Epidemiological and biochemical studies of cataract and diabetes. A. Pirie

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1 Epidemiological and biochemical studies of cataract and diabetes A. Pirie A survey has been made of the prevalence of diabetes among patients who have a senile cataract extracted, and the carbohydrates in senile cataractous lenses of diabetics and nondiabetics have been exaviined to determine whether the lens of the diabetic human, like that of the diabetic animal, accumulates sorbitol. All patients having a cataract extracted at the Oxford Eye Hospital during 1957 through 1962 were examined. With only patients living within a defined area and having a first operation for senile cataract considered, 13 per cent were diabetic. Among these, one third presented with cataract and the diagnosis of diabetes xoas made at the Eye Hospital. Extraction of a senile cataract is four to six times more common in diabetic persons over the age of 5 than in the nondiabetic. Those with poorly controlled diabetes are more likely to have a cataract extracted than those with loell-controlled diabetes. The lens of a diabetic contains more sorbitol, glucose, and fructose than that of a nondiabetic. This finding, which applies to both senile cataractous lens, and non-cataractous lens obtained post mortem, is considered in relation to theories of the cause of formation of cataract in diabetes. There is an inverse relationship between the inositol and the glucose content of the senile cataractous lens. T..his work on the epidemiology and biochemistry of diabetic cataract has been done in collaboration with Dr. Francis Caird of the Radcliffe Infirmary and with Dr. Ruth van Heyningen and Miss M. Hutchinson of the Nuffield Laboratory of Ophthalmology. I am grateful to them for permission to present this general survey. Patterson 1 found that the development of cataract in young rats made diabetic with alloxan was directly related to the level of blood sugar. This connection between blood sugar level and rate and severity of cataract formation received support from van Heyningen's work 2 ' 3 showing that a high blood sugar level caused accumulation of sorbitol and fructose in From the Nuffield Laboratory of Ophthalmology, University of Oxford, England. 629 the lens; and this finding led to the theory presented by van Heyningen, 3 Kinoshita, Merola, and Dikmak, 4 that formation and retention of sorbitol in the diabetic lens and of dulcitol in the lens of the galactosemic rat is conducive to formation of lens opacity. While it is generally stated that young diabetics develop a specific cataract, there is no general agreement that mature diabetics have more cataract than nondiabetics of the same age. Yet if sorbitol accumulation is harmful, it is surely true that diabetics of all ages will be prone to cataract unless their blood sugar is rigorously controlled at all times. Caird, Hutchinson, and Pirie 5 have examined this question by a study of the hospital records of patients who have had a cataract extracted, and Pirie and van Heyningen by a study of the sorbitol con- Downloaded From: on 1/4/218

2 63 Pirie Investigative Ophthalmology August 1965 tent of the normal and cataractous lenses of diabetic and nondiabetic patients. Table I shows that in ophthalmoscopic surveys cataract has as often as not been found to be more common in nondiabetic than in diabetic subjects. Surveys of patients who have had a cataract extracted have, on the other hand, shown an over-all proportion of diabetics that is higher than any reported percentage in a general population. The purpose of our clinical investigation has been to define as accurately as possible the true prevalence of diabetes in a group of adult patients who had a senile cataract extracted, to estimate the frequency with which those with undiscovered diabetes present with cataract in an Eye Department, and to study, in diabetics who had had a cataract extracted, the age at diagnosis, and the duration and control of diabetes. Table I. Previous studies of the relationship between diabetes and cataract* Cataract Author Waite and Beetham 1 Heinsius and Arndt 17 Dollfus 1 * Kato et al. 19 Tulloch 12 Author Clegg-o Anthonisen 21 Townes and Casey 22 examined ophthalmoscopically No. of subjects Cataract extractions No. of extraction. il,66 1,717 Age 4,1 Over Over Over Over Over 45 Over Over Over Over 2 25 Over 2 No. of diabetics % with cataract % diabetics 5 8 1, 'From Caird, Hutchinson, and Pirie: Brit. M. J. 2: 665, Aylesbury Cirencester High Wycombe Swindon READING 1 I V Miles Fig. 1. Sketch map of defined area. (From Caird, Hutchinson, and Pirie: Brit. M. J. 2: 665, ) Downloaded From: on 1/4/218

3 Volume 4 Number 4 Studies of cataract and diabetes 631 The purpose of our experimental investigation has been to determine the distribution of sorbitol and other carbohydrates in human lenses. Clinical investigation of cataract and diabetes A study was made of the case records of all patients over the age of 2 who had had a cataract extracted in the Oxford Eye Hospital in the six years 1957 through A few definitions are necessary. Cataract: In both diabetic and nondiabetic subjects, cataract was considered nonsenile when it was thought to have a congenital basis or when it occurred in association either with other possibly causal ocular disease, in particular trauma, uveitis, and glaucoma, or with general disease other than diabetes. All other cataracts were considered "senile." Doinicile: In order to be certain that our prevalence studies had some meaning, patients were divided by their address at the time of operation into two groups, those living outside and those living inside an area from which it is virtually certain that all ophthalmic operations are carried out in the Oxford Eye Hospital. It is the results of the study of this inner group that have most significance. Fig. 1 shows the inner and outer areas studied. The total population in 1961 of the area defined is 284, (General Registry Office, 1961). Diabetes: Among all patients investigated in Oxford, diabetes was diagnosed on customary biochemical criteria (a random blood sugar of 18 mg. per 1 ml. or more, a fasting level of 13 mg. per 1 ml. or more, or a glucose tolerance curve of diabetic type). Those with proved diabetes were considered to have been found as a result of cataract when the principal symptom leading to the diagnosis of diabetes was impairment of vision due to cataract. All others, including those whose diabetes was diagnosed as a result of ocular symptoms other than those of cataract, were considered "knoion diabetics." The Table II. Patients with first operation for senile cataract* Patients Male Female Total Total patients ,24 : Known Found Total %of diabetics "From Caird, Hutchinson, and Pirie: Brit. M. J. 2: 665, Table III. Patients living within defined area with first operation for senile cataract* Patients Male Female Total Total patients Known Found Total % diabetics From Caird, Hutchinson, and Pirie: Brit. M. J. 2: 665, criteria for diagnosis of diabetes in the Jamaican cases is not known, but seems unlikely to have differed from those outlined above. Table II gives the patients with first operation for senile cataract. There were 1,24 such patients of whom 1.7 per cent were diabetic. An interesting sidelight is that 3 per cent of all patients having a senile cataract extracted were previously "undiscovered" diabetics. Taking only the patients living within our defined area the results are even more clear-cut. Table III shows the total number of patients with first operation for senile cataract was 454, and 13 per cent (59) of these were diabetic. Of the total 454 patients, 19, or 4.2 per cent, were previously undiscovered diabetics who presented with cataract, thus leaving 8.8 per cent of known diabetics. Among the diabetics, one third (19 of 59) presented with cataract and their diabetes was diagnosed at the Eye Hospital. The visual indications for operation in diabetics and nondiabetics were identical (Table IV). Downloaded From: on 1/4/218

4 632 Pirie Itwestigative Ophthalmology August 1965 KNOWN DIABETICS BB NON - Table IV. Preoperative visual acuity in first operation for senile cataract*! Total patients Visual acuity: Less than 6/6 6/6 to 6/18 6/12 or better Nondiabetic Diabetic (82%) 89 (82%) 15 (17%) 18 (17%) 9(1%),1 ( 1%) "Preoperative visual acuity not known in 1 nondiabetics and 2 diabetics. ffrom Caird, Hutchinson, and Pirie: Brit. M. J. 2: 665, Table V shows a calculation of the relative frequency of first extraction of senile cataract in the age groups 5 to 69 and over 7 in those with known diabetes (i.e., excluding those who presented with cataract) and nondiabetics living in the defined area. Cataract extraction is seen to be between four and six times more common in known diabetics than in nondiabetics. The steep rise in cataract extraction with age is also shown and the larger number of cataract extractions in women. The results are presented graphically in Fig. 2. Fig. 3 compares the duration of diabetes and age at diagnosis of 11 diabetics who had a senile cataract extracted, 12 with SEX AGE Fig. 2. Relative frequency of first senile cataract extraction in nondiabetic persons and those with known diabetes living in the area. retinopathy, and 134 with persistent proteinuria. Age at diagnosis of those who have a cataract extracted is obviously higher than in other groups. Thus far, therefore, it seems clear that diabetics of mature age have more cataract extractions than nondiabetics of the same age, but their cataract has been diagnosed as senile and unconnected with their diabetes. It was therefore of great interest to try to establish whether control of diabetes was related to cataract extraction. Control was assessed from the proportion of urine tests that showed 2 per cent or more sugar in Benedict's test on routine attendance at the Radcliffe Infirmary Dia- M F Table V. Relative frequency of first senile cataract extraction in nondiabetics and known diabetics living in the area* Age and over Male Female Male Female Estimated total population 24,34 29,92 7,37 1,21 Known diabetics in population ( % ) f Estimated number of known diabetics First senile cataract extraction Known diabetics Cataract extraction (rate per 1,/yr.) Known diabetics Ratio of cataract extraction rates known diabetics/nondiabetics "From Caird, Hutchinson, and Pirie: Brit. M. J. 2: 665, fworking Party (1962), personal communication. Cf. Brit. M. J. 1: 1497, Downloaded From: on 1/4/218

5 Volume 4 Number 4 Studies of cataract and diabetes 633 YEARS 3O- 2O IIO DIABETICS WITH CATARACT EXTRACTION 79 KNOWN 31 FOUND IO. V «o 2O 6O 8O to UJ \BE1 3O 2O 126 DIABETICS WITH RETINAL H'GES AND/OR EXUDATES DURATION OF IO O ** *. Vr v ' * 2O 4O 6O 8O DIABETICS WITH PROTEINURIA. 2 1 «2O 4O 6O 8O YEARS AGE AT DIAGNOSIS OF DIABETES Fig. 3. Duration of diabetes and age at diagnosis of 11 diabetics who had had a senile cataract extracted, in 126 with retinopathy, and in 134 with persistent proteinuria. (From Caird, Hutchinson, and Pirie: Brit. M. J. 2: 665, ) betic Clinic. Of the diabetics who had had a cataract extracted, only those were considered who had attended the Clinic on five or more occasions before their operation. They were compared with 1 diabetics, chosen at random from those at present attending the Clinic, who had also been tested five or more times. No attempt was made to match this random group with the patients who had had a cataract extracted since previous experience had shown that such attempts result in much bias. 7 Fig. 4 shows the effect of control of diabetes on cataract extraction. The proportion of patients with a high frequency of 2 per cent glycosuria is significantly greater (at the 1 per cent level) among those who had had a cataract extracted. Table VI gives the calculations of significance. The effect of poor control of diabetes in the genesis of recognized diabetic cataract Downloaded From: on 1/4/218

6 634 Pirie Investigative Ophthalmology August WITH CAT. EXT! ^ H IOO RANDOM <I9 2O-39 >4O PERCENT OF 3+ URINE TESTS Fig. 4. Relation of control of diabetes to cataract extraction. has been suggested by clinical studies, 8 and by experimental work in the rat 9 and in the dog. 1 Our findings suggest that the development of cataract leading to lens extraction in the older diabetic is also influenced by control of diabetes. This is reasonable from consideration of the peculiar metabolism of the lens. There thus exists at least the theoretical possibility of prevention, or delay in maturation, of cataract in some patients, by early diagnosis and scrupulous control of the diabetes. Some 16,75 patients over 45 have a cataract extracted each year in England and Wales. 11 If 13 per cent of these are diabetics, the annual number of operations on diabetics is 2,18. At least 3 per cent of all patients having a senile cataract extracted have previously undiscovered diabetes. Thus diabetes is diagnosed in some 44 persons every year in England and Wales on account of cataract alone. Routine urine testing of all patients with Table VI. Effect of control of diabetes* Total No. of patients % of routine clinic urine tests showing 2 % glycosuria 19% or less 2-39 % Over 4% with cataract extraction "Random" diabetic clinic patients X 2 = 15.2, d.f. = 2, P = <.1 From Caird, Hutchinson, and Pirie: Brit. M. J. 2: 665, Table VII. Oxford. Average values and range for sorbitol, glucose and fructose, and sum of all three, in senile cataracts*! Carbohydrate Sorbitol Glucose Fructose Sum of all these Nondiabetic Average (fimoles/ Gm. lens) Range (fimoles/ Gm. lens) Diabetic Average (pmoles/ Gm. lens) * Range (pmoles/ Gm. lens] "From Pirie and van Heyningen: Exper. Eye Res. 3: 124, 1964, Academic Press, Inc. f Trace amounts have been neglected. I One value of 17.8 excluded. {One value of 18.9 excluded. senile cataract, on their first attendance and on as many subsequent occasions as possible, would seem obligatory. Biochemical investigation of human senile cataract lens We turn now to the biochemical investigation. are four to six times more prone to cataract extraction than nondiabetics. Do their lenses contain an abnormally high amount of sorbitol and fructose? van Heyningen 2 has already examined a small number of cataractous lenses of diabetics and foimd an excess of sorbitol but we thought it worthwhile to extend this observation. A factor to be borne in mind is that a diabetic in the hospital has controlled diabetes with blood sugar as near normal as careful treatment can make it. Therefore the lens of a diabetic removed at operation will have had several days, at least, of normal blood sugar and normal sugar in blood and aqueous humor, so that if excess sorbitol in the lens is characteristic of diabetes any excess found in hospital patients will be minimal. The lenses were obtained at operation and frozen within one-half to one hour of removal. Our series came from operations at the Oxford Eye Hospital and a second from operations at the University College of the West Indies where it appeared there might be a higher proportion of diabetics, but this did not turn out to be so. 12 Downloaded From: on 1/4/218

7 Volume 4 Number 4 Studies of cataract and diabetes 635 Table VIII. Oxford. Percentage of senile cataractous lenses containing appreciable amounts of sorbitol, glucose, or fructose from diabetic and nondiabetic patients* Percentage of lenses containing carbohydrate at a level of.5 (imoles/gm. lens, or higher Carbohydrate Nondiabetic Diabetic Sorbitol 59 Glucose Fructose Total number of noncliabetics 32; of diabetics 22 "From Pirie and van Hevningen: Exper. Eye Res. 3: 124, 1964, Academic Press, Inc. Table IX. Jamaica. Sorbitol, glucose, and fructose in senile cataractous lenses from nondiabetic and diabetic patients* Carbohydrate No. and % of lenses containing more than.5 nmole/gm. lens Nondiabetic No. i% Diabetic No. i% Sorbitol Glucose Fructose Total number of nondiabetics 24; of diabetics 7 "From Pirie and van Heyningen: Exper. Eye Res. 3: 124, 1964, Academic Press, Inc. The sugar levels were estimated chromatographically as previously described by van Heyningen 2 and Pirie and van Heyningen. Table VII shows the average values and range found in 22 senile cataracts from diabetics and 32 from nondiabetics operated on in Oxford. Sorbitol is absent from the senile cataractous lens of the nondiabetic but is on average 1. mm. with a range of to 4. mm. in the diabetic lens. Glucose and fructose are also higher in the cataractous lens of the diabetic. In one lens from a diabetic a very high level of glucose was present. This was excluded in determining the average. Table VIII shows the percentage of lenses showing more than.5 mm. carbohydrate. Owing to method of collection of lenses in Jamaica, estimation of carbohydrates was not possible but Table IX shows that % of the 7 diabetic lenses had more than.5 mm. sorbitol while only 1 /?4 of the nondiabetic had any sorbitol. Table X shows the results of analysis of 7 noncataractous lenses obtained post mortem in Oxford, 4 nondiabetic and 3 diabetic. The difference is clear. Inositol in senile cataract Chromatography of sorbitol, glucose, and fructose by our method also demonstrates inositol and this has been estimated in the whole series of lenses. We found it varied very greatly, the concentration ranged from 1 to 47 mm. and did not seem to be correlated with that of sorbitol or fructose, with the presence of diabetes, weight of lens, or age or sex of patient. But van Heyningen noticed an inverse correlation between inositol and glucose concentration in the cataractous lens (Table XI). Of the cataractous lenses of nondiabetics nearly all (82 per cent) which had low glucose (<1 mm.) had high inositol (1 Table X. Oxford. Sorbitol, glucose, fructose, and inositol in the noncataractous lens (postmortem material)* Sex F M MM M MM Age (years) Presence or absence of diabetes - _ Fasting blood sugar (mg./loo ml.) Sorbitol (fimoles/gm. lens) Trace Trace Glucose (fimoles/gm. lens) Trace Trace "From Pirie and van Heyningen: Exper. Eye Res. 3: 124, 1964, Academic Press, Inc. Fructose Inositol (fimoles/gm. (fimoles/gm lens) lens) Trace 32 Trace Downloaded From: on 1/4/218

8 636 Pirie Investigative Ophthalmology August 1965 Table XI. Relation between inositol and glucose in the cataractous lens*f Nondiabetic subjects Diabetic subjects No. lenses analyzed Lens glucose (limoles/gm. lens) to.9 1. and above to.9 1. and above Inositol 1 nmoles/gm. lens and above No No. and % of lenses Inositol < 1 fimoles/gm. lens From Pirie and van Heyningen: Exper. Eye Res. 3: 124, 1964, Academic Press, Inc. fthe 72 lenses are all the cataractous lenses, Oxford and Jamaica, nondiabetic and diabetic, in which both glucose and inositol were assayed. mm. or more). If the lens had a high glucose concentration, 1 mm. or greater, very few (1 per cent) had high inositol. Of the lenses from diabetics all with low glucose and about half of those with high glucose had high inositol. The inverse relation is not so clear, perhaps because the concentration of glucose in aqueous humor may be abnormally high in the diabetic patient, so that our arbitrary dividing line of 1 mm. glucose in the lens is unsuitable. In a single experiment a direct comparison between a cataractous and a normal lens was possible. An x-ray cataract was induced in a rabbit and the inositol and glucose content of the two lenses was compared. Table XII shows that the glucose is high and the inositol low in the cataractous lens. The weight of the lens is increased, showing that permeability is abnormal. During development of x-ray cataract the weight of the irradiated lens may be 1 per cent less than that of the normal contralateral lens owing to loss of epithelial cells and retarded growth, but Table XII. Comparison between the glucose and inositol content of the x-ray cataract and normal lens of a rabbit* X-ray cataract Lens weight (mg.) Glucose (jumoles/gm. lens) Inositol (/imoles/gm. lens) Right lens <.5 Left lens - 45 >5.5 "From Pirie and van Heyningen: Exper. Eye Res. 3: 124, 1964, Academic Press, Inc. No when the cataract becomes mature the lens swells and its weight is greater than that of the normal. This suggests that the cataractous lens, however the cataract is produced, is no longer able to maintain the concentration gradients between lens fiber and aqueous humor. Substances which are normally more concentrated in the lens, e.g., inositol, will leak out and those more concentrated in the aqueous humor, e.g., glucose, will leak in. Lenses with less inositol also have diminished amounts of free amino acids and glutathione. 13 These amino compounds are usually at a higher concentration in the lens than in the aqueous humor, and presumably diffuse out when the capsule becomes more permeable, whereas sodium and chloride ions, kept out of the normal lens, diffuse in. 14 Change of permeability in sugar cataracts in rats has been conclusively demonstrated by Patterson and Bunting 15 who find that the sudden appearance of cataract in young diabetic rats is associated with an equally sudden change in the permeability of the lens fiber membrane causing a leaking out of sorbitol and fructose and a leaking in of glucose. There is at the same time an increase in lens weight and in the extracellular space. In similar experiments in which cataracts were produced by galactose feeding, Patterson and Bunting 15 found a loss of dulcitol and an increase of extracellular space at the time of sudden cataract formation. Kinoshita, Merola, and Dikmak 4 had found loss of dulcitol as the opacity developed, but they Downloaded From: on 1/4/218

9 Volume 4 Number 4 Studies of cataract and diabetes 637 also noted loss of water, perhaps because the cataract process was less advanced than in the rats studied by Patterson and Bunting. It may not be justifiable to apply these results on the sudden cataract in young rats to the gradual cataract in elderly diabetic patients, but there is probably much in common between the two processes. Taken together with our finding of loss of inositol from the human lens they may explain the low level of sorbitol and fructose found in cataractous lenses of diabetics. The small amounts demonstrated in lenses removed at operation cannot be considered as osmotically harmful. There may have been larger amounts, harmful amounts, present at an earlier stage before change in permeability set in, as our analysis of noncataractous lenses of diabetics does suggest. But though our results bring the cataract of the human diabetic into line with the cataract of the alloxan diabetic rat, they do not show that accumulation of sorbitol and fructose is the toxic factor. It seems unlikely that this can be proved in man. What our results have shown is that 13 out of every 1 operations for senile cataract are in diabetics, a finding which, as it increases our concern about diabetes and its control, must proportionally reduce our concern about senile cataract as a cause of blindness and disability. After study of the 1, or so case notes of patients who had had a senile cataract extraction, I believe that there may be further groups of patients whose cataract, listed as senile, may be due to a cause other than simple old age. Understanding of cataract can I believe be gained in this way. The notes of the ophthalmologist could be the source book for biochemical research. REFERENCES 1. Patterson, J. W.: Development of diabetic cataracts, Am. J. Ophth. 35: 68, May (part ;2), van Heyningen, R.: Formation of polyols by the lens of the rat with "sugar" cataract, Nature 184: 194, van Heyningen, R.: The sorbitol pathway in the lens, Exper. Eye Res. 1: 396, Kinoshita, J. H., Merola, L. O., and Dikmak, E.: Osmotic changes in experimental galactose cataracts, Exper. Eye Res. 1: 45, Caird, F. I., Hutchinson, M., and Pirie, A.: Cataract and diabetes, Brit. M. J. 2: 665, 6. Pirie, A., and van Heyningen, R.: The effect of diabetes on the content of sorbitol, glucose, fructose, and inositol in the human lens, Exper. Eye Res. 3: 124, 7. Caird, F. I.: Survival of diabetics with proteinuria, Diabetes 1: 178, O'Brien, C. S., Molsberry, J. M., and Allen, J. H.: Diabetic cataract, J. A. M. A. 13: 892, Patterson, J. W.: Course of diabetes and development of cataracts after injecting dehydroascorbic acid and related substances, Am. J. Physiol. 165: 61, Ricketts, H. T., Petersen, E. S., Lints, H., Tupikova, N., and Steiner, P. E.: Degenerative lesions in dogs with experimental diabetes, Diabetes 8: 298, Sorsby, A.: Cataract: Some statistical and genetic aspects, Exper. Eye Res. 1: 296, Tulloch, J. A.: Diabetes mellitus in the tropics, London, 1962, E. & S. Livingston, Ltd. 13. van Heyningen, R.: Unpublished data. 14. Salit, P. W.: Mineral constituents of sclerosed human lenses, Arch. Ophth. 3: 255, Patterson, J. W., and Bunting, K. W.: Lens cell membrane permeability and cataract formation, Proc. Soc. Exper. Biol. & Med. 115: 1156, 16. Waite, J. H., and Beetham, W. P.: The visual mechanism in diabetes mellitus, New England J. Med. 212: 367 and 429, Heinsius, E., and Arndt, G.: t)ber Haufigkeit des Vorkommens, Form und Genese der echten diabetischen Katarakt und Katarakt bei Diabetes, Graefes Arch. Ophth. 15: 555,, Dollfus, M. A.: Discussion du rapport, Bull, et mem. Soc. franc, opht. 67: 62, Kato, K., Amaha, E., Hagai, A., and Matusui, M.: Statistical observation on the incidence of cataract in diabetic patients, Acta Soc. Ophth. Jap. 64: 577, Clegg, J. G.: Diabetes in relation to diseases of the eye, Trans. Ophth. Soc. United Kingdom 4: 37, Anthonisen, H.: The frequency of diabetic cataract and diabetic glaucoma as compared to the frequency of diabetes in the general population of Denmark, Acta ophth. 14: 15, Townes, C. D., and Casey, E. R.: Cataract surgery in diabetic patients, South. M. J. 48: 844, Downloaded From: on 1/4/218