443

The Latest on L.A.T.S.

ALMOST 20 years ago, ADAMS and PURVES 1 in New

Zealand, using a guineapig bioassay system to

measure serum thyroid-stimulating hormone (T.S.H.),reported the presence of an abnormal thyroidstimulator (long-acting thyroid stimulator or L.A.T.s.)in the serum of some patients with Graves’ disease.The aetiology of this disease, it seemed, was soon tobe explained. But, as the years have passed, ourknowledge of the role of L.A.T.S. in hyperthyroidismhas become increasingly confused and we seem littlenearer to the truth. The first doubts about L.A.T.s.arose from inability to demonstrate it in all cases ofGraves’ disease. 2 Insensitivity of the assay systemwas originally blamed, but assays of concentrated

IgG fractions of hyperthyroid sera produced onlyabout 80% positive results 3; a core of about 20% ofhyperthyroid patients seemed to have no detectablecirculating L.A.T.S. L.A.T.s.-detractors soon appearedon the scene, dismissing its presence in hyper-thyroid sera as an

"

epiphenomenon " and postulating

new theories to account for the disease. The most

popular of these theories have been based on a con-cept of disturbed cell-mediated immune responses 4or on proposed primary abnormalities of the thyroid-cell receptor site for T.s.H. resulting in continuousactivation of the cyclic-A.M.P. protein-kinase com-plex.5 Ingenious as these theories are, they do notadequately explain two highly incriminating facts-first, L.A.T.S. is almost invariably found in the serumof hyperthyroid neonates born to mothers withGraves’ disease, and its concentration closely parallelsthe course of the disease; second, for practical pur-poses L.A.T.S. has been found only in patients whohave or have had Graves’ disease or, occasionally,in their euthyroid relatives. 6

It took ADAMS and his colleagues again to thrownew light-and new confusion-on the scene.7,sTo understand their latest contribution some

historical backtracking is necessary. Shortly afterL.A.T.S. was described, it was shown to be an immuno-globulin and was therefore assumed to be an antibody.1. Adams, D. D., Purves, H. D. Proc. Univ. Otago med. Sch. 1956,

34, 11.2. McKenzie, J. M. Metabolism, 1972, 21, 883.3. Carneiro, L., Dorrington, K. J., Munro, D. S. Clin. Sci. 1966, 31,

215.4. Volpé, R., Farid, N. R., von Westarp, C., Row, V. V. Clin. Endocr.

1974, 3, 239.5. Solomon, D. H., Chopra, I. J. Mayo Clin. Proc. 1972, 47, 803.6. Wall, J. R., Good, B. F., Hetzel, B. S. Lancet, 1969, ii, 1024.7. Adams, D. D., Kennedy, T. H. J. clin. Endocr. 1967, 27, 173.8. Adams, D. D., Kennedy, T. H. ibid. 1971, 33, 47.

Search for the responsible antigen proved sadlyunrewarding. But a L.A.T.s.-neutralising factor hasbeen located in or associated with thyroid-cellplasma membranes,9-11 the effect of which is demon-strable in the original mouse bioassay system ofMcKENZIE.12 MUNRO’S group in Sheffield have

played an important role in the purification andcharacterisation of this factor ,13,14 to which theyapplied the name L.A.T.s.-absorbing activity (L.A.A.).Their studies suggest it is a 4S protein probablycontaining a specific follicle-cell-membrane receptorsite for L.A.T.S. ; its role as the antigen responsiblefor the appearance of L.A.T.S. has generally beendismissed. In 1967 ADAMS and KENNEDY reportedthe presence of a substance in some hyperthyroidsera which could block the effect of L.A.T.s. on human

thyroid tissue,7 and a follow-up paper in 1971 8

suggested that this acted specifically on humanthyroid gland and was ineffective in the mouse

bioassay. They applied the rather unfortunatelychosen name L.A.T.s.-protector (L.A.T.S.P.) to it.It was suggested that sera from most if not all

hyperthyroid patients contained abnormal thyroid-stimulating immunoglobulins, either human-specificL.A.T.S.P. which gave a negative response in themouse assay system, or non-human specific L.A.T.s.8,15Once again an abnormal stimulating antibody seemedlikely to provide the clue to the setiology of the disease.But advances have been slow, owing largely to thecrudeness of the assay systems, to their insensitivityand relative lack of specificity, and to the problemsof quantifying a positive response. A more sensitiveand specific assay has been badly needed.An ingenious method of exquisite sensitivity was

described by BITENSKY et al.,16 based on the knowneffect Of T.S.H. on thyroid-cell lysosomes, in which therelease of a lysosomal marker enzyme, leucine

2-naphthylamide, was identified by histochemicalmeans. Interest in this technique was greatly en-hanced when L.A.T.s. and L.A.T.S.P. were shown to

produce positive responses, presumably by activatinga receptor site common to these stimulators and toT.S.H. Unfortunately the system is technicallydemanding and tedious-the current techniqueyields about one result a day. Attention was once

again turned to L.A.A. and efforts have been made toestablish a receptor-binding system for thyroid-stimulating substances in line with others that havebeen devised in endocrine work. Early attemptswere only partly successful, perhaps because too

9. Beall, G., Doniach, D., Roitt, I., El Kabir, D. J. Lab. clin. Med.1969, 73, 988.

10. Chopra, I. J., Beall, G. N., Solomon, D. H. J. clin. Endocr. 1971,32, 772.

11. Sato, S., Noguchi, S., Noguchi, A. Biochim. biophys. Acta, 1972,273, 299.

12. McKenzie, J. M. Endocrinology, 1958, 63, 372.13. Smith, B. R. J. Endocr. 1970, 46, 45.14. Dirmikis, S., Munro, D. S. ibid. 1973, 58, 577.15. Shishiba, Y., Shimizu, T., Yoshimura, S., Shizume, K. J. clin.

Endocr. 1973, 36, 517.16. Bitensky, L., Alaghband-Zadeh, J., Chayen, J. Clin. Endocr. 1974,

3, 363.

444

stringent efforts were made to isolate the receptorin pure form, with possible damage or distortion ofbinding SlteS.l’ 18 A more promising approach usingcrude thyroid-cell-membrane preparations has beendeveloped by MEHDI and associates,ls-21 and bySMITH and HALL,22 who report a refined assay systemin this issue (p. 427). It now seems possible to testhuman sera for L.A.T.S., L.A.T.S.P., and T.S.H. invitro using displacement of 1251-labelled T.S.H. fromthyroid plasma membranes derived from human oranimal glands. But problems still exist: the assayis apparently somewhat insensitive (for T.s.H. about10 u); both groups of workers report some per-sistently negative byperthyroid sera in their assaysfor both L.A.T.S. and L.A.T.S.P.; and SMITH and HALLhave found positive results in some sera from patientswith thyroid cancer and Hashimoto’s disease. Thesenew developments should take our understanding ofGraves’ disease a step or two nearer the truth. But,if past events are anything to go by, we are not yetat the point of identifying the elusive agent thatcauses hyperthyroidism.

Portacaval Anastomosis forMetabolic Disease

HEPATIC glycogen-storage disease and homozygoustype-na hyperlipoproteinasmia are two inheriteddiseases which manifest themselves in childhoodand severely decrease life expectancy. For boththese conditions STARZL and his co-workers 23,24

have advocated the operation of portacaval anasto-mosis. For hepatic glycogen-storage disease porta-caval transposition was the procedure used in theearly days,25,26 but this has been replaced by thetechnically simpler end-to-side portacaval anasto-

mosis.27,28 STARZL 23 has now reviewed experiencewith this form of treatment, including 7 of his owncases and 8 reported from other centres. 10

patients had type- glycogenosis, 4 had type III,and 1 had type VI, and age at operation rangedfrom one to eleven years. Astonishingly good resultswere reported, with survival-times of up to nine

17. Fayet, G., Verrier, B., Giraud, A., Lissitzky, S., Pinchera, A.,Romaldini, J. H., Fenzi, G. FEBS Letters, 1973, 33, 299.

18. Amir, S. M., Carraway, T. F., Kohn, L. D., Winaud, R. J. J. biol.Chem. 1973, 248, 4092.

19. Mehdi, S. Q., Nussey, S. S., Gibbons, C. P., El Kabir, D. J.Biochem. Soc. Trans. 1973, 1, 1005.

20. Mehdi, S. Q., Nussey, S. S., Simpson, R. D., Adlköfer, F. Endo-crinologia experimentalis, 1974, 8, 163. (Report of 6th AnnualMeeting of European Thyroid Association, Prague, June 1974.)

21. Schleusener, H., Kottula, P., Adlköfer, F., Nussey, S., Mehdi, Q.ibid. p. 226.

22. Smith, B. R., Hall, R. FEBS Letters, 1974, 42, 301.23. Starzl, T. E., Putnam, C. W., Porter, K. A., Halgrimson, C. G.,

Corman, J., Brown, B. I., Gotlin, R. W., Rodgerson, D. O.,Greene, H. L. Ann. Surg. 1973, 178, 136.

24. Starzl, T. E., Chase, H. P., Putnam, C. W., Porter, K. A. Lancet,1973, ii, 940.

25. Starzl, T. E., Marchioro, T. L., Sexton, A. W., Illingworth, B.,Waddell, W. R., Faris, T. D., Hermann, T. J. Surgery, 1965,57, 687.

26. Riddell, A. G., Davies, R. P., Clark, A. D. Lancet, 1966, ii, 1146.27. Hermann, R. D., Mercer, R. D. Surgery, 1969, 65, 499.28. Starzl, T. E., Brown, B. I., Blanchard, H., Brettschneider, L.

ibid. p. 504.

years. Among the most dramatic long-term effectshave been accelerated body growth, bone mineralisa-tion, liver shrinkage, and reduction of the hyper-lipidxmia characteristic of type-i disease. Sympto-matic hypoglycaemia and metabolic acidosis were

still present but were much decreased.The reasoning behind this form of treatment was

that diversion of foodstuffs, particularly absorbedglucose, allowed extrahepatic tissues to obtain

adequate supplies, with a decrease in the amountof glucose which otherwise became trapped, as

glycogen, in the liver .29 FOLKMANN 30 showed that,even before operation, patients improved sympto-matically if fed parenterally rather than orally. ButSTARZL has since suggested that diversion of insulinmay be just as important as diversion of glucose.Insulin is normally delivered direct from the pancreasto the liver, where half or more of it is destroyed.31It will also enhance glycogen deposition. If theliver is bypassed, peripheral insulin concentrationswill be increased,32 and this will serve both to decreaselipid mobilisation and to promote protein synthesisand thus growth.

Despite the good results reported, a word ofcaution is in order; The operation itself is not

without risks, though preoperative intravenous

feeding may make it less hazardous. 30 3 of the 15

patients have died, 2 of them after the now no-longer-used portacaval transposition; in 2 further patients theshunt or anastomosis has clotted, and a splenectomywas required in 1 other patient. Where measured,blood-ammonia levels have been normal, but thereally long-term effects of this form of treatmentremain to be determined. It is possible, for example,that the chronic hyperinsulinaemia may have adverseeffects on large vessels. 33 Patients who survive toadolescence without treatment improve spontane-ously,34 so operation is probably not advisable at thisjuncture. Non-operative treatments should not beignored entirely: both glucagon and thyroxine havegiven promising short-term results. 35-37 However,until such time as these have been fully assessed,portacaval shunt deserves serious consideration forsevere unremitting cases of types I and ill glycogen-storage disease in childhood.

Perhaps more exciting, but also more contentiousand less well proven, is the use of portacaval shuntingfor refractory type-ma hyperlipoproteinaemia (familialhypercholesterolsemia). To date, a single patient, a12-year-old girl with the homozygous form of this

29. Boley, S. J., Cohen, M. I., Gliedman, M. L. Pediatrics, 1970,46, 929.

30. Folkmann, J., Philippart, A., Tze, W.-J., Crigler, J., Jr. Surgery,1972, 72, 306.

31. Blackard, W. G., Nelson, N. C. Diabetes, 1970, 19, 302.32. Holdsworth, C. D., Nye, L., King, E. Gut, 1972, 13, 58.33. Stout, R. W., Vallance-Owen, J. Lancet, 1969, i, 1078.34. Van Creveld, S. Archs Dis. Childh. 1952, 27, 113.35. Gitzelmann, R. Helv. pœdiat. Acta, 1957, 12, 425.36. Koulischer, N., Pickering, D. E. Am. J. Dis. Child. 1956, 91, 103.37. Lowe, C. U., Sokal, J. E., Doray, B. H., Sarcione, E. J. J. clin.

Invest. 1959, 38, 1021.