1040

who had been taking oral contraceptives, but it was

thought to be doubtful in 2 of the 15 who had not.The report 4 from the records unit and research

advisory service of the Royal College of GeneralPractitioners is based on evidence supplied by 29 generalpractitioners. They were asked to complete, for eachyear that records had been kept up to the end of June,1966, a list of names of all women aged 15-49 who hadattended with a new episode of one or other of: vascularlesions affecting the central nervous system, arterio-sclerotic heart-disease, arterial embolism and thrombosis,phlebitis, thrombophlebitis, and pulmonary embolism.Two controls were selected for each patient-one

" list-matched " and the other " disease-matched." Eachdoctor then sought an interview with all the affectedand control patients and recorded marital status andobstetric and contraceptive history at or before thethromboembolic episode. The required informationwas compiled for 147 patients and 294 controls. Negli-gible differences were observed between the two controlgroups in contraceptive habits, and no significantdifferences emerged between the affected women andthe control groups in the use of other methods of

contraception or of no methods at all. So the twocontrol groups were combined, and women usingcontraceptive methods other than oral were groupedwith those using none at all. Among the women inwhom the specified thromboembolic diseases developed,more were pregnant or in the puerperium at the timethan would be expected from the experience of thecontrol group (30, as against a calculated expectationof 75); and more had taken an oral contraceptive (16,compared with 7-3). The diagnoses of subarachnoidhaemorrhage, cerebral thrombosis, and arterial throm-bosis were so infrequent that no conclusions could bereached, though none of the women who had subarach-noid haemorrhage or coronary thrombosis had recentlyeither been pregnant or taken an oral contraceptive. In

fact, the excess frequency of these two factors was con-centrated among women treated for venous thrombosisor pulmonary embolism (three-quarters of this grouphad superficial phlebitis of the legs). From this analysis,it seems that the risk of venous thrombosis or pulmonaryembolism may be increased about six times in womenwho are pregnant or in the puerperium and about threetimes in women who are taking an oral contraceptive.There were no fatal episodes among the 147 patients;and the vast majority of venous thromboses arose inapparently normal women not taking oral contraceptives.The results of the three inquiries agree qualitatively,

even though the choice of control groups and themethods of investigation were different; and the pro-portion of women in the control groups who said theywere taking oral contraceptives is fairly close to the

figure estimated from the quantity of oral contraceptivessupplied for sale in this country. So it is unlikely thatsubstantial bias was introduced into any of the threesets of data. And, the subcommittee concludes, " thesum of evidence ... is so strong that there can be no

4. Jl R. Coll. gen. Practnrs, 1967, 13, 267.

reasonable doubt that some types of thromboembolicdisorder are associated with the use of oral contracep-tives." Venous thrombosis and pulmonary embolismand infarction were the conditions most closely associ-ated with oral contraceptives; and, for coronary throm-bosis, there was little to indicate any connection at all.Though the numbers are small, they support earlier

suggestions 5 6 of a link between oral contraceptives andcerebral vascular disease. On the other hand, in theirretrospective investigation of 500 carotid strokes

(reported on p. 1019), Mr. JENNETT and Mr. CROSSfound no sign that oral contraceptives were responsiblefor producing or precipitating cerebral arterial occlusionin young women.

For the first time, therefore, a substantial and

thoroughly controlled search (indeed three searches) hasdelivered an affirmative answer to the question " canoral contraceptives cause thromboembolism " The

mortality data indicate that the risk of death may beof the order of 3 per 100,000 users per year; and thismust be set against the maternal mortality-rate for

England and Wales of 12 per 100,000 completed preg-nancies-and an annual death-rate from all causes inwomen aged 15-44 of 97 per 100,000. Nevertheless,not everyone will accept the information now availableas reassuring; and one of the aims must clearly be tofind a means of identifying women for whom thrombo-embolism may be a particular risk if they are givenoral contraceptives.

Autoimmunity in IdiopathicAddison’s Disease

THE association of idiopathic Addison’s disease andhypothyroidism in the same patient is sufficientlycommon to have been recognised as a syndrome(usually attributed to SCHMIDT but described earlier byFALTA 8 and by others). The diminished production ofadrenal and thyroid hormones in such patients is due toloss of glandular epithelium in these organs, accompaniedby infiltration of the diseased tissues by lymphocytes andplasma cells, the cellular mediators of immunologicalreactions. There is now reason to believe that theselesions may be the result of organ-specific autoimmunity.Somewhat similar inflammatory lesions have been foundin the thyroid glands or adrenals of experimentalanimals immunised by injecting extracts of the appro-priate tissues in Freund’s adjuvant.9]0 In man, thechronic thyroiditis underlying primary hypothyroidismis often accompanied by circulating antibodies directedagainst thyroglobulin 11 and an antigen present in themicrosomal fraction of thyroid epithelium.12 Antibody5. Illis, L., Kocen, R. S., McDonald, W. I., Mondkar, V. P. Br. med. J.

1965, ii, 1164.6. Bickerstaff, E. R., Holmes, J. M. ibid. 1967, i, 726.7. Schmidt, M. B. Verh. dt. path. Ges. 1926, 21, 212.8. Falta, W. Klin. Wschr. 1912, 49, 1477.9. Rose, N. R., Witebsky, E. J. Immun. 1956, 76, 417.

10. Colover, J., Glynn, L. E. Immunology, 1958, 1, 172.11. Roitt, I. M., Doniach, D., Campbell, P. N., Hudson, R. V. Lancet, 1956,

ii, 820.12. Roitt, I. M., Ling, N. R., Doniach, D., Couchman, K. G. Immunology,

1964, 7, 375.

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reacting with an antigen in the adrenal cortex,13 probablymicrosomal,14 15 has been described in the serum ofpatients with idiopathic Addison’s disease.Most organ-specific autoimmune diseases, such as

Hashimoto’s disease and pernicious anaemia, arise pre-dominantly in females, but organ-specific autoantibodiesare found equally often in affected members of bothsexes. Idiopathic Addison’s disease seemed to be anexception to this rule. Adrenal antibodies have been

sought in four large series totalling 235 patients thoughtduring life to have idiopathic Addison’s disease 15-ls; andamong the 122 females and 113 males, adrenal antibodywas found in 81 females and 43 males. These findingssuggest that the sex-distribution of idiopathic Addison’sdisease may be roughly equal and that adrenal antibodyis present more often in affected females, contrary toexperience with autoimmune diseases of the stomachand thyroid. IRVINE et ap6 have drawn attention to a

high female/male ratio (perhaps 2/1) in idiopathicAddison’s disease in which the diagnosis has been

firmly established at necropsy (the equal sex-distributionof Addison’s disease of all types apparently being due toa predominance of adrenal tuberculosis in males). Thepossibility must therefore be considered that, in thelarge series described, tuberculous Addison’s disease insome males has been wrongly diagnosed as idiopathic andthere is something approaching a more equal frequencyof adrenal antibody in males and females who are

affected by the disease.

Idiopathic Addison’s disease is rather uncommon, andrecent surveys of large numbers of cases for auto-

immune lesions in tissues other than adrenal are likelyto have been biased by case selection. By the use ofantibody tests for detection of subclinical autoimmunedisease, or by comparison with control cases of tuber-culous Addison’s disease, it has been possible to over-come the bias of case selection to some extent, and it isnow evident that patients with idiopathic Addison’sdisease, particularly females, are remarkably prone to avariety of other autoimmune disorders. 15-1 The highfrequency of symptomless chronic thyroiditis in patientswith idiopathic Addison’s disease is reflected by the com-mon finding of thyroid antibodies in these patients evenwhen the thyroid gland is clinically normal; and examplesof Hashimoto’s disease and thyrotoxicosis have beenfound among addisonian patients with clinical thyroiddisorders in addition to primary myxaedema.15-17The study of sera from non-addisonian patients with

chronic thyroiditis, thyrotoxicosis, or pernicious ansemiahas shown that thyroid and gastric autoantibodies tendto be present together in a single individual more oftenthan would be expected, and there is strong evidencethat the tendency to form these antibodies is often13. Anderson, J. R., Goudie, R. B., Gray, K. G., Timbury, G. C. Lancet,

1957, i, 1123.14. Blizzard, R. M., Kyle, M. J. clin. Invest. 1963, 42, 1653.15. Goudie, R. B., Anderson, J. R., Gray, K. G., Whyte, W. G. Lancet,

1966, i, 1173.16. Irvine, W. J., Stewart, A. G., Scarth, L. Clin. exp. Immun. 1967, 2, 31.17. Blizzard, R. M., Chee, D., Davis, W. ibid. p. 19.18. Nerup, J., Søborg, M., Halberg, P., Brøchner-Mortensen, K. Acta med.

scand. 1966, 445, suppl. 383.

familial and possibly hereditary.19 It is thus scarcelysurprising that gastric parietal-cell and intrinsic-factorantibodies are commonly found in the serum of patientswith idiopathic Addison’s disease; when present, theseantibodies are associated with impaired gastric secretionand sometimes with pernicious anxmia. 16 BLIZZARDet al,17 found 6 cases of pernicious anaemia among 47children with adrenal insufficiency, and other examplesof this combination of diseases have been reported; butthere is as yet no good statistical evidence that thesediseases appear together more often than would beexpected by chance. CARPENTER et a1. 20 have shown

convincingly from a review of the published reports thatdiabetes mellitus is much more common in the idiopathicthan in the tuberculous form of Addison’s disease. Againthe link may be autoimmunity; for patients with diabetesmellitus are known to have thyroid and gastric auto-antibodies more often than controls,21 and some observa-tions suggest that diabetics may form autoantibody toendogenous insulin.22

Idiopathic hypoparathyroidism is another member ofthe " club " of diseases associated with Addison’s

disease; antibodies reacting with human parathyroidtissue have been found in 28 (38%) of 74 patients withidiopathic hypoparathyroidism 23 (18 of whom also hadAddison’s disease) and in 12 (18%) of 65 patients withAddison’s disease in the absence of overt hypopara-thyroidism. 17 The rare syndrome of idiopathic hypo-parathyroidism, Addison’s disease, and mucocutaneousmoniliasis shows striking familial clustering 24 and mayappear in incomplete forms.25 Parathyroid-hormoneinsufficiency is known to be capable of causing abnormal-ities of the teeth and nails, and changes in the epidermishave been thought to predispose to mucocutaneous

moniliasis. In families with idiopathic hypopara-thyroidism, siblings who themselves do not have hypo-parathyroidism have been described with moniliasis orabnormalities of teeth or nails, and it is clear that

parathyroid-hormone deficiency is not a completelyadequate explanation for these ectodermal abnormalities.Pernicious ansemia, steatorrhoea, alopecia, and cirrhosisof the liver are additional inconstant features of the

syndrome. It is possible that an immunological abnor-mality underlies certain cases of steatorrhaea 26 and ofcirrhosis of the liver.27 The very rare associationsbetween Addison’s disease and premature menopause 17or demyelination of the central nervous system 16 17

remain to be explained.Now that replacement therapy has greatly prolonged

the life of patients with Addison’s disease, it is especially19. Doniach, D., Roitt, I. M. Seminars Hœmat. 1964, 1, 313.20. Carpenter, C. C. J., Solomon, N., Silverberg, S. G., Bledsoe, T.,

Northcutt, R. C., Klinenberg, J. R., Bennett, I. L., Harvey, A.Medicine, Baltimore, 1964, 43, 153.

21. Moore, J. M., Neilson, J. M. Lancet, 1963, ii, 645.22. Mancini, A. M., Zampa, G. A., Vecchi, A., Costanzi, G. ibid. 1965, i,

1189.23. Blizzard, R. M., Chee, D., Davis, W. Clin. exp. Immun. 1966, 1, 119.24. Whitaker, J., Landing, B. H., Esselborn, V. M., Williams, R. R. J. clin.

Endocr. 1956, 16, 1374.25. Wuepper, K. D., Fudenberg, H. H. Clin. exp. Immun. 1967, 2, 71.26. Malik, G. B., Watson, W. C., Murray, D., Cruickshank, B. Lancet,

1964, i, 1127.27. Doniach, D., Roitt, I. M., Walker, J. G., Sherlock, S. Clin. exp. Immun.

1966, 1, 237.

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important for the physician to be aware of these possiblecomplications. Many of these are insidious in onset andcause chronic ill health, but they are largely remediable.Positive antibody tests may be of value in drawingattention to early or subclinical lesions in tissues otherthan the adrenal, though negative antibody tests do notexclude the presence of autoimmune destruction of anyorgan.

Annotations

ALCOHOL SHIFT

ALCOHOL-INDUCED pain is a well-recognised thoughstill a mysterious phenomenon. It was first described inassociation with Hodgkin’s disease,1 which has remainedits commonest cause; but occasionally other neoplasticdiseases,2-5 and, rarely, osteomyelitis, bone fractures, orpyogenic lymphadenitis,6-8 have been responsible. Char-acteristically, the pain is confined to one site, even when,in cancer, the disease is widespread.2 9 Less familiaralcohol-related symptoms include itching, cough, nausea,bleeding, flushing, sudden distaste or lack of desire foralcohol, or increased susceptibility to intoxication and

" hangover " effects.Brewin 9 has lately drawn attention to a peculiarity

of such alcohol-induced discomfort-a sequence ofevents he calls " alcohol shift ". Irradiation of a focus ofdisease that has been causing alcohol symptoms mayresult in the prompt replacement of these symptoms bynew ones which the patient has never experienced before.Thus, pain in one place may be replaced by pain inanother, or by quite different symptoms, such as drowsi-ness, nausea, or sweating. Unlike the original alcoholsymptoms, which commonly had persisted unchangedfor a long time, the new effect, especially when of thesystemic or multifocal type, often proves transient.Sometimes it appears only once, and when alcohol istaken again it has gone, being succeeded by normaltolerance or by a second new form of intolerance(" double shift "). Sometimes the shift of pain to a newsite is accompanied by a rapid increase in the size of

peripheral lymph-nodes or subcutaneous deposits at

that site. Drug treatment, with cytotoxic agents,phenylbutazone, or anti-histamines, may also producealcohol shift, though when this is transient there may bea return to the original alcohol effect-a type of reversalnot seen in patients who have had radiotherapy. In somepatients an alcohol symptom may appear for the firsttime either during treatment or with the first alcoholicdrink taken after treatment. A few of these patientslater experience a shift of symptoms. Brewin pointsout that local or systemic symptoms may be abolished,or a shift produced, by a dose of radiation far smallerthan is needed to eradicate the local disease.He also describes " alcohol dysphagia ", a burning sen-

sation experienced while swallowing alcohol, in patientswith neoplastic disease but without involvement of theoropharynx or upper alimentary tract. This symp-

1. Hoster, H. A. Am. J. Roentg. 1950, 64, 913.2. James, A. H. Q. Jl Med. 1960, 29, 47.3. Healy, J. B. Lancet, 1959, ii, 296.4. Wanka, J. Br med. J. 1965, ii, 88.5. Brewin, T. B. ibid. 1966, ii, 437.6. Alexander, D. ibid. 1963, ii, 1376.7. Braun, W. E., Scnider, B. I. J. Am. med. Ass. 1958, 168, 1882.8. Conn, H. O. Archs intern. Med. 1957, 100, 241.9. Brewin, T. B. Br. J. Cancer, 1966, 20, 688.

tom may be accompanied by alcohol-induced pain else-where or by systemic alcohol symptoms; and it may bethe initial symptom of alcohol intolerance or the mani-festation of a shift.We hope this painstaking work by Brewin will stimu-

late a lot more inquiry and thought about this strangeeffect of alcohol-which may have been too readily dis-missed as " just another oddity ". If the explanationcan be uncovered, it may conceivably throw light on anunexpectedly wide area.

COAGULATION-FIBRINOLYSIS

BLOOD alternates between the fluid and the gel phaseaccording to local need. This versatility is subserved bycoagulation and fibrinolysis; and if, as seems likely, thesetwo mechanisms are in dynamic balance, they shouldperhaps be viewed as a unity-a coagulation-fibrinolysissystem concerned not only with the patency and occlusionof blood-vessels but also with healing and repair. Thoughmuch is known about the mechanism of coagulation invitro, and rather less about fibrinolysis, their behaviourin vivo is largely conjectural. Enough is known, however,to fortify the belief that interaction between coagulationand fibrinolysis, and hence the deposition and removal offibrin, is of great importance to the body’s economy.Unfortunately, each system tends to be studied in isola-tion, and the confusion to which this can lead is exempli-fied by the bleeding diatheses which may complicatechildbirth. Here opinions differ as to how far depletionof circulating fibrinogen results from a disorder of coagula-tion or of fibrinolysis. These differences might bereconciled if it were more generally appreciated that

changes-in coagulation may excite compensatory changesin fibrinolysis, and vice versa, and that the pendulum mayswing to overactivity of either system. The problem iscomplex, and unless continuous monitoring of coagulationand fibrinolysis becomes possible, it is unlikely to besolved.

Despite the limitations and uncertainties of presentmethods, any information about the day-to-day or hour-to-hour behaviour of the coagulation-fibrinolysis systemis welcome. In a study of 42 patients admitted to hos-pital with a wide variety of injuries Innes and Sevitt 1found that the first few hours after injury were dominatedby accelerated fibrinolysis and clotting-time, followed byan abrupt swing to slower fibrinolysis and normal clotting.Reduced fibrinolytic activity lasted several days, and wasfollowed by lengthening of the clotting-time and a raisedplasma-fibrinogen level. This study suggests that the

changes in clotting and in fibrinolytic activity are recipro-cally related, and that the situation after trauma may beessentially similar to that encountered in obstetrichoemorrhage. A basic pattern of change in coagulationand fibrinolysis may, possibly, be common to conditionsof shock irrespective of xtiology. Several studies offibrinolysis after myocardial infarction 2-4 suggest a

pattern of fibrinolytic behaviour similar to that foundby Innes and Sevitt after injury. Bennett and his col-leagues 4 observed the behaviour of plasminogen activator,anti-activator, antiplasmin, plasminogen, and fibrinogenin twelve men during the first 15 days after myocardial

1. Innes, D., Sevitt, S. J. clin. Path. 1964, 17, 1.2. Hume, R. Br. Heart J. 1958, 20, 15.3. Lackner, H., Merskey, C. Br. J. Hœmat. 1960, 6, 402.4. Bennett, N. B., Ogston, C., Ogston, D. Clin. Sci. 1967, 32, 27.