HEPATIC CIRRHOSIS AND DIABETES MELLITUS

275 was shown. The frefor each of the commonly found hereditary types of colour-vision defect in the alcoholic and non-alcoholic groups

association, of statistical significance,

quencies were as

follows:

It is evident that the two groups do not differ. The frequency for the total hospital population does not differ from that for the schoolboy population in this area. Analysis of the frequency for deutan in hospital population v. ’

general population by the x2

test

gives: 2=3-546,

D.F.

in the Dolphin (1766-69), then:

showing that the expression was used

"

On the 9th September, in the morning, while the ship lay at anchor in the road of Madeira, nine of the best seamen belonging to the Swallow swam on shore, having only their money tied round their bodies in handkerchiefs. Capt. Carteret immediately wrote to the govenor to assist him in the recovery of these men; but in the mean time a message was brought him, that they had been found naked on the shore. A boat immediately set off to bring them on board, where the figure they made was truly ridiculous, insomuch so as to make them ashamed even of themselves. However, the captain forgave them, as it appeared, that they had ran this risk only with a view, to speak in their own phrase, to get a skinful of liquor, as they knew they were bound on a long voyage, from which it was uncertain who might return."1

1,

the phrase is used again with the but under different circumstances. Enmore, near Bridgwater, RAYNER THROWER. Somerset.

Later in the same

For protan this value with Yates’ correction is: =0768, D.F. 1, p>O’05.

p>005.

same account

meaning,

These results, in addition to showing that there is no difference in frequency for common hereditary colour-vision defects between alcoholics and the remainder of the hospital population, also indicate that there is no significant difference for these factors between this neuropsychiatric hospital population and the general population.

HEPATIC CIRRHOSIS AND DIABETES MELLITUS SIR,-In your annotation (Jan. 7, p. 35) you say that the increase over chance expectation in the frequency of patients affected both by hepatic cirrhosis and by diabetes mellitus " implies that one disease predisposes to the other ". Because Veterans Administration Hospital, cirrhosis tends to precede diabetes, you argue that intrahepatic H. C. THULINE. American Lake, Washington 98493. disturbance of sugar metabolism probably gives rise to diabetes. An alternative interpretation should perhaps be considered: that one or more factors may be common to the z* This letter has been shown to Dr. Cruz-Coke, whose pathogenesis of both diseases. reply follows.-ED. L. From a study of their sex and age distributions, we propose we in I data I our table the SIR,-May put explain why hypothesis that diabetes mellitus and hepatic cirrhosis are " obtained at a time when patients were acutely ill " ? The both spontaneous disturbed-tolerance autoimmune disorders. first step in confirming a gene/disease association is to discard Each is confined to specific genotypes, and the disease process the bias of a racial stratification. The investigations of Dr. is probably initiated in predisposed individuals through the Thuline and associates reveal an association between colouroccurrence of specific somatic mutations in lymphoid stemcells. These random gene changes probably initiate the vision defects and cirrhosis in a " full " Caucasian popula" tion acutely ill.I This is a basic finding for our table I, growth of a forbiddexi-clone " 2which synthesises primary which shows a significant association in three different racial humoral autoantibodies belonging to the a2-macroglobulin populations. We ignored the fact of change to normal in serum-protein fraction. The target tissue ( ? pancreatic (Icolour-vision-test results as the patients’ sensoriums cleared, islet-cells in diabetes) should be located behind a blood-tissue because we have not yet completed the study of the multiple barrier such as a continuous basement membrane. factors which influence the intensity of this association which We find that the sex-specific and age-specific initiationhas been discovered. rates (dP/dt) for both diseases (adult onset)-in common with R. CRUZ-COKE. those of many others-conform satisfactorily to the general Santiago, Chile. stochastic equation 3:

dP/dt=rkSotr-l exp(-kt’). A SKINFUL OF ALCOHOL

SIR,-May I add a further comment to the correspondence2 on the use of’ Tetmosol ’ in the treatment of scabies ? In West Africa tetmosol, dissolved in a local " rubbing oil " such as coconut oil or boiled palm oil, was found to be an economical and excellent method of treating scabies.3 Since many of the local people use rubbing oils regularly, the whole family, including the aged and house-bound, were more likely to treat themselves. While working as a paediatrician I contracted scabies from a child with malnutrition and " Norwegian scabies ". My family and I had an opportunity to compare treatment with tetmosol in coconut oil and with benzyl benzoate. The former was more; pleasant and seemed to be more effective. Institute of Child Health, 30 Guilford Street, London W.C.I. W.C.1.

DAVID MORLEY.

SIR,-Your correspondents need have no misgivings about the correct term which by long usage has been expressed as a "

skinful of liquor ". At the moment I have before me a contemporary account of Captain Carteret’s voyage round the world Fialkow, P. J., Thuline, H. C., Fenster, F., New Engl. J. Med. 1966, 275, 584. 2. Gold, S. Lancet, 1966, ii, 1417; Erskine, D. ibid. 1967, Jan. 7, p. 54. 3. Morley, D. Trans. Roy Soc. Trop. Med. Hyg. 1963, 57, 81. 1.

of the pathogenesis of diabetes mellitus the value of r, the number of " dependent-type " somatic mutations needed to initiate the disease process is 5, and the value of the constant k (both sexes) is approximately 1O-9yr.-s. The major onset mode occurs at 60-70 years, although a juvenile form of diabetes, characterised by a distinctive genotype, has a modal onset age at about 15 years. The value of So, the fraction of the population predisposed to the adult form of the disease at birth, is sex-dependent, and it is not the same in all populations. In the United States population studied by Spiegelman and Marks,5 So.F (the female fraction) is not less than 0-067, and So,M is not less than 0-040. The corresponding values in the Oslo and Bergen populations studied by Westlund6 are similar. A sex-ratio (So,F/So,M) of nearly 1-7 in these populations suggests that one factor in the polygenic predisposition to diabetes mellitus (adult onset) is an X-linked allele with dominant effect. (It is of interest that in a Japanese population an X-linked allele In

our

interpretation4

1. The Polite Traveller and British

Navigator: vol. vii; Captain Carteret’s Voyage round the World, Begun in the Year 1766, and finished in 1769. London, 1783. 2. Burnet, F. M. The Clonal Selection Theory of Acquired Immunity. London, 1959; Br. med. J. 1965, i, 338. 3. Burch, P. R. J. J. theoret. Biol. 1966, 12, 397. 4. Burch, P. R. J. in Radiation and Ageing (edited by P. J. Lindop and G. Sacher); p. 117. London, 1966. 5. Spiegelman, M., Marks, M. H. Am. J. publ. Hlth, 1946, 36, 26. 6. Westlund, K. Br. J. prev. soc. Med. 1966, 20, 105.

276 with recessive rather than dominant effect seems to be tolerance autoimmunity. The main factor responsible for the implicated7). In the United States and Norwegian populations, association between the diseases is likely to be genetic in the frequency of the postulated predisposing X-linked allele is origin. In the polygenic predisposition to diabetes and just over 0-3. If the autosomal contribution to the genotype cirrhosis, a recessive-effect autosomal factor may be common to is simple recessive, then the frequency of the predisposing both genotypes. autosomal allele will be not less than 0-35. The interval P. R. J. BURCH The General Infirmary between initiation and diagnosis-the latent period-is N. R. ROWELL. at Leeds. typically 5 years for both sexes. The age-pattern of cirrhosis of the liver (portal, adult onset 8) can be described by the above general stochastic equation, with r = 4, and a k value (both sexes) of approximately RENAL FUNCTION IN YOUNG DIABETICS 1’2B 10-lyr.’. The modal onset-age occurs at 50-60 yearsSiR,—The pathogenesis of diabetic nephropathy is largely that is, between 10 and 15 years in advance of the corresponding unknown. In its later stages renal vascular complications mode for diabetes mellitus. Again, the value is sexSo lead to continuously decreasing kidney function which not but in this where males are disease, dependent, consistently rarely ends in fatal uraemia. Kidney function in patients with more commonly affected than females, So,M/So,F is typically recent onset of diabetes is usually considered to be normal, about 3. This accords with the view that an X-linked factor A few investigators, however, have found several strikingly with recessive effect (and frequency about 0-3) is implicated high values for inulin clearance in juvenile diabetics with disease in the polygenic predisposing genotype(s). of short duration.1 Consequently, if the inheritance of the X-linked allele We have investigated glomerular filtration in 30 individuals predisposing to diabetes is independent of that predisposing to cirrhosis, the probability that a male will carry both alleles (18 diabetics and 12 healthy control subjects). All were will be in the region of 0- 11. On the independence assumption, below 35 years of age and the probability that a female will carry both predisposing without prior kidney disease, X-linked alleles will be about 0-06. These values are close to and had normal blood-presthe recent prevalences of cirrhosis (all forms) in diabetic subsure, urinary sediment, jects and of diabetes in cirrhotic subjects noted in your erythrocyte- sedimentation annotation, and this indicates that predisposing homozygous rate, and plasma-creatinine autosomal alleles are probably common to both conditions. Of level. The duration of disease in of an individual who the incidence both conditions course, in the diabetics, all insulinis predisposed to both will be strikingly age-dependent, and treated, was 1-9 years. this may help to account for the increased concordance that has Glomerular-filtration rate was been observed over the past 30 years. measured as the 5’Co-cyanocoWe have suggested9 that a positive association between balamin-clearance by the autoimmune diseases often arises from the pleiotropic effect of Aurell modification of the by predisposing alleles-that is, one allele or combination of and Hume.’ method of Slapak alleles predisposes to more than one disease. Many tissues Glomerular filtration, share common histocompatibility antigens. Diabetes is in this way by measured associated, not only with cirrhosis, but also with various other radioactive vitamin BI2, is diseases such as gout,lO obesity,’O shin spots," coronary heart-

qf

statistically highly significantly correlated to the inulin clearance,3 but has none of the disadvantages of that

disease, atherosclerosis, optic atrophy,l2 neuropathy, retinopathy, cataract, and a tendency to produce offspring with Klinefelter’s syndrome.I3 14 Such clustering is predicted 9 from our unified theory7 of growth-control and autoimmunity, and it is evidently widespread. We also predict that mutual exclusion, or negative association between autoimmune diseases, should be demonstrable. Because of the potential clinical importance, it would be useful to test this prediction. If our analysis is substantially correct, the initiation of both cirrhosis and diabetes should involve a stochastic process, and hence the sequence of appearance of the two diseases will be largely governed by the random events (probably somatic mutations) described by the relevant stochastic equations. However, the latent period (typically about 2-5 years from initiation to diagnosis in cirrhosis and about 5 years for diabetes) will have some (small) effect on the sequence. Accordingly, diabetes will by chance sometimes precede cirrhosis (as is observed) but, more often, cirrhosis will precede diabetes, because the modal onset-age (10 to 15 years earlier in cirrhosis) and the relative values of r (the number of somatic mutations, 4 for cirrhosis and 5 for diabetes) both favour this sequence. Summarising, we suggest that regardless of precipitating factors the underlying cause of most, and possibly all, instances of diabetes mellitus and hepatic cirrhosis is disturbed7. Burch, P. R. J., Burwell, R. G. Q. Rev. Biol. 1965, 40, 252. 8. Brick, I. B., Palmer, E. D. Archs intern. Med. 1964, 113, 501. 9. Burch, P. R. J., Rowell, N. R., Burwell, R. G. Lancet, 1966, ii, 748. 10. Br. med. J. 1966, ii, 1280. 11. Danowski, T. S., Sabeh, G., Sarver, M. E., Shelkrot, J., Fisher, F. R. Am. J. med. Sci. 1966, 251, 570. 12. Rose, F. C., Fraser, G. R., Friedmann, A. I., Kohner, E. M. Q Jl Med. 1966, 35, 385. 13. Nielsen, J. Lancet, 1966, i, 1376; ii, 748. 14. Wais, S., Salvati, E. ibid. 1966, ii, 747.

" Co-cyanocobalamin- clearance in ml. per minute per 1-73 square metres (ordinate) of 18 diabetics and 12 controls.

minute per 1-73 square

method. The result of the investigation (see accompanying figure) shows that many young diabetics have very high clearance values (up to 213 ml. per minute per 1-73 square metres). The average clearance values in diabetics (137-8 ml. per minute per 1-73

metres) are significantly higher than in healthy control subjects (102-9 ml. per metres). The difference is highly square

significant (p < 0-01). The reason for the raised glomerular-filtration rate in young diabetics without kidney disease is at present unknown. It may be due to increased capillary permeability caused by a vascular response, leading to stasis, hyperaemia, and increased filtration pressure in the glomerular capillary loops, similar to the

pathophysiological vascular responses observed in the conjunctival vascular bed.4 A connection between the early functional disturbance of the filtration mechanism in diabetes and the pronounced structural changes of long-term diabetes, known as glomerulosclerosis, is conceivable. Functional 1. 2. 3.

Stalder, G., Schmid, R., Wolff, M. V. Dt. med. Wschr. 1960, 85, 346. Slapak, M., Hume, D. M. Lancet, 1965, i, 1095. Granberg, P. O., Reizenstein, P. Acta med. scand. 1966, 179, suppl. 445,

4.

Ditzel, J., Duckers, J. Acta pœdiat., Stockh. 1957, 46,

p. 451.

535.