- Email: [email protected]
Four Controversies about the Cause of Hyperthyroidism
78
ducts into account because a realistic pricing for N.H.S. factor-VIII concentrate has never been made public (cynics suggesting that this is because it is more expensive per activity unit than the 9.25p of the cheapest commercial product). At current commercial prices on-demand home therapy in the United Kingdom costs about ,2000 per patient per year. If the doses were increased to the Norwegian level the outlay would more than double. Further work is needed to determine the lowest dose of factor VIII which is acceptable to the hæmmophiliac-i.e., it stops most of his bleeding episodes and prevents or slows the progression of chronic haemophilic arthropathy-and to the doctor in terms of both efficacy and safety. The safety aspect is important: although neither the British nor the Norwegian workers encountered serious side-effects the true risks of long-term, intensive, multidonor transfusion therapy remain unknown. The substantial improvements in the quality of life provided in the past decade by improved management of hxmophilia, including home therapy, may be bought at the expense of shorter survival. Clearly, the careful monitoring of home-therapy programmes must continue. The London-Oxford survey was far too short to allow comment on the effect of earlier treatment on the development of haemophilic arthropathy, and the progress of the Norwegian patients was checked only by joint-motion studies (which showed no deterioration in the two year period) and not by radiological evaluation. Whether early therapy will reduce the incidence of arthropathy, or delay its onset, remains to be seen. What both surveys do show clearly is that home therapy is of considerable social and economic benefit to haemophiliacs with severe clinical disease. In 1976, JoNES and his colleagues8 estimated that 60% of the eligible haemophilic population of the United Kingdom were on, or were in training for, home therapy. With their demonstration of cost effectiveness, INGRAM’S team have now provided the rationale to make it a full house.
of thyroid-stimulating immunoglobulins (TSI) in this group of patients. These TSI have been clearly shown to be IgG molecules2 whose thyroid-stimulating activity is formed by the combination of the heavy and light chains in the Fab (antigen-binding) part of the molecule,3 suggesting that they are in fact thyroid-stimulating antibodies (TSAb). Four aspects of these thyroid-stimulating antibodies are controversial. How should the activity measured in the different assay systems be described? What is the thyroid antigen to which these TSAb are responsive ? What is their role, if any, in the causation of nodular goitre, both non-toxic and toxic? And what is the underlying abnormality which allows the production of these abnormal immunoglobulins ? The term thyroid-stimulating antibody can be used as a generic term for all thyroid-stimulating activity detected in the serum of patients with Graves’ disease. In assays which do not depend on the demonstration of thyroid stimulation such as the receptor assay4 employed by Dr BoLK and coworkers in the work recorded on p.61, the activity can be described in relation to the method used-
thyrotrophin-binding-inhibiting immunoglobulins (TBII)-although an alternative terminology is considered later. The term thyrotrophin-displacing activity (TDA) should not be used since in the receptor assay the immunoglobulins do not displace the activity of labelled TSH but inhibit its binding. Some immunoglobulins which inhibit TSH binding in the receptor assay are known not to be biologically active in viv05 or in vitro.6Similarly in the modified receptor assay of ADAMS and KENNEDY7
activity is best - described as LATS-protector (LATS-P) since the immunoglobulins prevent the binding of LATS to human thyroid membranes. Unfortunately the assay which does measure the effect of Graves’ immunoglobulins on adenylatecyclase activity8.9 depends on the use of normal human thyroid tissue, a scarce commodity. The
the
relation between the
measurements
obtained in
2. McKenzie
Four Controversies about the Cause of Hyperthyroidism THE
causes of hyperthyroidism in countries are Graves’ disease and toxic multinodular goitre. Since the discovery by ADAMS and PuRVES of a long-acting thyroid stimulator (LATS) in the serum of patients with Graves’ disease,l many workers have confirmed the presence common
western
1. Adams DD, Purves HD. Abnormal responses in the assay for Proc Univ Otago Med School 1956; 34: 11-12.
thyrotrophin.
JM. Fractionation of plasma containing the long-acting thyroid stimulator. J Biol Chem 1958; 237: 3571-72. 3. Smith BR, Dorrington KJ, Munro DS. The thyroid-stimulating properties of long-acting thyroid stimulator &ggr; G subunits. Biochim Biophys Acta 1969; 142: 277-85. 4. Rees Smith B, Hall R. Thyroid-stimulating immunoglobulins in Graves’ disease. Lancet 1974; ii: 427-31. 5. Clague R, Mukhtar ED, Pyle GA, et al. Thyroid-stimulating immunoglobulins and control of thyroid function. J Clin Endocrinol Metab 1976; 63: 550-56. 6. Endo K, Kasagi K, Konishi J, et al. Detection and properties of TSH-binding inhibitor immunoglobulins in patients with Graves’ disease and Hashimoto’s thyroiditis. J Clin Endocrinol Metab 1978; 46: 734-39. 7. Adams DD, Kennedy TH. Occurrence in thyrotoxicosis of a gamma globulin which protects LATS from neutralization by an extract of thyroid gland J Clin Endocrinol Metab 1967; 27:173-77. 8. Orgiazzi J, Williams DE, Chopra IJ, Solomon DH. Human thyroid adenyl cyclase-stimulating activity in immunoglobulin G of patients with Graves’ disease. J Clin Endocrinol Metab 1976; 42: 341-54. 9. Holmes SD, Dirmikis SM, Martin TJ, Munro DS. Effects of human thyroidstimulating hormone and immunoglobulins on adenylate cyclase activity and the accumulation of cyclic AMP in human thyroid membranes and
slices. J Endocrinol 1978; 79: 121-30.
79
these different assays is not always significant10 and further correlative studies are required. What of the nature of the thyroid component which reacts with TSAb? Studies with receptor assays for TSH and TSAb have shown that TSAb inhibit the binding of labelled TSH to human thyroid membranes in dose-dependent fashion.4 It is tempting to speculate, therefore, that TSAb are in fact antibodies to the cell-membrane receptor for TSH which, by interacting with the receptor, may cause the hyperthyroidism and goitre of Graves’ disease. Certainly there are many points of action which are shared by the two stimulators and both lead to activation of adenylate cyclase. Without full characterisation of the receptor it is not possible to be sure that TSAb are antibodies to this particular antigen, but the circumstantial evidence is strong. Studies involving solubilisation of the TSH receptor" have shown that TSAb also inhibit the binding of TSH to its solubilised receptors, indicating that the TSAb are unlikely to be binding to sites different from the TSH receptor in such a way as to induce changes in the thyroid membrane which then inactivate the TSH receptor. Sensitised lymphocytes from Graves’ patients can produce TSAb in vitro after non-specific12,13 as well as after specific stimulation with thyroid homogenate.14 MAKINEN et al. 15 have shown that the lymphocyte-stimulating effect of thyroid membranes is abolished by preincubation with TSH, suggesting that the TSH receptor is the mitogenic antigen. Thus there is much to support the view of ADAMS 16 that in thyrotoxicosis "clear and comprehensive evidence shows that the disorder is caused by autoantibodies which stimulate the thyroid gland because they have specificity for the thyroid cell’s receptor to the pituitary hormone (thyrotrophin) which normally regulates the gland". It would be consistent with this view to refer to Graves’ immunoglobulins which interact with the TSH receptor as TSHreceptor antibodies. Graves’ disease therefore fits into the group of receptor-antibody diseases which
10.
Sugenoya A, Kidd A, Row VV, Volpé R. Correlation between thyrotropindisplacing activity and human thyroid-stimulating activity by immunoglobulins from patients with Graves’ disease and other thyroid disorders. J Clin Endocrinol Metab 1979; 48: 398-402. VB, Dawes PJD, Rees Smith B, Hall R. The interaction of human
myasthenia gravis (antibodies to the acetylcholine receptor"), a rare variety of diabetes
includes
mellitus with variable insulin resistance and acanthosis nigricans (antibodies to the insulin receptor18), and possibly chronic renal failure with inappropriately high parathyroid hormone levels (antibodies to the PTH receptor). 19 The role of TSAb in the pathogenesis of nodular goitre, whether non-autonomous, or autonomous, non-toxic or toxic, is of some interest since there is little evidence other than of iodine deficiency for the pathogenesis of these abnormalities in nonendemic regions. In their article this week Dr BOLK and his colleagues report no increase in frequency of TSAb, as measured by a receptor assay, in 51 patients with multinodular goitres. Their findings agree with some20,21 but not a1122 previous work. This discrepancy may well reflect differences in definition, selection procedures, geography, or assay technique. At present it seems likely that in western countries most non-toxic nodular goitres are not the result of TSAb action whereas some hyperthyroid patients with nodular glands have Graves’ disease superimposed on a longstanding nodular goitre. Although TSAb are likely to be the cause of the hyperthyroidism and goitre of Graves’ disease, the underlying defect for their development remains unknown. One view, ably expressed by VOLPE, 23 is that Graves’ disease is due to an inherited defect in immune surveillance, presumably due to a defect in action of suppressor T lymphocytes which would allow a specific randomly mutating self-reactive "forbidden" clone of helper T cells to survive if it chanced to appear, and to interact with its antigen subsequently cooperating with antibody-producing B lymphocytes. Another exciting hypothesis from ADAMS16 proposes that the genetic basis of inherited autoimmune disease lies in an abnormality of the immunoglobulin V genes which code for antibody specificity. An alternative or even complementary view can be based on the network system of JERNE.24 In this system the production of specific antibody is followed by synthesis of a second popu17. Drachman DB. Medical progress:
thyroid-stimulating antibodies with solubilised human thyrotrophin receptor. FEBS Letters 1977;83:63-67. 12. Knox AJ, von Westarp C, Row VV, Volpé R. Demonstration of the production of human thyroid-stimulating immunoglobulins (HTSI) by Graves’ lymphocytes cultured in vitro with phytohæmagglutinin (PHA). Metabolism 1976; 25: 1217-23. 13. McLachlan SM, Rees Smith B, Petersen VB, Davies TF, Hall R. A system for studying thyroid stimulating antibody production in vitro. J Clin Lab
Immunol 1978; 1:45-50. AJ, von Westarp C, Row VV, Volpé R. Thyroid antigen stimulates lymphocytes from patients with Graves’ disease to produce thyroid-stimulating immunoglobulins (TSI). J Clin Endocrinol Metab 1976; 43:
14 Knox
330-37. 15. Mäkinen T, Wägar G, Apter L, von Willebrand E, Pekonen F. Evidence that the TSH receptor acts as a mitogenic antigen in Graves’ disease. Nature
1978; 275: 314-15. 16. Adams DD. The
V gene theory
Immunol 1978; 1: 17-24.
disease. J
Clin Lab
N
Engl J Med 1978;
18. Kahn CR, Flier JS, Bar RS, et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med
1976; 294: 739-45.
Juppner H, Bialasiewicz AA, Hesch RD. Autoantibodies to parathyroid hormone receptor. Lancet 1978; ii: 1222-24. 20. Mukhtar ED, Smith BR, Pyle GA, Hall R, Vice P. Relation of thyroid-stimulating immunoglobulins to thyroid function and effects of surgery, radioiodine, and antithyroid drugs. Lancet 1975; i: 713-15. 21. McGregor AM, Petersen MM, Capiferri R, Evered DC, Rees Smith B, Hall R. A prospective study of the effects of radio-iodine therapy on thyroidstimulating antibody synthesis in Graves’ disease. J. Endocrinol 1979; 81: 19.
114P-115P. 22. Brown RS, Jackson
munoglobulins
IMD, Pohl SL, Reichlin S. Do thyroid-stimulating imand toxic multinodular goitre? Lancet
cause non-toxic
1978; i: 904-06. 23.
of inherited autoimmune
myasthenia gravis.
298: 136-42.
11. Petersen
Volpé
R. The
pathogenesis
of Graves’ disease:
an
overview. Clin Endocr
Metab 1978; 7: 3-29. 24. Jerne NK. The immune system. Sci Am 1973; 224: 52-60.
80
lation of antibodies against the variable region (idiotype) of the first antibody. These anti-idiotype antibodies could then control the synthesis of the first-population antibodies by interacting with idiotypic determinants on the particular T and B cells involved in synthesis of the first antibody. Defects in this network system with impaired response to the TSAb idiotype could be involved in the pathogenesis of Graves’ disease. Which of these three possibilities or combinations of them is likely to be nearest the truth awaits further experimentation. But the ability of TSAb in Graves’ disease to stimulate not only the thyroid but also the minds of its investigators remains unsurpassed.
Conservative
Operations for Gastric Ulcers
a
PARTIAL gastrectomy for chronic gastric ulcer is destructive operation and surgeons have been
more conservative treatments. Ideally, is based on ætiology; but with chronic gastric ulcer there is dispute over the aetiology, so there is also dispute over the best line of treatment. It was HARPER and DRAGSTEDTl who first suggested that gastric ulcers resulted from gastric stasis leading to excessive antral gastrin release and, in its turn, to hypersecretion. They therefore used vagotomy and pyloroplasty in the treatment of gastric ulcers, with outstanding results. Other enthusiastic vagotomists took up this line of treatment with equal success.2The first setback to DRAGSTEDT’S theory of gastric stasis came when surgeons took the next logical step-treating gastric ulcers simply by improving gastric drainage combined with local excision of the ulcer. The results were disastrous, with recurrence rates as high as 100%.3 Then in 1967 CAPPER4 reported that there was no evidence that either gastric stasis or gastric hypersecretion was associated with ulcers in the body of the stomach. He suggested instead that reflux of duodenal contents leading to atrophic gastritis was the mair cause of gastric ulcer. A third theory was put forward by 01.5 He pointed out that there are twc junctional zones on the lesser curve. The first is the junction between antral and parietal cell mucosa
examining treatment
1.
Harper PV, Dragstedt LR. Section of vagus nerve to stomach in treatment of benign gastric ulcer. Arch Surg 1947;55:141-50. 2. Burge H, Morton Gill A, MacLean C, Stedeford R. Four-year to eight-year results of vagotomy and simple drainage for benign lesser-curve gastric ulcer. Br Med J 1970;iii:376-78. 3. Stemmer EA, Zahn RL, Hom LW, Connolly JE. Vagotomy and drainage procedures for gastric ulcer. Arch Surg 1968; 96: 586-91. 4. Capper WM. Factors in the pathogenesis of gastric ulcer. Ann Roy Coll Surg Engl 1967;40:21-35. 5. Oi M, Ito Y, Kumagai F, et al. A possible dual control mechanism in the origin of peptic ulcer. A study on ulcer location as affected by mucosa and musculature. Gastroenterology 1969;57:280-93.
and the second is the junction between longitudinal and oblique muscle layers. Gastric ulcers occur most commonly in stomachs where these two junctional zones coincide. This confusion led DUTHIE6 to do a controlled prospective trial comparing vagotomy and pyloroplasty with Billroth I gastrectomy. Of those patients treated by vagotomy 14% needed a further operation and DuTHiE concluded that vagotomy and pyloroplasty could not replace partial gastrectomy in the treatment of gastric ulcer. Since then vagotomy and pyloroplasty have vied in popularity with gastrectomy as the surgical treatment of choice for gastric ulcer, and the time has now come to see whether any firm conclusions can be reached. EASTMAN and GEAR7 now report the results ot vagotomy and pyloroplasty in 80 patients with chronic gastric ulcer, many of whom had subsequent endoscopic examinations. The recurrence rate was 8% overall, but of those patients followed up for more than 5 years 22% had recurrent ulcer. These late recurrences were often symptomless, being picked up only on endoscopy. How then can we reconcile the enthusiastic success of DRAGSTEDT and BuRGE with the more modest results of others? Careful long-term follow-up with endoscopy is undoubtedly important and, as EASTMAN and GEAR have shown, will reveal a higher incidence of recurrent ulcers than was previously recognised. Equally important is careful consideration of the type of ulcer dealt with. In 1957 JOHNSON8 identified’three types of gastric ulcer: type-I ulcers occur in the body of the stomach and are accompanied by gastritis and low levels of gastric acid; type-II ulcers occur in the pyloric antrum and are associated with gastric hypersecretion; type-III ulcers occur in association with duodenal ulcers and are also accompanied by gastric hypersecretion. Types II and III ulcers can therefore reasonably be expected to respond to operations aimed at reducing gastric secretion ; treating them in the same way as duodenal ulcers seems logical, and these are the ones that respond to vagotomy and pyloroplasty. Nevertheless, there are some type-I ulcers which heal after vagotomy. So where do we stand? The mortality of Billroth I gastrectomy is about 2%, while that of vagotomy and pyloroplasty is around 1%. The failure rate of gastrectomy is about 2%, while that of vagotomy and drainage is at least 10%, the figure increasing with the length of follow-up. Benign ulcer cannot reliably be distinguished, with the naked eye at operation, from
Kwong NK. Vagotomy or gastrectomy for gastric ulcer. Br Med J 1973;iv:79-81. 7. Eastman MC, Gear MWL. Vagotomy and pyloroplasty for gastric ulcers. Br J Surg 1979;66:238-41. 8. Johnson HD. Gastric ulcer classification, blood group characteristics secretion patterns and pathogenesis. Ann Surg 1965; 162: 996-1004.
6. Duthie HL,
ducts into account because a realistic pricing for N.H.S. factor-VIII concentrate has never been made public (cynics suggesting that this is because it is more expensive per activity unit than the 9.25p of the cheapest commercial product). At current commercial prices on-demand home therapy in the United Kingdom costs about ,2000 per patient per year. If the doses were increased to the Norwegian level the outlay would more than double. Further work is needed to determine the lowest dose of factor VIII which is acceptable to the hæmmophiliac-i.e., it stops most of his bleeding episodes and prevents or slows the progression of chronic haemophilic arthropathy-and to the doctor in terms of both efficacy and safety. The safety aspect is important: although neither the British nor the Norwegian workers encountered serious side-effects the true risks of long-term, intensive, multidonor transfusion therapy remain unknown. The substantial improvements in the quality of life provided in the past decade by improved management of hxmophilia, including home therapy, may be bought at the expense of shorter survival. Clearly, the careful monitoring of home-therapy programmes must continue. The London-Oxford survey was far too short to allow comment on the effect of earlier treatment on the development of haemophilic arthropathy, and the progress of the Norwegian patients was checked only by joint-motion studies (which showed no deterioration in the two year period) and not by radiological evaluation. Whether early therapy will reduce the incidence of arthropathy, or delay its onset, remains to be seen. What both surveys do show clearly is that home therapy is of considerable social and economic benefit to haemophiliacs with severe clinical disease. In 1976, JoNES and his colleagues8 estimated that 60% of the eligible haemophilic population of the United Kingdom were on, or were in training for, home therapy. With their demonstration of cost effectiveness, INGRAM’S team have now provided the rationale to make it a full house.
of thyroid-stimulating immunoglobulins (TSI) in this group of patients. These TSI have been clearly shown to be IgG molecules2 whose thyroid-stimulating activity is formed by the combination of the heavy and light chains in the Fab (antigen-binding) part of the molecule,3 suggesting that they are in fact thyroid-stimulating antibodies (TSAb). Four aspects of these thyroid-stimulating antibodies are controversial. How should the activity measured in the different assay systems be described? What is the thyroid antigen to which these TSAb are responsive ? What is their role, if any, in the causation of nodular goitre, both non-toxic and toxic? And what is the underlying abnormality which allows the production of these abnormal immunoglobulins ? The term thyroid-stimulating antibody can be used as a generic term for all thyroid-stimulating activity detected in the serum of patients with Graves’ disease. In assays which do not depend on the demonstration of thyroid stimulation such as the receptor assay4 employed by Dr BoLK and coworkers in the work recorded on p.61, the activity can be described in relation to the method used-
thyrotrophin-binding-inhibiting immunoglobulins (TBII)-although an alternative terminology is considered later. The term thyrotrophin-displacing activity (TDA) should not be used since in the receptor assay the immunoglobulins do not displace the activity of labelled TSH but inhibit its binding. Some immunoglobulins which inhibit TSH binding in the receptor assay are known not to be biologically active in viv05 or in vitro.6Similarly in the modified receptor assay of ADAMS and KENNEDY7
activity is best - described as LATS-protector (LATS-P) since the immunoglobulins prevent the binding of LATS to human thyroid membranes. Unfortunately the assay which does measure the effect of Graves’ immunoglobulins on adenylatecyclase activity8.9 depends on the use of normal human thyroid tissue, a scarce commodity. The
the
relation between the
measurements
obtained in
2. McKenzie
Four Controversies about the Cause of Hyperthyroidism THE
causes of hyperthyroidism in countries are Graves’ disease and toxic multinodular goitre. Since the discovery by ADAMS and PuRVES of a long-acting thyroid stimulator (LATS) in the serum of patients with Graves’ disease,l many workers have confirmed the presence common
western
1. Adams DD, Purves HD. Abnormal responses in the assay for Proc Univ Otago Med School 1956; 34: 11-12.
thyrotrophin.
JM. Fractionation of plasma containing the long-acting thyroid stimulator. J Biol Chem 1958; 237: 3571-72. 3. Smith BR, Dorrington KJ, Munro DS. The thyroid-stimulating properties of long-acting thyroid stimulator &ggr; G subunits. Biochim Biophys Acta 1969; 142: 277-85. 4. Rees Smith B, Hall R. Thyroid-stimulating immunoglobulins in Graves’ disease. Lancet 1974; ii: 427-31. 5. Clague R, Mukhtar ED, Pyle GA, et al. Thyroid-stimulating immunoglobulins and control of thyroid function. J Clin Endocrinol Metab 1976; 63: 550-56. 6. Endo K, Kasagi K, Konishi J, et al. Detection and properties of TSH-binding inhibitor immunoglobulins in patients with Graves’ disease and Hashimoto’s thyroiditis. J Clin Endocrinol Metab 1978; 46: 734-39. 7. Adams DD, Kennedy TH. Occurrence in thyrotoxicosis of a gamma globulin which protects LATS from neutralization by an extract of thyroid gland J Clin Endocrinol Metab 1967; 27:173-77. 8. Orgiazzi J, Williams DE, Chopra IJ, Solomon DH. Human thyroid adenyl cyclase-stimulating activity in immunoglobulin G of patients with Graves’ disease. J Clin Endocrinol Metab 1976; 42: 341-54. 9. Holmes SD, Dirmikis SM, Martin TJ, Munro DS. Effects of human thyroidstimulating hormone and immunoglobulins on adenylate cyclase activity and the accumulation of cyclic AMP in human thyroid membranes and
slices. J Endocrinol 1978; 79: 121-30.
79
these different assays is not always significant10 and further correlative studies are required. What of the nature of the thyroid component which reacts with TSAb? Studies with receptor assays for TSH and TSAb have shown that TSAb inhibit the binding of labelled TSH to human thyroid membranes in dose-dependent fashion.4 It is tempting to speculate, therefore, that TSAb are in fact antibodies to the cell-membrane receptor for TSH which, by interacting with the receptor, may cause the hyperthyroidism and goitre of Graves’ disease. Certainly there are many points of action which are shared by the two stimulators and both lead to activation of adenylate cyclase. Without full characterisation of the receptor it is not possible to be sure that TSAb are antibodies to this particular antigen, but the circumstantial evidence is strong. Studies involving solubilisation of the TSH receptor" have shown that TSAb also inhibit the binding of TSH to its solubilised receptors, indicating that the TSAb are unlikely to be binding to sites different from the TSH receptor in such a way as to induce changes in the thyroid membrane which then inactivate the TSH receptor. Sensitised lymphocytes from Graves’ patients can produce TSAb in vitro after non-specific12,13 as well as after specific stimulation with thyroid homogenate.14 MAKINEN et al. 15 have shown that the lymphocyte-stimulating effect of thyroid membranes is abolished by preincubation with TSH, suggesting that the TSH receptor is the mitogenic antigen. Thus there is much to support the view of ADAMS 16 that in thyrotoxicosis "clear and comprehensive evidence shows that the disorder is caused by autoantibodies which stimulate the thyroid gland because they have specificity for the thyroid cell’s receptor to the pituitary hormone (thyrotrophin) which normally regulates the gland". It would be consistent with this view to refer to Graves’ immunoglobulins which interact with the TSH receptor as TSHreceptor antibodies. Graves’ disease therefore fits into the group of receptor-antibody diseases which
10.
Sugenoya A, Kidd A, Row VV, Volpé R. Correlation between thyrotropindisplacing activity and human thyroid-stimulating activity by immunoglobulins from patients with Graves’ disease and other thyroid disorders. J Clin Endocrinol Metab 1979; 48: 398-402. VB, Dawes PJD, Rees Smith B, Hall R. The interaction of human
myasthenia gravis (antibodies to the acetylcholine receptor"), a rare variety of diabetes
includes
mellitus with variable insulin resistance and acanthosis nigricans (antibodies to the insulin receptor18), and possibly chronic renal failure with inappropriately high parathyroid hormone levels (antibodies to the PTH receptor). 19 The role of TSAb in the pathogenesis of nodular goitre, whether non-autonomous, or autonomous, non-toxic or toxic, is of some interest since there is little evidence other than of iodine deficiency for the pathogenesis of these abnormalities in nonendemic regions. In their article this week Dr BOLK and his colleagues report no increase in frequency of TSAb, as measured by a receptor assay, in 51 patients with multinodular goitres. Their findings agree with some20,21 but not a1122 previous work. This discrepancy may well reflect differences in definition, selection procedures, geography, or assay technique. At present it seems likely that in western countries most non-toxic nodular goitres are not the result of TSAb action whereas some hyperthyroid patients with nodular glands have Graves’ disease superimposed on a longstanding nodular goitre. Although TSAb are likely to be the cause of the hyperthyroidism and goitre of Graves’ disease, the underlying defect for their development remains unknown. One view, ably expressed by VOLPE, 23 is that Graves’ disease is due to an inherited defect in immune surveillance, presumably due to a defect in action of suppressor T lymphocytes which would allow a specific randomly mutating self-reactive "forbidden" clone of helper T cells to survive if it chanced to appear, and to interact with its antigen subsequently cooperating with antibody-producing B lymphocytes. Another exciting hypothesis from ADAMS16 proposes that the genetic basis of inherited autoimmune disease lies in an abnormality of the immunoglobulin V genes which code for antibody specificity. An alternative or even complementary view can be based on the network system of JERNE.24 In this system the production of specific antibody is followed by synthesis of a second popu17. Drachman DB. Medical progress:
thyroid-stimulating antibodies with solubilised human thyrotrophin receptor. FEBS Letters 1977;83:63-67. 12. Knox AJ, von Westarp C, Row VV, Volpé R. Demonstration of the production of human thyroid-stimulating immunoglobulins (HTSI) by Graves’ lymphocytes cultured in vitro with phytohæmagglutinin (PHA). Metabolism 1976; 25: 1217-23. 13. McLachlan SM, Rees Smith B, Petersen VB, Davies TF, Hall R. A system for studying thyroid stimulating antibody production in vitro. J Clin Lab
Immunol 1978; 1:45-50. AJ, von Westarp C, Row VV, Volpé R. Thyroid antigen stimulates lymphocytes from patients with Graves’ disease to produce thyroid-stimulating immunoglobulins (TSI). J Clin Endocrinol Metab 1976; 43:
14 Knox
330-37. 15. Mäkinen T, Wägar G, Apter L, von Willebrand E, Pekonen F. Evidence that the TSH receptor acts as a mitogenic antigen in Graves’ disease. Nature
1978; 275: 314-15. 16. Adams DD. The
V gene theory
Immunol 1978; 1: 17-24.
disease. J
Clin Lab
N
Engl J Med 1978;
18. Kahn CR, Flier JS, Bar RS, et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med
1976; 294: 739-45.
Juppner H, Bialasiewicz AA, Hesch RD. Autoantibodies to parathyroid hormone receptor. Lancet 1978; ii: 1222-24. 20. Mukhtar ED, Smith BR, Pyle GA, Hall R, Vice P. Relation of thyroid-stimulating immunoglobulins to thyroid function and effects of surgery, radioiodine, and antithyroid drugs. Lancet 1975; i: 713-15. 21. McGregor AM, Petersen MM, Capiferri R, Evered DC, Rees Smith B, Hall R. A prospective study of the effects of radio-iodine therapy on thyroidstimulating antibody synthesis in Graves’ disease. J. Endocrinol 1979; 81: 19.
114P-115P. 22. Brown RS, Jackson
munoglobulins
IMD, Pohl SL, Reichlin S. Do thyroid-stimulating imand toxic multinodular goitre? Lancet
cause non-toxic
1978; i: 904-06. 23.
of inherited autoimmune
myasthenia gravis.
298: 136-42.
11. Petersen
Volpé
R. The
pathogenesis
of Graves’ disease:
an
overview. Clin Endocr
Metab 1978; 7: 3-29. 24. Jerne NK. The immune system. Sci Am 1973; 224: 52-60.
80
lation of antibodies against the variable region (idiotype) of the first antibody. These anti-idiotype antibodies could then control the synthesis of the first-population antibodies by interacting with idiotypic determinants on the particular T and B cells involved in synthesis of the first antibody. Defects in this network system with impaired response to the TSAb idiotype could be involved in the pathogenesis of Graves’ disease. Which of these three possibilities or combinations of them is likely to be nearest the truth awaits further experimentation. But the ability of TSAb in Graves’ disease to stimulate not only the thyroid but also the minds of its investigators remains unsurpassed.
Conservative
Operations for Gastric Ulcers
a
PARTIAL gastrectomy for chronic gastric ulcer is destructive operation and surgeons have been
more conservative treatments. Ideally, is based on ætiology; but with chronic gastric ulcer there is dispute over the aetiology, so there is also dispute over the best line of treatment. It was HARPER and DRAGSTEDTl who first suggested that gastric ulcers resulted from gastric stasis leading to excessive antral gastrin release and, in its turn, to hypersecretion. They therefore used vagotomy and pyloroplasty in the treatment of gastric ulcers, with outstanding results. Other enthusiastic vagotomists took up this line of treatment with equal success.2The first setback to DRAGSTEDT’S theory of gastric stasis came when surgeons took the next logical step-treating gastric ulcers simply by improving gastric drainage combined with local excision of the ulcer. The results were disastrous, with recurrence rates as high as 100%.3 Then in 1967 CAPPER4 reported that there was no evidence that either gastric stasis or gastric hypersecretion was associated with ulcers in the body of the stomach. He suggested instead that reflux of duodenal contents leading to atrophic gastritis was the mair cause of gastric ulcer. A third theory was put forward by 01.5 He pointed out that there are twc junctional zones on the lesser curve. The first is the junction between antral and parietal cell mucosa
examining treatment
1.
Harper PV, Dragstedt LR. Section of vagus nerve to stomach in treatment of benign gastric ulcer. Arch Surg 1947;55:141-50. 2. Burge H, Morton Gill A, MacLean C, Stedeford R. Four-year to eight-year results of vagotomy and simple drainage for benign lesser-curve gastric ulcer. Br Med J 1970;iii:376-78. 3. Stemmer EA, Zahn RL, Hom LW, Connolly JE. Vagotomy and drainage procedures for gastric ulcer. Arch Surg 1968; 96: 586-91. 4. Capper WM. Factors in the pathogenesis of gastric ulcer. Ann Roy Coll Surg Engl 1967;40:21-35. 5. Oi M, Ito Y, Kumagai F, et al. A possible dual control mechanism in the origin of peptic ulcer. A study on ulcer location as affected by mucosa and musculature. Gastroenterology 1969;57:280-93.
and the second is the junction between longitudinal and oblique muscle layers. Gastric ulcers occur most commonly in stomachs where these two junctional zones coincide. This confusion led DUTHIE6 to do a controlled prospective trial comparing vagotomy and pyloroplasty with Billroth I gastrectomy. Of those patients treated by vagotomy 14% needed a further operation and DuTHiE concluded that vagotomy and pyloroplasty could not replace partial gastrectomy in the treatment of gastric ulcer. Since then vagotomy and pyloroplasty have vied in popularity with gastrectomy as the surgical treatment of choice for gastric ulcer, and the time has now come to see whether any firm conclusions can be reached. EASTMAN and GEAR7 now report the results ot vagotomy and pyloroplasty in 80 patients with chronic gastric ulcer, many of whom had subsequent endoscopic examinations. The recurrence rate was 8% overall, but of those patients followed up for more than 5 years 22% had recurrent ulcer. These late recurrences were often symptomless, being picked up only on endoscopy. How then can we reconcile the enthusiastic success of DRAGSTEDT and BuRGE with the more modest results of others? Careful long-term follow-up with endoscopy is undoubtedly important and, as EASTMAN and GEAR have shown, will reveal a higher incidence of recurrent ulcers than was previously recognised. Equally important is careful consideration of the type of ulcer dealt with. In 1957 JOHNSON8 identified’three types of gastric ulcer: type-I ulcers occur in the body of the stomach and are accompanied by gastritis and low levels of gastric acid; type-II ulcers occur in the pyloric antrum and are associated with gastric hypersecretion; type-III ulcers occur in association with duodenal ulcers and are also accompanied by gastric hypersecretion. Types II and III ulcers can therefore reasonably be expected to respond to operations aimed at reducing gastric secretion ; treating them in the same way as duodenal ulcers seems logical, and these are the ones that respond to vagotomy and pyloroplasty. Nevertheless, there are some type-I ulcers which heal after vagotomy. So where do we stand? The mortality of Billroth I gastrectomy is about 2%, while that of vagotomy and pyloroplasty is around 1%. The failure rate of gastrectomy is about 2%, while that of vagotomy and drainage is at least 10%, the figure increasing with the length of follow-up. Benign ulcer cannot reliably be distinguished, with the naked eye at operation, from
Kwong NK. Vagotomy or gastrectomy for gastric ulcer. Br Med J 1973;iv:79-81. 7. Eastman MC, Gear MWL. Vagotomy and pyloroplasty for gastric ulcers. Br J Surg 1979;66:238-41. 8. Johnson HD. Gastric ulcer classification, blood group characteristics secretion patterns and pathogenesis. Ann Surg 1965; 162: 996-1004.
6. Duthie HL,