, L., Neve, P. Lancet, 1967, ii, 1221. 14. Fowler, P. B. S. Br. med. J. 1968, iv, 56. 15. Morris, J. N., Marr. J. W., Heady, J. A., Mills, G. L., Pilkington, T. R. E. ibid. 1963, i, 571.
IRON THERAPY IN PATIENTS ON MAINTENANCE HÆMODIALYSIS
toms.
patients L-thyroxine. While many have doubted the relationship of c.A.D. there is an association between degenerative arterial disease and autoimmune thyroiditis. Basteriie et al.13 found a significant association between thyroid antibodies and the occurrence of obesity, hypertension, diabetes mellitus, and C.A.D. A significantly higher proportion of patients with C.A.D. not associated with obesity, hypertension, and diabetes had thyroid antibodies as compared with a normal population. Patients with focal rather than diffuse thyroiditis may have hypercholesterolæmia and never develop hypothyroidism. These persons may be more prone to C.A.D. than those with diffuse thyroiditis who comparatively rapidly develop myxcedema and are treated. In fact, low-titre antibodies with minimal thyroiditis causing a modest hypercholesterolæmia lasting for many years may be most significant to the development of C.A.D.14
to myxcedema,
G. D. PEGRUM MARIAN S. EDWARDS R. CURTIS J.
Hœmatology Department, Fulham Hospital, London W.6 The stainable bone-marrow iron has been studied in twenty-four patients with chronic renal failure on maintenance dialysis. Dialysis contributes to iron depletion in these patients and unless receiving more than 10 units of transfused blood per year, iron supplements are required. A recommended parenteral dose of 2 g. per year has been calculated and proves to have been of benefit in these patients. It is also advisable to monitor the iron status by periodic observation of the bone-marrow stores.
Sum ary
Introduction
IRON deficiency is not a primary feature of the anaemia of renal failure, although there may be associated haemorrhagic manifestations such as menorrhagia, hxmaturia, purpura, and gastrointestinal bleeding leading to iron depletion. With increasing use of hasmodialysis another cause for blood-loss has been introduced-namely, loss into the kidney machine and as a result of blood-sampling for analysis.
HYPERCHOLESTEROLÆMIA IN BORDERLINE HYPOTHYROIDISM STAGE OF PREMYXŒDEMA
P. B. S. FOWLER J. SWALE HILARY ANDREWS
Charing Cross Hospital, London W.C.2
Hypercholesterolæmia precedes all evidence of thyroid failure in patients with autoimmune thyroiditis. This stage of autoimmune thyroiditis has been called premyxœdema. Fifty euthyroid patients are described in whom hypercholesSum ary
terolæmia
was
considered
to
be due
thyroiditis. Coronary-artery disease these patients and their relatives.
to
autoimmune in
was common
Introduction
THYROID antibodies are often the sole finding in autoimmune thyroiditis. These -antibodies may be present in hyperthyroidism, but it is more usual for autoimmune thyroiditis at first to be associated with normal thyroid function. This euthyroid stage of latent hypothyroidism may persist or develop into myxoedema. Fowler and Swale1 described a family in which hypercholesterolaemia preceded by many years all evidence of hypothyroidism. This stage of autoimmune thyroiditis, characterised by hypercholesterolaemia alone, has been called " premyxoedema ". We report here premyxoedema in fifty more patients. Thyroid antibodies may be detected in about 10% of the population. The presence of thyroid antibodies in apparently healthy people has been correlated with changes in the thyroid gland.2 The pathological condition can be described as asymptomatic, focal, atrophic thyroiditis, and corresponds to the clinical state of latent hypothyroidism. Autoimmune thyroiditis embraces focal thyroiditis, diffuse thyroiditis, and Hashimoto’s disease. The difference between focal and diffuse thyroiditis is a matter of degree which may dictate whether myxoedema develops or no. Diffuse atrophic thyroiditis and Hashimoto’s disease differ mainly in the degree of DR. NORRIS AND OTHERS: REFERENCES
Billings, F. T., Jr., Kalstone, B. M., Spencer, J. L., Ball, C. O. T., Meneeley, G. R. Am. J. Med. 1949, 7, 356. 2. Doscher, N., Poindexter, C. A. ibid. 1950, 8, 623. 3. Beard, O. W., Hipp, H. R., Robins, M., Taylor, J. S., Ebert, R. V., Beran, L. G. ibid. 1960, 28, 871. 4. Restieaux, N., Bray, C., Bullard, H., Murray, M., Robinson, J., Brigden, W., McDonald, L. Lancet, 1967, i, 1285. 5. Sloman, G., Stannard, M., Goble, A. J. Am. Heart J. 1968, 75, 1.
140.
6. Norris, R. M., Brandt, P. W. T., Lee, A. J. Lancet, 1969, i, 278. 7. Norris, R. M., Brandt, P. W. T., Caughey, D. E., Lee, A. J., Scott, P. J. ibid. p. 274. 8. Kendall, M., Stuart, A. The Advanced Theory of Statistics; vol. III, p. 317. London, 1966. 9. Honey, G. E., Truelove, S. C. Lancet, 1957, i, 1155. 10. Rosenberg, B. A., Malack, M. Am. J. Cardiol. 1961, 8, 799. 11. Cole, D. R., Singian, E. B., Katz, L. N. Circulation, 1954, 9, 321. 12. Pell, S., D’Alonzo, C. A. New Engl. J. Med. 1964, 270, 915. 13. Bjorck, G., Sievers, J., Blomquist, G. Acta. med. scand. 1958,
162, 81. 14. Second Report of the
Working Party on Anticoagulant Therapy in Coronary Thrombosis to the Medical Research Council. Br. med. J. 1964, ii, 837. 15. Leven, P. Acta med. scand. 1966, suppl. no. 466. 16. Report of a Research Committee to the Medical Research Council. Lancet, 1968, ii, 693. 17. Favaloro, R. G. J. thorac. cardiovasc. Surg. 1969, 58, 178.
lymphocytic infiltration, but in both conditions functional impairment eventually develops. The functional stages through which autoimmune thyroiditis may pass can be summarised as follows: (1) a thyrotoxic person or a healthy individual enters a state of latent hypothyroidism in which tests of thyroid function are all normal 3; (2) this latent state proceeds to premyxoedema, in which hypercholesterolaemia is the only abnormality 1; (3) eventually, a state of myxcedema may be reached, and here thyroid function is impaired. Serum-cholesterol may increase before the thyroid fails for reasons other than autoimmune thyroiditis (e.g., gradual obliteration of the gland by irradiation). Although we show here that the serum-cholesterol may rise years before hypothyroidism develops, hypercholesterolsemia is a poor index of hypothyroidism. It is found in other disorders such as nephrosis, obstructive jaundice, diabetes mellitus, and, more important, as an idiopathic familial disorder with or without xanthomatosis. The serum-cholesterol may be lowered by anxmia,4 inanition,5and inflammation.6 Thus, there is a fall after a myocardial infarction with a rise to the preinfarction levels that corresponds to the return of the erythrocyte-sedimentation rate to normal.’7 Thirdly, the serum-cholesterol varies unpredictably in some patients depending to some extent on the method of estimation. Although these are three valid reasons for mistrusting the serum-cholesterol as a diagnostic test of hypothyroidism, we have found that a rising serum-cholesterol is often the first evidence that autoimmune thyroiditis is passing from the latent stage towards hypothyroidism. When other tests of thyroid function are normal, this hypercholesterolaemia may be thought to be unrelated to thyroid disease. We describe here fifty patients, euthyroid by objective tests, who had hypercholesterolaemia related to thyroid disease. Patients and Methods Examples of premyxoedema had been found in one family, but was this family unique ? To answer this question, we investigated patients attending one of us (P. B. S. F.). Tests for thyroid antibodies were done on patients with ischasmic heart-disease associated with hypercholesterolaemia. Other patients who were screened included those with goitres, past or family history of thyroid disease and those with other specific autoimmune diseases such as pernicious anxmia. This group of fifty patients, although they were followed up for longer periods, were mostly collected in one year.
A serum-cholesterol of 300 mg. per 100 ml. or more was accepted as hypercholesterolaemia. Patients were investigated if, besides hypercholesterolasmia, thyroid antibodies were present (or the thyroid had been ablated) at a time when the patient was clinically and objectively euthyroid. Tests for thyroid antibodies were often negative after thyroid ablation even when there was histological proof of autoimmune thyroiditis. Since the association of antibodies with hypercholesterolaemia could be fortuitous, other signs of thyroid disease such as the eventual development of overt hypothyroidism or evidence of diminished thyroid reserve by stimulation with thyrotrophin (T.S.H.) were looked for. Methods
Although patients were euthyroid at first, a number later developed definite hypothyroidism when signs rather than symptoms were significant. Symptoms developed so
489
insidiously that it was only their disappearance on treatment that made the patient aware of their previous presence. Objective tests of thyroid function were done on all
patients. The duration of the ankle reflex was measured with an electromagnetic device or, later, by a photoelectric method.8 It was the best single measurement of thyroid function. Fogel et al. give the normal range by this method as 230400 milliseconds from the blow to half-relaxation. We find that recordings in most normal persons fall between 240 and 320 milliseconds. Some patients with premyxoedema developing hypothyroidism were found with consistent recordings around 360 milliseconds before there was other evidence of thyroid failure. Protein-bound iodine (P.B.I.) and serum-cholesterol estimations were done in parallel. Cholesterol estimations were repeated after a period on L-thyroxine. Hobbs et al. accord significance to a cholesTABLE I-SERUM-P.B.I.
AND/OR
NORMAL
3-DAY 131r
UPTAKE
terol fall of 60 mg. per 100 ml. on oral L-thyroxine as an objective test of thyroid function. Radioactive-iodine-uptake studies were done in many patients, and correlated well with the P.B.I. estimation and ankle-reflex recordings. Early on, we did a T.s.H.-stimulation test using 10 I.U. of T.S.H. daily for 3 successive days. This test was helpful only in confirming that an athyreotic patient had no thyroid reserve at all or that the condition of the thyroid was primary and not secondary to pituitary insufficiency. The test is superstimulatory and not without danger, and we have known it to cause decubital angina and to precipitate heart-failure and adrenal insufficiency. A discriminatory test is needed for patients with premyxoedema to demonstrate a diminished thyroid reserve. The 4-hour uptake of iodine-132 before and 22 hours after stimulation with 2-5 l.U. of T.S.H.9 was helpful in demonstrating a diminished thyroid reserve in patients who
(N.I.U.),
CHOLESTEROL
VALUES,
PRESENTATION AND COMMENTS IN
FIFTY PATIENTS WITH PREMYXOIDEMA
t With thyroid disease. T4=On L-thyroxine, dose in mg. A.J.T.=Ankle-jerk test in milliseconds. Cholesterol= Serum-cholesterol in mg. per 100 ml. P.B.I. = Serum-protein-bound-iodine in µg. per 100 ml. Hobbs= Hobbs-test results shown as % uptake, at 4 hours, of iodine-132 before and after T.s.H.
*Follow-up.
490
euthyroid by other objective tests. In this " Hobbs test ", the figures refer to the percentage uptake at 4 hours
were
of
a dose of iodine-132 before and after T.s.H. We accept " normal " if, after stimulation, more than response as 35% of the dose is taken up at 4 hours; "no thyroid reserve " if only 3% or less of the dose is taken up after T.S.H. ; and " diminished reserve ", as between normal and no thyroid reserve (i.e., 3-35% of the dose taken up after
a
T.S.H.). Basal metabolic rates and thyroid biopsies were rarely done. The P.B.I. was estimated using a Technicon’AutoAnalyzer’. 3-8 µg. per 100 ml. serum is the lower limit of normal for our laboratory. The cholesterol was estimated by the method of Abell et a1.10 Antibodies to thyroglobulin were estimated by the tanned red-blood-cell technique using Wellcome thyroglobulin-sensitised sheep cells as described,’.’ modified for the microtitre apparatus. Serum diluted 1/10 was screened by the immunofluorescent technique for antibodies to thyroid epithelial-cell cytoplasm,12 except that tissues were frozen and stored in liquid nitrogen
(-196°C). Fifty patients in the surgical wards were paired with the premyxmdematous patients for sex and age. They all seemed to be euthyroid and had no past or family history of thyroid disease and no history of coronary-artery disease (C.A.D.). The same technique in the controls and the patients with premyxcedema were used for the P.B.I., cholesterol, and thyroid antibodies. Results
There were sixteen men and thirty-four women in the premyxcedema group (average age 51, range 24-72). Cholesterol and P.B.I.
Table i shows simultaneous cholesterol and P.B.I. levels in the fifty patients. There were no patients with a serum-p.B.I. of less than 40 µg. per 100 ml. There was no correlation between the serum-cholesterol and P.B.I. levels, but the serum-cholesterol rose further as the P.B.I. fell in those patients with autoimmune thyroiditis who became hypothyroid. The serum-cholesterol levels in these patients fell dramatically with L-thyroxine. For example, case 8 had a serum-cholesterol of 430 mg. per 100 ml. when her iodine-131 uptake was normal in 1961. She was investigated at this time because of a strong family history of autoimmune thyroiditis. Her serum-cholesterol was 570 mg. per 100 ml. in 1965 when she had definite hypothyroidism and the level fell to 260 mg. per 100 ml. on replacement therapy. The serum-cholesterol of case 24 was 446 mg. per 100 ml. at the stage of premyxoedema and fell to 195 mg. per 100 ml. on L-thyroxine 0-2 mg. daily, while the level of case 9 fell from 500 mg. per 100 ml. at the stage of premyxcedema to 250 mg. per 100 ml. on 0-3 mg. Thyroid Antibodies
L-thyroxine
daily.
Forty-four out of the fifty patients with premyxoedema had thyroid antibodies. The thyroid had been ablated in all six of the fifty with premyxcedema who had no thyroid antibodies. Two had thyroidectomy, three had therapeutic iodine-131, one had both forms of treatment. There were no thyroid antibodies in case 13 after thyroid ablation although the gland showed the changes of thyroiditis. Thyroid antibodies have waned in the sisters of cases 8 and 20 as they developed myxcedema, in contrast to the large amount found in a nephew and
niece with latent hypothyroidism. (Removal of the antigenic stimulus of the thyroid gland accounts for the frequent disappearance of antibodies in patients with gross myxoedema and in those who have had
thyroid ablation.) Controls Four (8%) of the controls had a serum-cholesterol above 300 mg. per 100 ml. and five (10%) had thyroid antibodies. All five controls with thyroid antibodies
Three of the five merely had low titres to antibodies of thyroglobulin. Only two (4%) had antibodies and one of these patients died microsomal after mitral-valve soon replacement. Necropsy revealed a severe atrophic thyroiditis despite the absence of signs or symptoms during life.
were women.
Other Evidence of
Thyroid Disease
Evidence of thyroid disease other than the presence of thyroid antibodies was sought in these patients.
Twenty-two (group A) (44%) progressed to hypothyroidism ; twenty-one (group B) (42%) had a diminished thyroid reserve, notable fall of cholesterol on thyroxine therapy, or an ankle reflex recording of 360 milliseconds; and seven (group C) (14%), excluding the above, had a history of thyroid disease. Group D (extra to the fifty patients described in this paper) constituted those who had no definite evidence of thyroid disease other than the presence of thyroid antibodies and hypercholesterolaemia. There were many in group D in whom the association of
thyroid antibodies to hypercholesterolsemia could be fortuitous. For example, a man with Addison’s disease had thyroid antibodies present in high titre; serum365 mg. per 100 ml. It was not felt justifiable to do a " Hobbs test " to demonstrate a diminished thyroid reserve in case it precipitated
cholesterol
was
adrenal insufficiency. Presentation
The fifty patients presented in the following ways: with thyroid disease when first seen (thirty), screening (nine), coronary-artery disease (ten), and hypertension
(one). Complications
Twenty-six (52%) of the fifty patients had degenerative arterial disease. This was due in part to selection since ten presented with C.A.D. and one with hypertension. Excluding the ten patients who presented with C.A.D., sixteen (40%) out of forty had degenerative arterial disease. Family History The familial tendency in autoimmune thyroiditis is well shown in cases 8, 20, and 30, three of eight sisters all with autoimmune thyroiditis. There was a striking tendency to c.A.D. in some families. This is best shown in the family tree of case 37 (table II). Carbimazole-induced Temporary
Premyxœdema Temporary premyxoedema characterised by hypercholesterolaemia in a euthyroid patient can be induced with antithyroid drugs. One woman (not in this series) presented with thyrotoxicosis in April, 1968. At this time the P.B.I. was 13-1 µg. per 100 ml. and the serum-cholesterol was 227 mg. per 100 ml. In July, 1969, on a maintenance dose of carbimazole 7-5 mg. daily, she was clinically euthyroid. The P.B.I. was normal at 4-4 µg. per 100
491 TABLE II--CAUSE OF DEATH
(OR
PRESENT CASE 37
HEALTH)
IN FAMILY OF
Morris et al.15 pointed out that C.A.D. is not found in communities with a serum-cholesterol under 180 mg. per 100 ml. In affluent societies with a serumcholesterol varying between 200 and 300 mg. per 100 ml. the incidence of C.A.D. is high. Furthermore, the incidence is directly proportional to the cholesterol level. There is the enigma that in a society with all at risk some are singled out to have higher cholesterol levels with an increased risk of C.A.D. Since thyroid antibodies are present in 10% of the population in affluent countries, further study is needed to assess the importance of the hypercholesterolaemia of premyxoedema as a cause of C.A.D. Fluorescein-conjugated anti-human IgG was kindly supplied by Dr. T. T. B. Phillips of the Lister Institute. We are grateful for the technical assistance given by Miss E. Ferguson, Miss R. Hurter, Miss P. Thome, and the department of radiotherapy. Requests for reprints should be addressed to P. B. S. F. REFERENCES
Fowler, P. B. S., Swale, J. Lancet, 1967, i, 1077. Goudie, R. B., Anderson, J. R., Gray, K. G. J. Path. Bact. 1959, 77, 389. 3. Bastenie, P. A., Neve, P., Bonnyns, M., Vanhaelst, L., Chailly, M. Lancet, 1967, i, 915. 4. Rifkind, B. M., Gale, M. ibid. 1967, ii, 640. 5. Adlersberg, D., Sobotka, H. in Cholesterol (edited by R. P. Cook); p. 397. New York, 1958. 6. London, M. G., Muirden, K. D., Hewitt, J. V. Br. med. J. 1963, i, 1. 2.
ml. with Another
a
serum-cholesterol of 375 mg. per 100 ml.
woman
previously thyrotoxic
was
clinically
carbimazole 10 mg. b.d. Her P.B.1. was 3-8 µg, per 100 ml. and the duration of her ankle reflex to half relaxation was within the normal range at the time when her serum-cholesterol was 400 mg. per 100 ml. The corollary of drug-induced premyxcedema is the hypercholesterolaemia of inadequately treated myxcedema. The serum-cholesterol was often high when less than 0-3 mg. of L-thyroxine as a replacement dose for myxcedema kept the patient symptom-free.
euthyroid
on
Discussion
If autoimmune thyroiditis is not associated with a goitre, the latent stage is asymptomatic and only likely to manifest itself when degenerative arterial disease related to the hypercholesterolsemia produces symp-
Patients with Hashimoto’s disease are treated with L-thyroxine both because these patients are known to develop hypothyroidism and because L-thyroxine makes the gland smaller. C.A.D. in these patients, when untreated, and the effect of L-thyroxine in correcting the hypercholesterolæmia suggests that prevention of C.A.D. is another important reason for giving these
1380.
7. Watson, W. C., Buchanan, K. D., Dickson, C. ibid. 1963, ii, 709. 8. Fogel, R. L., Epstein, J. A., Stopak, J. H., Kupperman, H. S. N.Y. State J. Med. 1962, 62, 1159. 9. Hobbs, J. R., Bayliss, R. I. S., Maclagan, N. F. Lancet, 1963, i, 8. 10. Abell, L. L., Levy, B. B., Brodie, B. B., Kendall, F. E. J. biol. Chem. 1952, 195, 357. 11. Fulthorpe, A. J., Roitt, I. M., Doniach, D., Couchman, K. J. clin. Path. 1961, 14, 654. 12. Balfour, B. M., Doniach, D., Roitt, I. M., Couchman, K. G. Br. J. exp. Path. 1961, 42, 307. 13. Bastenie, P. A., Vanhaelst, L., Neve, P. Lancet, 1967, ii, 1221. 14. Fowler, P. B. S. Br. med. J. 1968, iv, 56. 15. Morris, J. N., Marr. J. W., Heady, J. A., Mills, G. L., Pilkington, T. R. E. ibid. 1963, i, 571.
IRON THERAPY IN PATIENTS ON MAINTENANCE HÆMODIALYSIS
toms.
patients L-thyroxine. While many have doubted the relationship of c.A.D. there is an association between degenerative arterial disease and autoimmune thyroiditis. Basteriie et al.13 found a significant association between thyroid antibodies and the occurrence of obesity, hypertension, diabetes mellitus, and C.A.D. A significantly higher proportion of patients with C.A.D. not associated with obesity, hypertension, and diabetes had thyroid antibodies as compared with a normal population. Patients with focal rather than diffuse thyroiditis may have hypercholesterolæmia and never develop hypothyroidism. These persons may be more prone to C.A.D. than those with diffuse thyroiditis who comparatively rapidly develop myxcedema and are treated. In fact, low-titre antibodies with minimal thyroiditis causing a modest hypercholesterolæmia lasting for many years may be most significant to the development of C.A.D.14
to myxcedema,
G. D. PEGRUM MARIAN S. EDWARDS R. CURTIS J.
Hœmatology Department, Fulham Hospital, London W.6 The stainable bone-marrow iron has been studied in twenty-four patients with chronic renal failure on maintenance dialysis. Dialysis contributes to iron depletion in these patients and unless receiving more than 10 units of transfused blood per year, iron supplements are required. A recommended parenteral dose of 2 g. per year has been calculated and proves to have been of benefit in these patients. It is also advisable to monitor the iron status by periodic observation of the bone-marrow stores.
Sum ary
Introduction
IRON deficiency is not a primary feature of the anaemia of renal failure, although there may be associated haemorrhagic manifestations such as menorrhagia, hxmaturia, purpura, and gastrointestinal bleeding leading to iron depletion. With increasing use of hasmodialysis another cause for blood-loss has been introduced-namely, loss into the kidney machine and as a result of blood-sampling for analysis.