Saturday 3 November 1979

FISH-EYE DISEASE A NEW FAMILIAL CONDITION WITH MASSIVE CORNEAL OPACITIES AND DYSLIPOPROTEINÆMIA

L. A. CARLSON

B. PHILIPSON

Departments of Internal Medicine and Ophthalmology, and the King Gustaf V Research Institute, Karolinska Hospital, Stockholm, Sweden A man and his three daughters had massive corneal opacities called in their home village "fish-eye disease" because of the resemblance of the eyes to those of boiled fish. The two living

Summary

daughters had the same dyslipoproteinæmia, characterised by normal serum cholesterol but raised serum triglycerides, raised very-low-density lipoproteins, strikingly high levels of low-density lipoprotein (LDL) triglycerides. LDL contained normal sized as well as abnormally large particles and a 90% reduction in the level of high-density lipoprotein (HDL) cholesterol. Lecithin:cholesterol acyltransferase (LCAT) activity and the percentage of plasma cholesterol esters were normal, which excluded LCAT-deficiency. Normal electrophoretic mobility of HDL as well as other lipoprotein findings excluded Tangier disease. The clinical and laboratory abnormalities in fish-eye disease are atherosclerosis at old age, visual impairment, and dense corneal opacification. Fish-eye disease thus differs both clinically and in its lipoprotein abnormalities from LCAT-deficiency and Tangier disease.

immediately obvious. The patient’s father and two elder sisters had had the same eye disease, while another sister and a brother had not. One of the afflicted sisters, patient 2, was still alive and the other had died in an accident at the age of 37. The father had died at the age of 76 from myocardial infarction. In her parents’ small village in northern Sweden the family was said to have had fiskögonsjukdomen, "fish-eye disease", because their eyes resembled those of boiled fish. Patient 7.—Born 1914, widowed, no children. She noted in childhood a slight impairment of vision, which thereafter slowly progressed. At age 15-20 years she was recognised to have had fish-eye disease. She had no other medical history and is in good general health. She lives alone but is handicapped, particularly in the dark winter months, by impaired vision. Both corneas were symmetrically opaque (fig. 1) and the irises could be seen only as indistinct shadows. Biomicroscopiwere

Introduction

CHANGES in the cornea occur in several conditions with hyperlipoproteinsemia or hypolipoproteinsemia. The best-known is the arcus cornea: (arcus lipoides, arcus senilis) often present when levels of low-density lipoproteins (LDL) are raised, as in familial hyperchotesterolsmia. Two

rare familial conditions in which there are low levels of high-density lipoproteins (HDL) are associated with corneal opacities-namely Tangier disease! (familial HDL deficiency) and lecithin:cholesterol serum

acyltransferase (LCAT) deficiency.2 We describe here a new syndrome in a Swedish family in which there is dense corneal opacification and low serum concentrations of HDL.

Case-reports patient (patient 1) was referred to L.A.C. in November, 1975, with hypertriglycehdaEmia. Corneal opacities The index

1-Corneal appearance in the two sisters with fish-eye dis(A and B, patient 1 ; E and F, patient 2) and in a normal person (C and D).

Fig.

ease

In A, C, and E the whole cornea is illuminated and in B, D, and F the cornea is illuminated with a broad slit light from the left side. In the fish-eye corneas the cloudiness and the peripheral opaque zone

with the thin yellow ring-shaped opacity (here appearing as a thin black line) can be seen. The mosaic pattern of the small opacities is seen in the slit lamp photos (B and F).

8149

922 corneal cloudiness appeared as small dotlike greywhite-yellow opacities forming a mosaic pattern. This cloudi-

cally the

present in all layers of the corneas except the epithemajor area of the cornea was uniformly turbid. The peripheral cornea was more opaque but no distinct corneal arcus could be distinguished. In this peripheral opaque zone a thin superficial yellow ring-shaped opacity was present about 1 mm from the limbus. Corneal sensation was normal. The conjunctiva appeared almost normal but slightly yellow, and the blood vessels were more distinct than is normal. The lids and adnexx were normal. Intraocular pressure was normal. Visual acuity in 1978 was 0.4 (6/15) right, and 0.3 (6/18), left. Physical examination has always been normal. Tonsils are small and of normal colour. Repeated examinations have revealed normal hoematology, liver and kidney functions, electrolytes, and thyroid function (including thyroid-stimulating hormone levels). Peripheral circulation (by pulse plethysmography strain-gauge) and blood-pressure gradients have

ness was

lium. The

3-Electron microscopy of isolated LDL (density 1.006-1.063). Magnification x40 000 (reduced to 4). Particle diameter 17-50 nm. Large particles are not present in normal LDL. Small particles seem

Fig. Tngtycendes and cholesterol in lipoproteins (mmol/lJ

identical

to

normal LDL.

1). She died suddenly in January, 1977, and no necropsy was done. The biochemical methods have been described elsewhere. 3,4 Post-heparin lipase activities5 were determined by Dr C. Enholm, Helsinki, and apolipoprotein AI, All, and D6by Dr 0. Wiklund, Gothenburg. A detailed biochemical report on patients 1 and 2 will be given elsewhere. -

i

1

Results

Fig. 2-Concentrations of cholesterol (CH) and triglycerides (TG) (mmol/1) in serum and in isolated serum lipoproteins in relation to normal values. .

patient 1; 0 patient 2.

Both patients had the same fasting serum lipoprotein abnormalities (fig. 2 and table i). Serum cholesterol was normal while serum triglycerides were raised. Very-lowTABLE II-CLINICAL AND LABORATORY FINDINGS

been normal. The heart was normal radiologically and there were calcifications in the aortic arch. The electrocardiogram at rest was normal and during exercise on a bicycle ergometer showed significant ST-segment depressions at a work load of 90 watts. Patient 2.-Born 1899, married, no children. She noted a thin coat over her eyes at age 15-20 years, and fish-eye disease was recognised in the village. Vision then slowly deteriorated but to a lesser extent than in patient 1. She had no medical history except for a myocardial infarction in May, 1976. The tonsils were small and had a normal colour. Biochemical laboratory investigations were normal except for raised serum uric acid (695 mol/1). Visual acuity (right) 0-3, (left) 0-4. The corneal appearance was almost identical to that of patient 1 (fig. TABLE I-TRIGLYCERIDE

dean age 65

(TG)

AND CHOLESTEROL

(CHOL)

IN TOTAL SERUM AND IN SERUM LIPOPROTEINS

(30-70) yr. Values adjusted to 65 years by the regression equations for lipids against age.33

(MMOL/L).

923 TABLE

III-MAJOR

density (VLDL) triglycerides and cholesterol were raised, as in a moderate type-iv hyperlipoproteinsemia, and the ratio of cholesterol to triglycerides was normal. Most strikingly, however, the triglyceride content of LDL was very high and that of HDL cholesterol was extremely low. Repeated analysis in patient 1 always gave similar results. The LDL triglyceride content is the highest seen in our lipoprotein laboratory. Lipoprotein electrophoresis of whole serum showed a faint ex-band and a broad p-band. However, islolated VLDL had normal mobility, and there was no floating p-band. Electronmicroscopy (fig. 3) of isolated LDL showed’abnormally large particles in addition to apparently normal LDL particles. ’

The content of cholesterol esters in serum and in isolated lipoproteins, as well as LCAT activity, was normal in both patients. Post-heparin plasma activity of lipoprotein lipase and hepatic lipase in patient 1 was normal. Polyacrylamide disc gel electrophoresis of apolipoproteins8 of HDL from patient 1 showed the presence of the same bands as in normals. Electroimmunoassay on whole serum from patient 1 showed that apolipoprotein AI, All, and D were present at approximately 15, 10, and 12% of the levels in healthy men.6 Discussion The two other familial conditions with low HDL levels and other lipoprotein abnormalities-Tangier disease (familial HDL deficiency) and LCAT deficiencyhave similarities with fish-eye disease, but there are also differences (tables n and III). In both LCAT-deficiency and fish-eye disease the corneal opacities are clearly visible to the naked eye, but in LCAT-deficiency visual acuity is not reduced2.9 except in one Indian,’O in whom the impairment was assumed to be due to old trachomatous corneal scarring. In Tangier disease corneal opacities are evident only on slit-lamp examination and do not cause visual impairment. Our patients had none of the characteristic symptoms and signs of either Tangier disease or LCAT-deficiency. Indeed, except for atherosclerosis in old age, corneal opacities are the most important clinical finding in fish-eye disease.

LIPOPROTEIN FINDINGS

Biochemically, fish-eye disease is most clearly differentiated from LCAT-deficiency by the normal percentage of cholesterol esters and the normal activity of LCAT (table 11). There are also several biochemical differences from Tangier disease (table m). Although there are only trace amounts of HDL in Tangier disease in some patients the concentration reaches about 10% of normal,’ values similar to those encountered in fish-eye disease. In lipoprotein electrophoresis, however, there is a faint otj-lipoprotein (HDL) band in fish-eye disease which is absent in Tangier disease. Another difference is the much lower plasma concentration of apolipoprotein AI in Tangier disease (table in). The basic biochemical defect in fish-eye disease is unknown. The low level of apparently normal HDL may be -the primary event, causing a faulty catabolism of triglyceride-rich lipoproteins with the accumulation of abnormally large LDL particles (fig. 3) and triglyceride enrichment of the LDL density fraction. Large LDL particles and triglyceride enrichment of LDL occur in LCAT deficiency2 but have also been reported in liver disease."’" It seems certain in LCAT -deficiency,2 and has been postulated in liver disease,12 that the triglyceride enrichment of LDL is due to deficient or low LCAT activity. The normal LCAT-activity and the normal percentage of cholesterol esters makes this an unlikely explanation for the triglyceride-rich LDL in fish-eye disease.

Perhaps cholesterol-ester/triglyceride exchange

between LDL and HDL is impaired. Human plasma contains an apolipoprotein which mediates transport of cholesterol esters from HDL to LDL and VLDL, with equimolar transport of triglycerides back in the other direction. 13 This transfer protein is a minor apolipoprotein of HDL. In fish-eye disease the 90% reduction of both HDL lipids and apolipoproteins may cause a significant reduction in lipid exchange between LDL and HDL and result in absolute deficiency of cholesterol esters and triglyceride enrichment of LDL. ’.

The work was supported by grants from the Swedish Medical Research Council (19X-204) and (12X-4204).

Requests for reprints should be addressed to L. A. C.

924

COMBINED USE OF GUAR AND ACARBOSE IN REDUCTION OF POSTPRANDIAL GLYCÆMIA DAVID

J. A. JENKINS

Department of the Regius Professor of Medicine, Radcliffe Infirmary, Oxford

acarbose was taken alone, 3 of the 8 subjects had troublesome symptoms and the 30 min rise in blood-glucose was reduced by only 28%. Thus, combination of these two agents effectively reduces the rate of carbohydrate absorption without increasing side-effects and may make combined acarbose and guar acceptable in the management of some diabetics.

RODNEY H. TAYLOR Central Middlesex Hospital, London NW10

Department of Gastroenterology, RICHARD NINEHAM*

DAVID V. GOFF

University Laboratory of Physiology, Oxford STEPHEN R. BLOOM

DAVID SARSON

Royal Postgraduate Medical School, London K. GEORGE M. M. ALBERTI

Department of Clinical Biochemistry, Royal Victoria Infirmary, Newcastle upon Tyne

Symptoms associated with carbohydrate malabsorption limit the usefulness to diabetics of a powerful glycoside-hydrolase inhibitor (acarbose) which reduces postprandial glycæmia. Addition of a low dose (50 mg) of a acarbose together with 14·5 g guar gum to a breakfast test meal taken by 8 healthy volunteers reduced the mean peak rise in bloodglucose at 30 min by 70%. Areas under the insulin and gastrointestinal-polypeptide response curves were also greatly reduced. No evidence of carbohydrate malabsorption, as assessed by measurement of breath hydrogen, was found during any of.the test periods. When Summary

Introduction INVESTIGATION of the possibility of treating diabetics by slowing the rate of glucose absorption from the gut1-5 has centred on the use of dietary fibre, especially guar gum, to modify glucose tolerance in healthyl.2 and diabetic volunteers3 and to reduce glycosuria in diabetics.’ It has been suggested that the mechanism of action is

related to physical properties such as viscosity, which both delays gastric emptying6 and reduces the rate of uptake of glucose from the lumen of the small intestine.2 An alpha-glycoside-hydrolase inhibitor (acarbose

[BAY g5421], Bayer UK Ltd., Haywards Heath, Sussex) blood-glucose after 100 g sucrose given to healthy subjects’ and diminishes the postprandial rises in glucose and metabolites in diabetics.! Its use has been limited by common and often unacceptable side-effects,5 including flatulence and diarrhoea secondary to colonic fermentation of malabsorbed reduces the rise in

sugars. To minimise these effects and reduce the dose of acarbose required, a combined approach using the physical properties of guar in combination with a low dose of acarbose has been tested in healthy volunteers. Methods

(age 37±3yr,116+3% ideal weight) were given of four different breakfasts in random order after overnight fasts. Meals were taken on four separate mornings separated by at least 2 days. The four tests were all completed within 2-3 weeks. On the day before the first test all subjects recorded their dietary histories. They followed the same meal plan on the day preceding all tests. The meals were identical in all respects, except that the guar meals contained 4 g extra protein in crispbread in addition to 14 g guar. The control meal consisted of 34 g carbohydrate, 1 g fat, and 32 g protein, taken as crispbread (Speywood Laboratories, Bingham, Nottingham), 21 g ’Flora’ margarine (Van den Burgh Ltd), 70 g marmalade (’Wiltshire Jams’, Samuel Moore Food Ltd, without artificial colouring, sweetener, or preservative), and 45 g homogenised milk in two cups of tea (300 ml total). These meals, containing a total of 85 g carbohydrate, were taken over 10-15 min. On two occasions, the breakfasts contained fourteen control crispbreads and on two other occasions, these were replaced by fourteen guar crispbreads each containing 1 g guar per slice. 60 s before one control and one guar breakfast, the subjects chewed and swallowed a tablet containing 50 mg acarbose in place of the placebo tablets taken before the other two meals. 8

men

one

*Mr Nineham died on Aug.

25.

1. Herbert PN, Gotto

AM, Fredrickson DS. Familial lipoprotein deficiency. In: Stanbury JB, Wyngarden JB, Fredrickson DS, eds. The metabolic basis of inherited disease. 4th edition. New York: McGraw-Hill, 1978: 544-88. 2. Gjone E, Norum KR, Glomset JA. Familial lecithin:cholesterol acyltransferase deficiency. In: Stanbury JB, Wyngarden JB, Fredrickson DS, eds. The metabolic basis of inherited disease. 4th edition. New York: McGraw-Hill, 1978:589-603. 3. Carlson LA, Ericsson M. Quantitative and qualitative serum lipoprotein analysis. Studies in healthy men and women. Atherosclerosis 1975; 21: 417-33. 4. Redgrave TG, Carlson LA. Changes in plasma very low density and low density lipoprotein content, composition, and size after a fatty meal in normoand hypertriglyceridæmic men. J Lipid Res 1979; 20: 217-29. 5. Huttunen JK, Enholm C, Kinnunen PKJ, Nikkilä E. An immunochemical method for the selective measurement of two triglyceride lipases in human post heparin plasma. Clin Chim Acta 1975; 63: 335-47. 6. Fager G, Olofsson SO, Wiklund O, Bondjers G. Apolipoproteins and actue myocardial infarction. Eur J Clin Invest 1979; 9: part II, p. 10; abstract 60. 7. Stokke KI, Norum KR. Determination of lecithin:cholesterol acyltransferase activity in human blood plasma. Scand J Clin Lab Invest 1971; 27: 21-27. 8. Carlson LA, Ballantyne D. Changing relative proportions of apolipoproteins CII and CIII of very low density lipoproteins in hypertriglyceridæmia. Atherosclerosis 1976; 23: 563-68. 9. Hørven I, Gjone E, Egge K. Ocular manifestations in familial LCAT deficiency. Birth Defects 1976; XII: 271-78. 10. Bron AJ, Lloyd JK, Fosbrooke AS, Winder AF, Tripathi RC. Primary LCAT-deficiency disease. Lancet 1975; i: 928-29. 11. Müller P, et al. Hypertriglyceridæmia secondary to liver disease. Eur J Clin

Invest 1974; 4: 419-28. J, Holme R, Blomhoff JP. Triglyceride lipase activity in postheparin plasma and plasma lipoproteins in liver disease. Clin Chim Acta 1978; 87:

12. Suar

327-40. 13. Chajek T, Fielding CJ. Isolation and characterisation of a human serum cholesteryl ester transfer protein. Proc Natl Acad Sci U.S.A. 1978; 75: 3445-49.

Blood

samples, taken

at

0, 15, 30, 60, 90, and 120 min

"butterfly" needle kept patent with heparinised saline, were analysed for glucose8 and by radioimmunoassay for insulin,9 gastrointestinal polypeptide (GIP)," and enteroglucagon.’1 End-expiratory gas samples were obtained at the same time as the blood samples and also at 135 and 150 min for analysis of breath hydrogen as an index of carbohydrate malabsorption. 12 The subjects recorded the timing and severity of any symptoms experienced in the 24 h after the test. The symptoms they were especially asked to note were: flatulence, abdominal distension, and alteration of bowel habit (looseness and frequency

through

a

Familial rheumatoid arthritis and HLA-DRw4.

Saturday 3 November 1979 FISH-EYE DISEASE A NEW FAMILIAL CONDITION WITH MASSIVE CORNEAL OPACITIES AND DYSLIPOPROTEINÆMIA L. A. CARLSON B. PHI...
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