- Email: [email protected]
VASCULAR DISEASE IN A DIABETIC CLINIC
985
In a series of 300
overall frequency
tests
was
with
a
wide range of needles the
TABLE I-INCIDENCE OF CLINICAL VASCULAR DISEASE IN 654 DIABETICS
69%.
There is no great variation in the frequency with different sizes of needles, but the skin fragment is roughly proportional to the size of the lumen. Side-opening needles and those with a fitted stilette do not remove skin fragments. We are very grateful to Prof. J. P. Todd and Mr. George Reid, of the Glasgow Royal College of Science and Technology, for much helpful advice and technical assistance. We are also greatly indebted to Prof. T. Symington for his help with the animal experiments. Mr. Robert McGregor and Mr. Donald Hay were responsible for the photographs. REFERENCES Crawford, L. D. (1955) Canad. med. Ass. J. 72, 374. Magath, T. B., McClellan, J. T. (1950) Amer. J. clin. Path. Mitchell, J. V. (1952) Anœsthesia, 7, 258.
20, 829.
VASCULAR DISEASE IN A DIABETIC CLINIC
J. G. LEWIS M.B.
Lond., M.R.C.P.
MEDICAL REGISTRAR
C. SYMONS Lond., M.R.C.P.
M.D. FIRST
ASSISTANT, CARDIAC DEPARTMENT
ROYAL FREE
HOSPITAL, LONDON, W.C.1
of those who attended over the three-year period, fulfilled these requirements and were included in this study. Two aspects were considered in the assessment of vascular disease in diabetics: (1) the specific vascular abnormalities of diabetes, such as retinopathy and nephropathy; and (2) the complications due to atherosclerosis such as atherosclerotic heart-disease and peripheral vascular disease. These vascular complications were regarded as evidence of clinical vascular disease. The incidence of hypertension, obesity, and hypercholesterolxmia and their relation to clinical vascular disease and electrocardiographic abnormalities were studied. We have not included cerebrovascular disease, which was present in 4% of patients and was almost invariably associated with vascular disease elsewhere.
Composition of Series
The number of women in the survey was 477 (73%) and of As the treatment of diabetes mellitus improves, so the men 177. 45% of all patients were treated by diet alone. prevalence of vascular disease increases; and now it has is shown in fig. lA; 90% of the patients were Age-distribution become the most important problem in the management over 40 years of age. The proportion of women in this series of diabetes. To estimate how frequently clinical vascular was higher than that reported in other diabetic clinics dealing disease occurs, a survey was made of patients who had with white people (Wilder et al. 1940, Munro et al. 1949, Joslin attended the diabetic department of the Royal Free and et al. 1952); and this was no doubt due largely to the preponHampstead General Hospitals during 1955, 1956, and derance of women attending the Royal Free Hospital. The 1957 either as outpatients or inpatients. A few patients duration of diabetes and the number of patients in each group is shown in fig. 1B. 90% of patients with diabetes of 0-5 years’ were also referred to the Royal Free diabetic clinic from an duration were over 40 years of age. Ophthalmic Hospital. Clinical Vascular Disease Material and Methods Clinical vascular disease was diagnosed when one or more of The criteria for acceptance in this study were that the patient the following complications was present: should have proven diabetes, have had a full clinical history and 1. Diabetic confirmed an
examination, blood-pressure estimations, height and weight recording, chest X-ray, serum-cholesterol estimation, and at least one recent electrocardiogram. At each visit the urine was tested for glucose and protein. 654 patients, representing 75%
retinopathy, by ophthalmologist. Nephropathy, indicated by persistant proteinuria in the absence of urinary infection. This was usually associated with retinopathy, hypertension, and oedema. Clinically, this was a mixed group, and consisted of those with intercapillary glomerular sclerosis (Kimmelstiel-Wilson kidney) and those with pyelonephiritis and nephrosclerosis of hypertensive origin. 3. Atherosclerotic heart-disease, which was diagnosed when one or more of the following were present: angina pectoris; cardiac infarction (on clinical and/or electrocardiographic evidence); or a loud basal systolic murmur in the absence of hypertension, which we considered suggestive of 2.
aortic
or
aortic valve atheroma.
Peripheral vascular disease, which was diagnosed when any of the following were 4.
present: intermittent claudication; ischxniic rest pain; or absent arterial pulsation with pallor and coldness of the lower limbs.
Findings
Fig. 1-A, age-distribution and, 13,
duration ot
disease, in 654 diabetic patients.
Incidence of Clinical Vascular Disease The incidence of clinical vascular disease and the frequency of individual complications are shown in table 1. 279 patients (42-5%) of the 654 had evidence of clinical vascular disease. As more than one vascular complication was present in many patients, the total of individual com-
986
11 patients had evidence making a total of 51 (7-8%).
of
Clinical Vascular Disease related
symptomless infarction, to
Age and Duration of
Diabetes
Fig. percentage incidence of clinical vascular disease in 654 patients related to, A, age of patients and, B, duration of diabetes. was greater than the number of patients with disease. vascular Nephropathy was found in 4-1% of the series. This figure is unlikely to be an underestimate as each patient was tested for proteinuria at every visit. The total incidence of proteinuria of non-infective origin, including cases with heart-failure and hypertension, was 7-2%. A third of all patients with angina had electrocardiographic evidence of old or recent infarction. Cardiac infarction, based on history and clinical examination, supplemented by electrocardiography, was found in 40 patients (6%). With routine electrocardiography a further
plications
Figs. 2A and 3A show the incidence of vascular disease in different age-groups. The results are presented as percentages of the total number of patients in each agegroup. Figs. 2B and 3B show that clinical vascular disease increased with the duration of the diabetes. The high figure in the 0-5-year-duration group reflects those with diabetes of late onset who have associated vascular disease; moreover in those over 40 the clinical onset is not always an accurate guide to the duration of the disease. Retinopathy increased steadily with duration of diabetes, attaining a maximum of 80% in the 21-25-year-duration group. In the 0-5-duration group 13% had retinopathy (in this group only 3% of patients under 40 years of age had this complication compared with 17% of those over 60). The high figure of 13% may be due to the difficulty in dating the onset of diabetes by symptoms alone; indeed, patients not infrequently presented with visual deterioration due to retinopathy as their main complaint. TABLE II-PROPORTION OF HYPERTENSIVES IN EACH AGE-GROUP
DECADES)
(BY
OF SERIES OF DIABETICS
Retinopathy also increased with age; the percentage for the third decade was 9-5%, and this rose to 29% in those over 80. Correlating age with duration, the incidence of retinopathy was highest in patients aged 41-60 who had had diabetes more than 21 years. The sex-distribution was almost equal. Nephropathy, apart from the first few years, increased with duration of diabetes. The relation to age was not impressive; the proportions were highest in patients in their 30’s and over 60. It occurred most often in those over 60 who had had diabetes for the longest period. Men comprised 50% of those with nephropathy, yet only 27% of the whole series. Atherosclerotic disease was present at all duration periods of diabetes. Age was more important than duration of the disease; the highest incidence of atherosclerosis was found in patients over 60 who had had diabetes more than twenty years. In patients aged 10-40 years the incidence of atherosclerosis, even in those with the longest duration, was no more than 5%.
Fig. 3-Percentage of patients with each vascular complication related to, A, age of patient and, B, duration of diabetes.
Clinical Vascular Disease, Obesity, and Hypertension Patients were considered overweight if 10% more than their expected weight for their sex, age, and height. 53°o of the women and 49% of the men were overweight. Of the women with clinical vascular disease 58% were obese, compared with 49% of those with no vascular disease; the respective figures for men were 50% and 46%. Hypertension was considered present when a bloodpressure of over 160/95 mm. Hg was repeatedly recorded.
987
The incidence of hypertension was 36% for men and 56% for women. The proportion of hypertensives in each age-group of the series is shown in table 11. Hypertension was, therefore, commoner in women than men, the incidence increasing with advancing decades. Over 60 years of age 70% of the women and 50% of the men were
30-6%, Kornerup (1955) 46.8%, Bryfogle and Bradley (1957) 35-8%. These series included a higher proportion of younger diabetics. The incidence of retinopathy in younger patients with diabetes of long duration may be as high as 70-80% (Lundbaek 1954).
Nephropathy Bryfogle and Bradley (1957) found this complication in 10% of their diabetic inpatients, and other series give figures as high as 25% of diabetics (Wilson et al. 1951, Bell 1953); but these studies were either on young patients with diabetes of long duration or on inpatients. In our series nephropathy was uncommon (4-1 %)-comparable with low figure reported by Freedman et al. (1958). The prognosis of nephropathy is such that there were few patients with this disorder in the clinic at any given time. Routine testing of urine has shown, however, that the interval between onset of proteinuria without symptoms and death can be as long as eight years.
hypertensive.
Of obese patients hypertension was present in 43% of men and 61% of women, compared with 28% and 42% respectively for those of normal weight. 56% of hypertensive women and 60% of hypertensive In normotensives men had clinical vascular disease. clinical vascular disease was less common-23% in men and 38% in women.
Cholesterol Levels and Clinical Vascular Disease There were 85 men with a raised cholesterol level (over 200 mg. per 100 ml.), of whom 34 (40%) had clinical vascular disease. 92 men had normal serum-cholesterol levels, and 46 (50%) of these had clinical vascular disease. The figures for women were 254 with raised cholesterol, of whom 109 (40%) had clinical vascular disease, and 223 with normal values of whom 90 (40 %) had vascular disease. Patients with diabetic nephropathy had raised bloodcholesterol levels but their numbers have not influenced the general conclusions. The cholesterol levels were also related to abnormal electrocardiograms, but again there was no positive relationship. The serum-cholesterol level was not significantly higher in the patients with atherosclerotic heart-disease than in the remainder, nor did it differ in patients with clinical vascular disease as compared to those without.
Atherosclerotic Heart-disease It is difficult to compare atherosclerotic disease in one series, with another, because criteria for diagnosis vary and interpretation may differ between observers, as may the sample for age, We have not included as evidence of sex, and duration. atherosclerotic heart-disease, non-hypertensive cardiomegaly, arterial calcification, or non-specific abnormalities in the
electrocardiogram. 19-3% of our patients had atherosclerotic heart-disease, but Liebow et al. (1955) and Bryfogle and Bradley (1957) found totals of 42% and 56-3% respectively, using wider criteria of diagnosis. If those patients with angina and infarction only are considered (17% over 40 years of age in this group) then all three studies show similar findings. The proportion of patients with angina pectoris in this study was 11-6%. This compares with 9-1% found by Bryfogle and Bradley (1957) and 10-2 % by Liebow et al. (1955). Atherosclerotic heart-disease occurs more commonly in diabetics than in the general population. Brown et al. (1957) reported an incidence of 8-4% in a general practice survey of
Routine Electrocardiography The total number of patients with an abnormal electrocardiogram was 280 (42-5%). Those with clinical vascular disease and/or an abnormal electrocardiogram constituted 59 5% of the series. When patients with hypertension The incidence of were included the figure rose to 73%. in abnormalities patients with clinical electrocardiographic vascular disease was 61%, compared with 30% in those without electrocardiographic changes. The routine use of the electrocardiogram showed that subclinical infarction occurred sufficiently often to warrant its use in all diabetics over 40 years of age.
in the seventh decade. In the present series for the same and decade 34% had atherosclerotic heart-disease. In nondiabetic subjects Oliver and Boyd (1955) found that the male: female ratio of coronary-artery disease under the age of 50 was 7 : 1. In this series the incidence of atherosclerotic heart-disease, using slightly different criteria, was 1 :11 under 50 years of age but over this age men predominated by 1-6 : 10. The cholesterol levels were not significantly raised in patients with atherosclerotic heart-disease, which is in agreement with Liebow et al. (1955). This is surprising in view of the generally accepted findings that the serum-cholesterol level is raised in coronary-artery disease both in the general population (Gertler et al. 1950, Oliver and Boyd 1953), and in diabetics (Barach and Lowy 1952).
men sex
Deaths
patients in this series died during the threeperiod under study. 28 (76%) of these patients died from cardiorenal causes; 11 of them had nephropathy. 37 of the
year
Peripheral Vascular Disease Oakley et al. (1956), in a large series, reported an overall figure of 35% rising to 10% in those over 70. Bryfogle and Bradley (1957), using similar criteria, found an incidence of 15-7%. In the present study peripheral vascular disease was diagnosed in 17% of patients. Intermittent claudication occurred more commonly than gangrene, although this was not the experience of Semple (1953). Hypertension Hamilton et al. (1954) and Bae et al. (1957) have stressed the difficulty of defining hypertension but have shown in the general population that blood-pressure increases with age. This trend is particularly apparent in diabetics. We found no
Discussion The incidence of clinical vascular disease in this study was substantially the same as that reported in other series. Bryfogle and Bradley (1957), using similar diagnostic criteria, found 49 5%clinical vascular disease in 394 inpatients, and Matthews (1954) found 53% in 545 diabetics. In general, vascular disease is related to age, and this is due largely to the increasing
prevalance of atherosclerosis in the older age-groups. The
specific diabetic angiopathies increased with duration of diabetes ; and this was also the experience of Dolger (1947), Lundbaek (1954), Matthews (1954), and Bryfogle and Bradley (1957).
Retinopathy Retinopathy was
found in 21-7% (table i) and an identical obtained by Matthews (1954) in a similar type of clinic. Other series have shown higher figures-Wagener (1945)
figure
-
was
correlation with duration of diabetes. In patients over 60 years of age 70% of the women and 50% of the men were hypertensive, and these figures are comparable with those of John (1932) and Boas (1952). The incidence of hypertension was increased in those with
988
TREATMENT OF THE NEPHROTIC SYNDROME WITH CONCENTRATED HUMAN ALBUMIN
obesity, but not notably. Liebow et al. (1955) in diabetics and Bee et al. (1957) in a general population survey found similar relationships. In the present series hypertensives had significantly more clinical vascular disease and electrocardiographic abnormalities than non-hypertensives. This may in part be due to the fact that those with
R. S. WILLIAMS * M.B. Lond., M.R.C.P. LATE CAPTAIN, R.A.M.C.
hypertension were in the older age-groups.
T. J. RYAN M.R.C.P.I. MAJOR, R.A.M.C.
Summary 654 diabetics were investigated to determine the incidence of vascular disease and its relationship to age and duration of diabetes, obesity, hypertension, cholesterol levels, and electrocardiographic abnormality. 90% of the patients were over 40 years of age and 73% were female. 42-5% had clinical vascular disease; 59-5% had clinical vascular disease or electrocardiographic abnormalities; with including hypertensive patients among those vascular disease, only 179 (27%) had a " normal vascular system. The incidence of atherosclerotic heart-disease was 19-3% (angina pectoris 11-6% and myocardial infarction 7-8%), of peripheral vascular disease 17%, of retinopathy 21-7%, of nephropathy 4-1%, and of hypertension 36% in men and 56% in women. The majority of patients with vascular disease had more than one com-
plication. Clinical vascular disease was twice as common in as in normotensives. Electrocardiographic abnormalities were twice as common in patients with clinical vascular disease as in those without. No relationship was found between clinical vascular disease and cholesterol level. Obesity was slightly more common in patients with clinical vascular disease than in others. Atherosclerotic disease and specific diabetic angiopathy were common in patients over 40 years of age at their first attendance.
hypertensives
We wish to thank Dr. Una Ledingham for permission to study heI patients and for her encouragement; Dr. Frances Gardner, who has reported on the majority of the electrocardiograms; Dr. A. G. Beckett, whose clinical records were of great help in enabling us tc complete the study; and Dr. John Knowelden, of the M.R.C, Statistical Research Unit, for criticism. REFERENCES
Barach, J. H., Lowy, A. D. (1952) Diabetes, 1, 441. Bell, E. T. (1953) ibid. 2, 376. Boas, E. P. (1952) J. Mt Sinai Hosp. 19, 411. Bøe, J., Humerfelt, S., Wedervang, F. (1957) Acta med. scand. 1957, suppl. 321.
Brown, R. G., Davidson, L. A. G., McKeown, T., Whitfield, A. G. W. (1957) Lancet, ii, 1073. Bryfogle, J. W., Bradley, R. F. (1957) Diabetes, 6, 159. Dolger, H. (1947) J. Amer. med. Ass. 134, 1289. Freedman, P., Moulton, R., Spencer, A. G. (1958) Quart. J. Med. 27, 293. Gertler, M. M., Garn, S. M., White, P. D. (1950) Circulation, 2, 696. Hamilton, M., Pickering, G. W., Fraser Roberts, J. A., Sowry, G. S. C. (1954) Clin. Sci. 13, 11, 273. John, H. J. (1932) Ann. intern. Med. 5, 1462. Joslin, E. P., Root, H. F., White, P., Marble, A. (1952) The Treatment of Diabetes Mellitus. London. Kornerup, T. (1955) Acta med. scand. 153, 81. Liebow, J. M., Hellerstein, H. K., Miller, M. (1955) Amer. J. Med. 8, 438.
Lundbaek, K. (1954) Lancet, i, 377. Matthews, J. D. (1954) ibid. ii, 573. Munro, H. N., Eaton, J. C., Glen, A. (1949) J. clin. Endocrin. 9, 48. Oakley, W., Catterall, R. C. F., Martin, M. M. (1956) Brit. med. J. ii, 953. Oliver, M. F., Boyd, G. S. (1953) Brit. Heart J. 15, 387. (1955) Minn. Med. 38, 794. Semple, R. (1953) Lancet, i, 1064. Wagener, H. P. (1945) Proc. Amer. Diabetes Ass. 5, 203. Wilder, R. M., Browne, H. C., Butt, M. R. (1940) Arch. intern. Med. 65, 390. Wilson, J. L., Root, H. F., Marble, A. (1951) Amer. J. med. Sci. 221, 479. —
—
Queen Alexandra Military Hospital, Millbank IN the treatment of the nephrotic syndrome the use of From The
plasma-expanders such as concentrated human albumin, dextran, or triple-strength plasma has on the whole been disappointing. Although they induce diuresis they do not affect the underlying lesion, and their benefit is usually temporary, as in the case reported by Edwards (1957) in which the oedema recurred a week after leaving hospital. The main indication for them is in cases which do not respond to steroid therapy and which show increasing oedema despite routine measures. In such a case, reported here, concentrated human albumin proved of great value. This case was also of interest because the nephrosis may have been due to an allergic reaction following inoculation with T.A.B.T. (a phenolised vaccine containing Salmonella typhi, S. paratyphi A and B, and tetanus toxoid).
Case-report On June 26, 1957, a 19-year-old private was admitted to hospital in Germany with swelling of the ankles which had started 3 days previously-10 days after a routine T.A.B.T. inoculation. There was no history of recent sore throat or past renal disease. He had previously been given T.A.B.T. in September and November, 1956. He had gross pitting oedema of the legs and genitalia, dullness and diminished air entry at the base of the right lung, and a blood-pressure of 140/110 mm. Hg. Hxmoglobin 112%; white blood-cells 5200 per c.mm. (differential count normal); erythrocyte-sedimentation rate (Wintrobe) 21 mm. in 1 hour; blood-urea 54 mg. per 100 ml.; serum-cholesterol 418 mg. per 100 ml.; serum-proteins 5-84 g. per 100 ml. (albumin 2-7 g., globulin 3-14 g.). The urine contained many granular casts, some leucocytes, and very occasional red cells. There was heavy albuminuria, ranging from 15 to 20 g. in 24 hours. Radiography showed a small right pleural effusion. Course of Illness He was put on a high-protein low-salt diet and 2 days later started on cortisone acetate by mouth (200 mg. daily). This was continued in reduced dosage until July 20 but without appreciable effect on urine output or albuminuria. During this time his weight increased by a stone and his bloodpressure rose to 190/130 mm. Hg. He was then invalided home and admitted first to Tidworth Military Hospital (where he was given prednisone 40 mg. daily) and on Aug. 8 to Queen Alexandra Military Hospital. By this time he was grossly oedematous, with bilateral pleural effusions and ascites: his weight had increased by over three stone. Running
transversely across the fingernails were paired white bands, separated from each other and from the lunula by areas of normal pink nail. The hypertension persisted (140/100). The fundi were normal. The blood-urea was
now 92 mg. and the serum-cholesterol 740 mg. Serum-proteins were 4-2 g. per 100 ml. (albumin 1-4 g., globulin 2-8 g.), the electrophoretic strip showing a very high (X2 peak. Electrophoresis of the urine showed a large albumin peak with a small p-globulin peak, the albumin/globulin ratio being 7-3 : 1. The serum-electrolytes were: sodium 143, potassium 5, chlorides 98, and alkali reserve 24.0 mEq. per litre. The urinary electrolytes were: sodium 14-5, potassium 46-5, and chloride 25-5 mEq. per litre. *
Present address: Postgraduate Medical School of London, Hammersmith
Hospital,
W.12.
In a series of 300
overall frequency
tests
was
with
a
wide range of needles the
TABLE I-INCIDENCE OF CLINICAL VASCULAR DISEASE IN 654 DIABETICS
69%.
There is no great variation in the frequency with different sizes of needles, but the skin fragment is roughly proportional to the size of the lumen. Side-opening needles and those with a fitted stilette do not remove skin fragments. We are very grateful to Prof. J. P. Todd and Mr. George Reid, of the Glasgow Royal College of Science and Technology, for much helpful advice and technical assistance. We are also greatly indebted to Prof. T. Symington for his help with the animal experiments. Mr. Robert McGregor and Mr. Donald Hay were responsible for the photographs. REFERENCES Crawford, L. D. (1955) Canad. med. Ass. J. 72, 374. Magath, T. B., McClellan, J. T. (1950) Amer. J. clin. Path. Mitchell, J. V. (1952) Anœsthesia, 7, 258.
20, 829.
VASCULAR DISEASE IN A DIABETIC CLINIC
J. G. LEWIS M.B.
Lond., M.R.C.P.
MEDICAL REGISTRAR
C. SYMONS Lond., M.R.C.P.
M.D. FIRST
ASSISTANT, CARDIAC DEPARTMENT
ROYAL FREE
HOSPITAL, LONDON, W.C.1
of those who attended over the three-year period, fulfilled these requirements and were included in this study. Two aspects were considered in the assessment of vascular disease in diabetics: (1) the specific vascular abnormalities of diabetes, such as retinopathy and nephropathy; and (2) the complications due to atherosclerosis such as atherosclerotic heart-disease and peripheral vascular disease. These vascular complications were regarded as evidence of clinical vascular disease. The incidence of hypertension, obesity, and hypercholesterolxmia and their relation to clinical vascular disease and electrocardiographic abnormalities were studied. We have not included cerebrovascular disease, which was present in 4% of patients and was almost invariably associated with vascular disease elsewhere.
Composition of Series
The number of women in the survey was 477 (73%) and of As the treatment of diabetes mellitus improves, so the men 177. 45% of all patients were treated by diet alone. prevalence of vascular disease increases; and now it has is shown in fig. lA; 90% of the patients were Age-distribution become the most important problem in the management over 40 years of age. The proportion of women in this series of diabetes. To estimate how frequently clinical vascular was higher than that reported in other diabetic clinics dealing disease occurs, a survey was made of patients who had with white people (Wilder et al. 1940, Munro et al. 1949, Joslin attended the diabetic department of the Royal Free and et al. 1952); and this was no doubt due largely to the preponHampstead General Hospitals during 1955, 1956, and derance of women attending the Royal Free Hospital. The 1957 either as outpatients or inpatients. A few patients duration of diabetes and the number of patients in each group is shown in fig. 1B. 90% of patients with diabetes of 0-5 years’ were also referred to the Royal Free diabetic clinic from an duration were over 40 years of age. Ophthalmic Hospital. Clinical Vascular Disease Material and Methods Clinical vascular disease was diagnosed when one or more of The criteria for acceptance in this study were that the patient the following complications was present: should have proven diabetes, have had a full clinical history and 1. Diabetic confirmed an
examination, blood-pressure estimations, height and weight recording, chest X-ray, serum-cholesterol estimation, and at least one recent electrocardiogram. At each visit the urine was tested for glucose and protein. 654 patients, representing 75%
retinopathy, by ophthalmologist. Nephropathy, indicated by persistant proteinuria in the absence of urinary infection. This was usually associated with retinopathy, hypertension, and oedema. Clinically, this was a mixed group, and consisted of those with intercapillary glomerular sclerosis (Kimmelstiel-Wilson kidney) and those with pyelonephiritis and nephrosclerosis of hypertensive origin. 3. Atherosclerotic heart-disease, which was diagnosed when one or more of the following were present: angina pectoris; cardiac infarction (on clinical and/or electrocardiographic evidence); or a loud basal systolic murmur in the absence of hypertension, which we considered suggestive of 2.
aortic
or
aortic valve atheroma.
Peripheral vascular disease, which was diagnosed when any of the following were 4.
present: intermittent claudication; ischxniic rest pain; or absent arterial pulsation with pallor and coldness of the lower limbs.
Findings
Fig. 1-A, age-distribution and, 13,
duration ot
disease, in 654 diabetic patients.
Incidence of Clinical Vascular Disease The incidence of clinical vascular disease and the frequency of individual complications are shown in table 1. 279 patients (42-5%) of the 654 had evidence of clinical vascular disease. As more than one vascular complication was present in many patients, the total of individual com-
986
11 patients had evidence making a total of 51 (7-8%).
of
Clinical Vascular Disease related
symptomless infarction, to
Age and Duration of
Diabetes
Fig. percentage incidence of clinical vascular disease in 654 patients related to, A, age of patients and, B, duration of diabetes. was greater than the number of patients with disease. vascular Nephropathy was found in 4-1% of the series. This figure is unlikely to be an underestimate as each patient was tested for proteinuria at every visit. The total incidence of proteinuria of non-infective origin, including cases with heart-failure and hypertension, was 7-2%. A third of all patients with angina had electrocardiographic evidence of old or recent infarction. Cardiac infarction, based on history and clinical examination, supplemented by electrocardiography, was found in 40 patients (6%). With routine electrocardiography a further
plications
Figs. 2A and 3A show the incidence of vascular disease in different age-groups. The results are presented as percentages of the total number of patients in each agegroup. Figs. 2B and 3B show that clinical vascular disease increased with the duration of the diabetes. The high figure in the 0-5-year-duration group reflects those with diabetes of late onset who have associated vascular disease; moreover in those over 40 the clinical onset is not always an accurate guide to the duration of the disease. Retinopathy increased steadily with duration of diabetes, attaining a maximum of 80% in the 21-25-year-duration group. In the 0-5-duration group 13% had retinopathy (in this group only 3% of patients under 40 years of age had this complication compared with 17% of those over 60). The high figure of 13% may be due to the difficulty in dating the onset of diabetes by symptoms alone; indeed, patients not infrequently presented with visual deterioration due to retinopathy as their main complaint. TABLE II-PROPORTION OF HYPERTENSIVES IN EACH AGE-GROUP
DECADES)
(BY
OF SERIES OF DIABETICS
Retinopathy also increased with age; the percentage for the third decade was 9-5%, and this rose to 29% in those over 80. Correlating age with duration, the incidence of retinopathy was highest in patients aged 41-60 who had had diabetes more than 21 years. The sex-distribution was almost equal. Nephropathy, apart from the first few years, increased with duration of diabetes. The relation to age was not impressive; the proportions were highest in patients in their 30’s and over 60. It occurred most often in those over 60 who had had diabetes for the longest period. Men comprised 50% of those with nephropathy, yet only 27% of the whole series. Atherosclerotic disease was present at all duration periods of diabetes. Age was more important than duration of the disease; the highest incidence of atherosclerosis was found in patients over 60 who had had diabetes more than twenty years. In patients aged 10-40 years the incidence of atherosclerosis, even in those with the longest duration, was no more than 5%.
Fig. 3-Percentage of patients with each vascular complication related to, A, age of patient and, B, duration of diabetes.
Clinical Vascular Disease, Obesity, and Hypertension Patients were considered overweight if 10% more than their expected weight for their sex, age, and height. 53°o of the women and 49% of the men were overweight. Of the women with clinical vascular disease 58% were obese, compared with 49% of those with no vascular disease; the respective figures for men were 50% and 46%. Hypertension was considered present when a bloodpressure of over 160/95 mm. Hg was repeatedly recorded.
987
The incidence of hypertension was 36% for men and 56% for women. The proportion of hypertensives in each age-group of the series is shown in table 11. Hypertension was, therefore, commoner in women than men, the incidence increasing with advancing decades. Over 60 years of age 70% of the women and 50% of the men were
30-6%, Kornerup (1955) 46.8%, Bryfogle and Bradley (1957) 35-8%. These series included a higher proportion of younger diabetics. The incidence of retinopathy in younger patients with diabetes of long duration may be as high as 70-80% (Lundbaek 1954).
Nephropathy Bryfogle and Bradley (1957) found this complication in 10% of their diabetic inpatients, and other series give figures as high as 25% of diabetics (Wilson et al. 1951, Bell 1953); but these studies were either on young patients with diabetes of long duration or on inpatients. In our series nephropathy was uncommon (4-1 %)-comparable with low figure reported by Freedman et al. (1958). The prognosis of nephropathy is such that there were few patients with this disorder in the clinic at any given time. Routine testing of urine has shown, however, that the interval between onset of proteinuria without symptoms and death can be as long as eight years.
hypertensive.
Of obese patients hypertension was present in 43% of men and 61% of women, compared with 28% and 42% respectively for those of normal weight. 56% of hypertensive women and 60% of hypertensive In normotensives men had clinical vascular disease. clinical vascular disease was less common-23% in men and 38% in women.
Cholesterol Levels and Clinical Vascular Disease There were 85 men with a raised cholesterol level (over 200 mg. per 100 ml.), of whom 34 (40%) had clinical vascular disease. 92 men had normal serum-cholesterol levels, and 46 (50%) of these had clinical vascular disease. The figures for women were 254 with raised cholesterol, of whom 109 (40%) had clinical vascular disease, and 223 with normal values of whom 90 (40 %) had vascular disease. Patients with diabetic nephropathy had raised bloodcholesterol levels but their numbers have not influenced the general conclusions. The cholesterol levels were also related to abnormal electrocardiograms, but again there was no positive relationship. The serum-cholesterol level was not significantly higher in the patients with atherosclerotic heart-disease than in the remainder, nor did it differ in patients with clinical vascular disease as compared to those without.
Atherosclerotic Heart-disease It is difficult to compare atherosclerotic disease in one series, with another, because criteria for diagnosis vary and interpretation may differ between observers, as may the sample for age, We have not included as evidence of sex, and duration. atherosclerotic heart-disease, non-hypertensive cardiomegaly, arterial calcification, or non-specific abnormalities in the
electrocardiogram. 19-3% of our patients had atherosclerotic heart-disease, but Liebow et al. (1955) and Bryfogle and Bradley (1957) found totals of 42% and 56-3% respectively, using wider criteria of diagnosis. If those patients with angina and infarction only are considered (17% over 40 years of age in this group) then all three studies show similar findings. The proportion of patients with angina pectoris in this study was 11-6%. This compares with 9-1% found by Bryfogle and Bradley (1957) and 10-2 % by Liebow et al. (1955). Atherosclerotic heart-disease occurs more commonly in diabetics than in the general population. Brown et al. (1957) reported an incidence of 8-4% in a general practice survey of
Routine Electrocardiography The total number of patients with an abnormal electrocardiogram was 280 (42-5%). Those with clinical vascular disease and/or an abnormal electrocardiogram constituted 59 5% of the series. When patients with hypertension The incidence of were included the figure rose to 73%. in abnormalities patients with clinical electrocardiographic vascular disease was 61%, compared with 30% in those without electrocardiographic changes. The routine use of the electrocardiogram showed that subclinical infarction occurred sufficiently often to warrant its use in all diabetics over 40 years of age.
in the seventh decade. In the present series for the same and decade 34% had atherosclerotic heart-disease. In nondiabetic subjects Oliver and Boyd (1955) found that the male: female ratio of coronary-artery disease under the age of 50 was 7 : 1. In this series the incidence of atherosclerotic heart-disease, using slightly different criteria, was 1 :11 under 50 years of age but over this age men predominated by 1-6 : 10. The cholesterol levels were not significantly raised in patients with atherosclerotic heart-disease, which is in agreement with Liebow et al. (1955). This is surprising in view of the generally accepted findings that the serum-cholesterol level is raised in coronary-artery disease both in the general population (Gertler et al. 1950, Oliver and Boyd 1953), and in diabetics (Barach and Lowy 1952).
men sex
Deaths
patients in this series died during the threeperiod under study. 28 (76%) of these patients died from cardiorenal causes; 11 of them had nephropathy. 37 of the
year
Peripheral Vascular Disease Oakley et al. (1956), in a large series, reported an overall figure of 35% rising to 10% in those over 70. Bryfogle and Bradley (1957), using similar criteria, found an incidence of 15-7%. In the present study peripheral vascular disease was diagnosed in 17% of patients. Intermittent claudication occurred more commonly than gangrene, although this was not the experience of Semple (1953). Hypertension Hamilton et al. (1954) and Bae et al. (1957) have stressed the difficulty of defining hypertension but have shown in the general population that blood-pressure increases with age. This trend is particularly apparent in diabetics. We found no
Discussion The incidence of clinical vascular disease in this study was substantially the same as that reported in other series. Bryfogle and Bradley (1957), using similar diagnostic criteria, found 49 5%clinical vascular disease in 394 inpatients, and Matthews (1954) found 53% in 545 diabetics. In general, vascular disease is related to age, and this is due largely to the increasing
prevalance of atherosclerosis in the older age-groups. The
specific diabetic angiopathies increased with duration of diabetes ; and this was also the experience of Dolger (1947), Lundbaek (1954), Matthews (1954), and Bryfogle and Bradley (1957).
Retinopathy Retinopathy was
found in 21-7% (table i) and an identical obtained by Matthews (1954) in a similar type of clinic. Other series have shown higher figures-Wagener (1945)
figure
-
was
correlation with duration of diabetes. In patients over 60 years of age 70% of the women and 50% of the men were hypertensive, and these figures are comparable with those of John (1932) and Boas (1952). The incidence of hypertension was increased in those with
988
TREATMENT OF THE NEPHROTIC SYNDROME WITH CONCENTRATED HUMAN ALBUMIN
obesity, but not notably. Liebow et al. (1955) in diabetics and Bee et al. (1957) in a general population survey found similar relationships. In the present series hypertensives had significantly more clinical vascular disease and electrocardiographic abnormalities than non-hypertensives. This may in part be due to the fact that those with
R. S. WILLIAMS * M.B. Lond., M.R.C.P. LATE CAPTAIN, R.A.M.C.
hypertension were in the older age-groups.
T. J. RYAN M.R.C.P.I. MAJOR, R.A.M.C.
Summary 654 diabetics were investigated to determine the incidence of vascular disease and its relationship to age and duration of diabetes, obesity, hypertension, cholesterol levels, and electrocardiographic abnormality. 90% of the patients were over 40 years of age and 73% were female. 42-5% had clinical vascular disease; 59-5% had clinical vascular disease or electrocardiographic abnormalities; with including hypertensive patients among those vascular disease, only 179 (27%) had a " normal vascular system. The incidence of atherosclerotic heart-disease was 19-3% (angina pectoris 11-6% and myocardial infarction 7-8%), of peripheral vascular disease 17%, of retinopathy 21-7%, of nephropathy 4-1%, and of hypertension 36% in men and 56% in women. The majority of patients with vascular disease had more than one com-
plication. Clinical vascular disease was twice as common in as in normotensives. Electrocardiographic abnormalities were twice as common in patients with clinical vascular disease as in those without. No relationship was found between clinical vascular disease and cholesterol level. Obesity was slightly more common in patients with clinical vascular disease than in others. Atherosclerotic disease and specific diabetic angiopathy were common in patients over 40 years of age at their first attendance.
hypertensives
We wish to thank Dr. Una Ledingham for permission to study heI patients and for her encouragement; Dr. Frances Gardner, who has reported on the majority of the electrocardiograms; Dr. A. G. Beckett, whose clinical records were of great help in enabling us tc complete the study; and Dr. John Knowelden, of the M.R.C, Statistical Research Unit, for criticism. REFERENCES
Barach, J. H., Lowy, A. D. (1952) Diabetes, 1, 441. Bell, E. T. (1953) ibid. 2, 376. Boas, E. P. (1952) J. Mt Sinai Hosp. 19, 411. Bøe, J., Humerfelt, S., Wedervang, F. (1957) Acta med. scand. 1957, suppl. 321.
Brown, R. G., Davidson, L. A. G., McKeown, T., Whitfield, A. G. W. (1957) Lancet, ii, 1073. Bryfogle, J. W., Bradley, R. F. (1957) Diabetes, 6, 159. Dolger, H. (1947) J. Amer. med. Ass. 134, 1289. Freedman, P., Moulton, R., Spencer, A. G. (1958) Quart. J. Med. 27, 293. Gertler, M. M., Garn, S. M., White, P. D. (1950) Circulation, 2, 696. Hamilton, M., Pickering, G. W., Fraser Roberts, J. A., Sowry, G. S. C. (1954) Clin. Sci. 13, 11, 273. John, H. J. (1932) Ann. intern. Med. 5, 1462. Joslin, E. P., Root, H. F., White, P., Marble, A. (1952) The Treatment of Diabetes Mellitus. London. Kornerup, T. (1955) Acta med. scand. 153, 81. Liebow, J. M., Hellerstein, H. K., Miller, M. (1955) Amer. J. Med. 8, 438.
Lundbaek, K. (1954) Lancet, i, 377. Matthews, J. D. (1954) ibid. ii, 573. Munro, H. N., Eaton, J. C., Glen, A. (1949) J. clin. Endocrin. 9, 48. Oakley, W., Catterall, R. C. F., Martin, M. M. (1956) Brit. med. J. ii, 953. Oliver, M. F., Boyd, G. S. (1953) Brit. Heart J. 15, 387. (1955) Minn. Med. 38, 794. Semple, R. (1953) Lancet, i, 1064. Wagener, H. P. (1945) Proc. Amer. Diabetes Ass. 5, 203. Wilder, R. M., Browne, H. C., Butt, M. R. (1940) Arch. intern. Med. 65, 390. Wilson, J. L., Root, H. F., Marble, A. (1951) Amer. J. med. Sci. 221, 479. —
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Queen Alexandra Military Hospital, Millbank IN the treatment of the nephrotic syndrome the use of From The
plasma-expanders such as concentrated human albumin, dextran, or triple-strength plasma has on the whole been disappointing. Although they induce diuresis they do not affect the underlying lesion, and their benefit is usually temporary, as in the case reported by Edwards (1957) in which the oedema recurred a week after leaving hospital. The main indication for them is in cases which do not respond to steroid therapy and which show increasing oedema despite routine measures. In such a case, reported here, concentrated human albumin proved of great value. This case was also of interest because the nephrosis may have been due to an allergic reaction following inoculation with T.A.B.T. (a phenolised vaccine containing Salmonella typhi, S. paratyphi A and B, and tetanus toxoid).
Case-report On June 26, 1957, a 19-year-old private was admitted to hospital in Germany with swelling of the ankles which had started 3 days previously-10 days after a routine T.A.B.T. inoculation. There was no history of recent sore throat or past renal disease. He had previously been given T.A.B.T. in September and November, 1956. He had gross pitting oedema of the legs and genitalia, dullness and diminished air entry at the base of the right lung, and a blood-pressure of 140/110 mm. Hg. Hxmoglobin 112%; white blood-cells 5200 per c.mm. (differential count normal); erythrocyte-sedimentation rate (Wintrobe) 21 mm. in 1 hour; blood-urea 54 mg. per 100 ml.; serum-cholesterol 418 mg. per 100 ml.; serum-proteins 5-84 g. per 100 ml. (albumin 2-7 g., globulin 3-14 g.). The urine contained many granular casts, some leucocytes, and very occasional red cells. There was heavy albuminuria, ranging from 15 to 20 g. in 24 hours. Radiography showed a small right pleural effusion. Course of Illness He was put on a high-protein low-salt diet and 2 days later started on cortisone acetate by mouth (200 mg. daily). This was continued in reduced dosage until July 20 but without appreciable effect on urine output or albuminuria. During this time his weight increased by a stone and his bloodpressure rose to 190/130 mm. Hg. He was then invalided home and admitted first to Tidworth Military Hospital (where he was given prednisone 40 mg. daily) and on Aug. 8 to Queen Alexandra Military Hospital. By this time he was grossly oedematous, with bilateral pleural effusions and ascites: his weight had increased by over three stone. Running
transversely across the fingernails were paired white bands, separated from each other and from the lunula by areas of normal pink nail. The hypertension persisted (140/100). The fundi were normal. The blood-urea was
now 92 mg. and the serum-cholesterol 740 mg. Serum-proteins were 4-2 g. per 100 ml. (albumin 1-4 g., globulin 2-8 g.), the electrophoretic strip showing a very high (X2 peak. Electrophoresis of the urine showed a large albumin peak with a small p-globulin peak, the albumin/globulin ratio being 7-3 : 1. The serum-electrolytes were: sodium 143, potassium 5, chlorides 98, and alkali reserve 24.0 mEq. per litre. The urinary electrolytes were: sodium 14-5, potassium 46-5, and chloride 25-5 mEq. per litre. *
Present address: Postgraduate Medical School of London, Hammersmith
Hospital,
W.12.