ATHEROSCLEROTIC GANGRENE OF T H E LOWER EXTREMITIES IN
DIABETIC AND NONDIABETIC PERSONS
E. T. BELL, M.D.
Department of Pathology, University of Minnesota Medical School, Minneapolis, Minnesota
This study is based on the autopsy records filed in this department during
the 45 years from 1911 through 1955. During this period an autopsy was performed on 59,733 nondiabetic and 2130 diabetic persons who were more than
20 years of age at death. Since there were no instances of atherosclerotic gangrene in those under the age of 20 years, the younger persons have not been
tabulated in this paper. Owing to the fact that there are approximately twice
as many men as women included in the autopsy records, the sexes are listed
separately whenever any differences exist. A numerical comparison of the
sexes may be made by doubling the number of women.
All persons in whom clinical diabetes was established are listed as examples
of diabetic gangrene. The histologic changes in the pancreas and the kidneys
suggest that a few of those listed as not having diabetes were, in fact, mildly
diabetic.
In the nondiabetic group, only atherosclerotic gangrene is included. No case
is listed in this group if the gangrene resulted from trauma, frostbite, burns, or
arterial embolism from cardiac mural thrombi. Gangrenes caused by thrombosis of an iliac or femoral artery are included because there was underlying atherosclerosis of the arteries in each instance.
This is a more comprehensive study than the report published in 1950,1 inasmuch as it includes 8 additional years of autopsy records.
R E S U L T S AND
DISCUSSION
Age and Sex Incidence (Tables 1 and 2)
Nondiabetic gangrene. There were no instances of nondiabetic gangrene in
persons less than 40 years of age; and in only a few patients less than 60 years
of age. In the group between 60 and 80 years of age, the incidence in the 2
sexes was equal, but there was a great preponderance of men in those more than
80 years of age. The proportion of men to women in the entire group was about
3 to 2.
Diabetic gangrene. Only 3 diabetic persons developed gangrene before the age
of 40 years. Approximately 14 per cent of those who died between the ages of
40 and 60 years and about 24 per cent of those between 60 and 80 years of age
at death exhibited gangrene. The incidence of diabetic gangrene was approximately the same in the 2 sexes, but, inasmuch as diabetes was about twice as
Received, January 22, 1957; revision received, February 18; accepted for publication
March 18.
Dr. Bell is Emeritus Professor of Pathology, University of Minnesota.
This work was aided by a grant from the Public Health Service, Department of Health,
Education, and Welfare.
27
28
Vol. 28
BELL
TABLE 1
T H E INCIDENCE O F ATHEROSCLEROTIC G A N G R E N E O F THE L O W E R E X T R E M I T I E S IN
N O N D I A B E T I C AND D I A B E T I C M E N
Number of
Nondiabetic
Men
Age at Death
Number
with
Gangrene
Per Cent
with
Gangrene
Number
of
Diabetic
Men
Number
with
Gangrene
Per Cent
with
Gangrene
Ratio of
Frequency
0
0.104
0.451
1.727
87
272
568
3
42
80
138
17
3.4
14.7
24.3
21.2
141:1
54:1
12:1
0.411
920
197
21.4
53:1
yr.
20-40
40-60
60-80
5,514
14,355
16,628
M o r e t h a n 80
2,837
0
15
75
49
33,820
139
T o t a l persons more
t h a n 40 y r .
TABLE 2
T H E INCIDENCE O F ATHEROSCLEROTIC G A N G R E N E O F T H E L O W E R E X T R E M I T I E S I N
N O N D I A B E T I C AND D I A B E T I C WOMEN
Number of
Nondiabetic
Women
Age at Death
Number
with
Gangrene
Per Cent
with
Gangrene
Number of
Diabetic
Women
Number
with
Gangrene
Per Cent
with
Gangrene
Ratio of
Frequency
yr.
20-40
40-60
4,035
60-80
More t h a n 80
T o t a l persons
t h a n 40 y r .
more
6,636
7,857
1,871
0
5
0
0.075
85
279
36
6
0.458
0.321
603
16,364
47
0.287
0
0
14.0
24.2
186:1
53:1
76
39
146
11
14.5
45:1
958
196
20.4
71:1
frequent in women, there were about twice as many of them as men with diabetic gangrene.
Relative Frequency of Gangrene in Diabetic and Nondiabetic Persons
The data in Table 1 indicate that gangrene develops 53 times as often in
diabetic as in nondiabetic men over 40 years of age. The ratio decreases from
141 to 1 in the group less than 60 years of age to 12 to 1 in those more than 80
years old. When a man less than 80 years old develops atherosclerotic gangrene,
the chances are 2 to 1 that he has diabetes, but, if he is more than 80 years of
age, the chances of his having diabetes are only 1 to 3.
In Table 2 it is demonstrated that gangrene develops 71 times as often in
diabetic as in nondiabetic women more than 40 years of age. The ratio does not
fall in those over 80 years old, as it does in men, since nondiabetic gangrene is
uncommon in women of this age. When a woman more than 40 years of age
develops atherosclerotic gangrene of the leg, the chances are greater than 4 to
1 that she has diabetes.
The reports dealing with amputation of the lower extremities for gangrene
July
1957
ATHEROSCLEROTIC GANGRENE
29
TABLE 3
INCIDENCE OF G A N G R E N E IN D I A B E T I C P E R S O N S IN T H E 3 P E R I O D S INDICATED
Period II—1931 to 1945
Period 1—1911 to 1930
Age at Death
Number
of
diabetic
persons
Number
with
gangrene
Per cent
with
gangrene
Number
of
diabetic
persons
Number
with
gangrene
Per cent
with
gangrene
Period 111—1946 to 1955
Number
. of
diabetic
persons
Number
with
gangrene
Per cent
with
gangrene
yr.
0-20
20-40
40-60
60-91
6
29
58
71
0
0
11
26
0
0
19.0
36.6
21
62
215
476
0
1
30
120
0
1.6
14.0
25.2
5
SI
27S
7S0
0
2
40
166
0
2.4
14.0
21.3
40-91
129
37
28.7
691
150
21.7
105S
206
19.4
usually indicate a predominance of females among those who have diabetes and
of males among those who do not. 6 ' 7 " 9
The frequency of diabetic gangrene in 3 periods is indicated by data in Table
3. I t seems that gangrene in persons more than 40 years of age has decreased
from 28.7 per cent in Period I to 19.4 per cent in Period III. This is noteworthy
since, during the 45-year period, there has been an increase in the length of the
diabetic life and a great increase in the percentage of deaths from other forms
of vascular disease. Blumberg and Zissermann,3 in a study of 400 deceased diabetic patients, noted the same phenomenon when comparing deaths during 1930
to 1938 with deaths during 1939 to 1950. Perhaps this improvement may be
attributed to the use of antibiotics, inasmuch as diabetic gangrene is frequently
the result of infection rather than arterial occlusion.
Hypertension
There is no significant difference in the frequency of hypertension in the 2
groups. Blood pressures below 150/90 mm. of Hg were found in 39 per cent of
the diabetic and 41 per cent of the nondiabetic patients with gangrene, and
pressures 180/90 mm. of Hg or higher in 29 per cent of those with diabetes and
25 per cent of those without diabetes.
The Relation Between Gangrene and the Known Duration of Diabetes
No definite relation may be established between the known duration of the
diabetes and the development of gangrene. In the 396 diabetic persons with
gangrene, the known duration of the diabetes was less than 5 years in 34 per
cent, and less than 6 months in 7 per cent. About one-fourth of the persons with
gangrene had diabetes more than 10 years; and 11 per cent, longer than 20
years.
In 60 persons, gangrene was the first sign that led to the diagnosis of diabetes.
Thirty-five of these patients died within 6 months after the appearance of gangrene, but 8 lived from 5 to 12 years. Since it is fairly well established that
vascular disease is a late manifestation of diabetes, it is almost certain that a
30
BELL
Vol. 28
long period of mild diabetes preceded the onset of gangrene in these 60 patients.
The duration of mild diabetes in elderly persons can seldom be determined
accurately.
The Relation Between the Clinical Severity of Diabetes and the Development
of Gangrene
On the basis of the requirement for insulin, the diabetic patients were classified as mild, moderate, and severe. The classification was based on the requirement prior to the onset of gangrene, since more insulin was sometimes administered after the development of gangrene. Of the 396 patients, 148 (37 per cent)
required no insulin at any time and they were classified as persons with mild
diabetes. There were 132 patients (33 per cent) whose daily requirement for
insulin ranged from 10 to 30 units; approximately one-half of this group were
regarded as fairly well controlled prior to the onset of gangrene. There were 94
persons (24 per cent) who had severe diabetes, such that more than 30 units of
insulin were required daily. A majority of the younger diabetic patients were
in this group. In 19 instances, the severity of the diabetes could not be determined from the clinical record. It seems, therefore, that the development of
gangrene is independent of the clinical severity of the diabetes. Whether or not
the onset of gangrene may be delayed or prevented by excellent control can not
be determined from the data available in this group of patients.
The Causes of Death in Persons with Gangrene
Gangrene was the chief cause of death in a large percentage of the patients,
and it was at least a contributory cause of death in nearly all instances. Since
persons with gangrene usually have generalized atherosclerosis, however, the
immediate cause of death is frequently some other form of vascular disease.
Occasionally death results from some disease that is not related to atherosclerosis.
Diabetic gangrene. Gangrene was regarded as the major cause of death in 180
of the 396 patients (46 per cent). Death was attributed to coronary atherosclerosis in 75, to renal atherosclerosis in 37, to myocardial failure in 17, to encephalomalacia in 15, and to cerebral hemorrhage in 1 instance. It is noteworthy
that there were 15 deaths from encephalomalacia, but only 1 from intracranial
hemorrhage. Forms of atherosclerosis other than gangrene were interpreted as
the cause of death in 145 persons. Death of 30 patients was caused by systemic
infections, usually pyemias, that were related to the diabetes. Six deaths resulted
from diabetic coma, and 32 from some disease that was not related to the diabetes.
Nondiabetic gangrene. Gangrene was regarded as the major cause of death in
121 of the 186 patients (65 per cent). In 42 instances, death resulted from other
forms of atherosclerosis, i.e., coronary diseases, 17; myocardial failure from
hypertension, 12; encephalomalacia, 10; mesenteric thrombosis, 2; and cerebral
hemorrhage, 1. In 23 instances, death was caused by some disease that was not
related to atherosclerosis (such as a malignant neoplasm).
July 1957
ATHEROSCLEROTIC GANGRENE
31
In the diabetic patients, gangrene was frequently a terminal complication of
some other form of vascular disease and was not far advanced at the time of
death. For this reason, it was not the major cause of death as frequently as in
the nondiabetic persons.
Unilateral gangrene. The gangrene involved only 1 lower extremity in 74 per
cent of the diabetic, and in 79 per cent of the nondiabetic, patients. In each
group, gangrene involved the foot or leg in 90 per cent and was restricted to
the toes in 10 per cent. Amputation of the leg or foot was performed in 59 of
147 nondiabetic patients (40.1 per cent), and in 180 of 293 diabetics (61.4 per
cent).
In the nondiabetic group, 42 of the 59 died within 1 month after the amputation and 12 others within 1 year. Five patients survived the operation 3 to 5
years. Eighty-seven of the diabetic patients died within 1 month and 47 others
within 1 year after the operation. Twenty survived from 1 to 3 years, 11 for 3
to 5 years, 14 from 5 to 10 years, and 1 for 15 years. The chances of a relatively
long postoperative survival are definitely better in patients who have diabetic,
rather than nondiabetic gangrene.
The better prognosis in diabetic gangrene is based on the fact that there
frequently is less vascular obstruction than in the nondiabetic form. A diabetic
patient with only moderate vascular obstruction may develop gangrene from
infection. Infection plays an important role in diabetic gangrene, but it is of
only minor importance in nondiabetic persons.4, 6
Bilateral gangrene. The gangrene was bilateral in 21 per cent of the nondiabetic and 26 per cent of the diabetic patients. In the 39 nondiabetic persons
with bilateral gangrene, 1 leg was amputated in 14 instances. Six of the patients
survived less than 1 month, 4 from 1 to 12 months, 3 from 1 to 3 years, and 1
for 6 years. Of the 13 persons with bilateral amputations, 9 survived less than 1
year, 2 from 1 to 5 years, and 2 over 7 years.
Of the 103 instances of bilateral gangrene in diabetic patients, 1 leg was
amputated in 30. Eleven of these survived from 1 to 5 years, and 1 for 12 years.
In 43 diabetic persons, both legs were amputated, usually at different times, the
interval between amputations ranging from 1 month to 7 years. Five others were
treated by bilateral amputations of only the toes. In the group with bilateral
gangrene, the outcome of amputation is also better in the diabetic persons.
Renal Arteries
The medium-sized and small renal arteries had advanced intimal atherosclerosis (grades 3 and 4) in 50 per cent of the diabetic and 25 per cent of the
nondiabetic patients. This reflects the more advanced generalized atherosclerosis
found in diabetic persons, but it does not distinguish those who have diabetes
from those who do not.
Renal Arterioles
In most persons with long-standing primary hypertension, subintimal accumulations of hyaline material are found in the afferent glomerular arterioles,
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Vol. 28
BELL
TABLE 4
INCIDENCE AND D E G R E E OK HYALINIZATION O F THE JUXTAGLOMERULAR S E G M E N T OK THE
A F F E R E N T GLOMERULAR A R T E R I O L E IN D I A B E T I C AND N O N D I A B E T I C P E R S O N S
WITH G A N G R E N E
Grade of
Hyalinization
tVonrliabe ic Persons
Number of cases
0
i
2
3
4
146
4
4
6
2
Total
162
Per cent
90.0
2.5
2.5
3.7
1.2
Diabetic Persons
Number of cases
Per cent
43
52
21
112
110
12.7
15.4
6.2
33.1
32.5
338
but the deposit seldom extends into the glomeruli. A thick layer of hyaline in
the juxtaglomerular segment of the afferent arteriole is almost pathognomonic
of diabetes, inasmuch as it is rarely observed in primary hypertension. A layer
of hyaline in the efferent glomerular arteriole is probably sufficient to establish
the diagnosis of diabetes.2 Table 4 includes comparative data from nondiabetic
and diabetic persons, with respect to the occurrence and the degree of hyalinization of the juxtaglomerular segment of the afferent glomerular arteriole. An
advanced degree of hyalinization (grade 4) is illustrated in Figures 1 and 2. It
is to be emphasized that only hyalinization of the juxtaglomerular segment of
the afferent arteriole is characteristic of diabetes; hyalinization of other parts
of the afferent arteriole is found frequently in nondiabetic patients with primary
hypertension. When the juxtaglomerular segment is hyalinized, a similar change
is observed in all parts of the afferent arteriole. The frequency of hyalinization
of the efferent arteriole was not determined accurately, but the efferent vessel
is involved less often than the afferent. The grades listed in Table 4 refer to the
maximal involvement found; there are always some arterioles with little or no
.hyaline material.
The data in Table 4 indicate that hyalinization of the juxtaglomerular segment of the afferent arteriole occurred in 87.3 per cent of the diabetic, but in
only 10 per cent of the nondiabetic persons. The advanced degrees of hyalinization (grades 3 and 4) are 13 times as frequent in diabetic as in nondiabetic patients; therefore, this lesion is highly suggestive of diabetes. The 1G nondiabetic
persons with hyalinization of the juxtaglomerular segment exhibited no clinical
signs of diabetes, but 5 of them had hyaline pancreatic islets.
Glomeruli
There was no instance of intercapillary glomerulosclerosis in the nondiabetic
patients, although 8 of them had.severe hyalinization of the juxtaglomerular
segment. Of those with diabetes, 36 per cent of the men and 61.5 per cent of the
women had intercapillary glomerulosclerosis.
The close relation between the degree of hyalinization of the juxtaglomerular
July 1957
ATHEROSCLEROTIC GANGRENE
33
F I G . 1 (upper). Advanced hyalinization of the juxtaglomerular
segment of the afferent arteriole illustrated in longitudinal section.
Note the diffuse intercapiliary glomerulosclerosis. Hematoxylin and
cosin. X 250.
F I G . 2 (lower). Advanced hyalinization of the juxtaglomerular
segment of the afferent arteriole illustrated in transverse section.
Hematoxylin and eosin. X 250.
portion of the arteriole and the presence of intercapiliary glomerulosclerosis is
indicated in Table 5. There was no instance of intercapillaiy sclerosis when the
arterioles were normal, but 75.9 per cent manifested this lesion when the arteriole had grade 4 hyalinization. On the basis of intercapiliary glomerulosclero-
34
Vol. 28
BELL
TABLE 5
T H E R E L A T I O N OP HYALINIZATION OF THE JUXTAGLOMERULAR S E G M E N T OF T H E A F F E R E N T
A R T E R I O L E TO INTERCAPILLARY
Tntercapillary Glomerulosclerosis
Degree of Hyalinization in the
Juxtaglomerular Arterioles
Negative
Per cent positive
0
17
66
82
40
58
54
26
0
22.7
55.0
75.9
165
178
48.1
Positive
Grade 0
Grades 1 and 2
Grade 3
Grade 4
Total
GLOMERULOSCLEROSIS
sis, 48.1 per cent of the diabetic patients with gangrene may
having diabetes by microscopic study of the kidneys. If we
hyalinization of the juxtaglomerular portion of the arteriole
diabetes, an additional 80 cases are included, making a total
positive diagnoses.
be recognized as
accept advanced
as diagnostic of
of 71.4 per cent
Hyaline Pancreatic Islets
Pancreatic tissue for microscopic study was available from 296 of the 39(3
diabetic and 116 of the 186 nondiabetic persons with gangrene. Hyaline islets
were found in 45.6 per cent of the patients with, and 15.5 per cent of the patients without, diabetes. If one believes that hyaline islets do not warrant the
diagnosis of diabetes, this observation has little significance; but if hyaline islets
are indicative of diabetes, then 15.5 per cent of the group listed as nondiabetic
are, in fact, persons with mild diabetes. Five of the 18 nondiabetic patients with
hyaline islets also had advanced hyalinization of the juxtaglomerular segment of
the afferent arteriole. It seems probable that hyaline islets and hyalinization of
the juxtaglomerular segment of the afferent arteriole, in the absence of clinical
diabetes, are both evidences of a prediabetic state.
SUMMARY AND CONCLUSIONS
1. In an autopsy study of 50,184 nondiabetic and 1878 diabetic persons who
were more than 40-years of age at death, 186 instances of atherosclerotic gangrene (of 1 or both lower extremities) were found in the nondiabetic and 393
instances in the diabetic patients.
2. Atherosclerotic gangrene is 53 times as frequent in diabetic as in nondiabetic men more than 40 years of age, and 71 times as frequent in diabetic as in
nondiabetic women of corresponding age.
3. About two-thirds of the cases of atherosclerotic gangrene in men less than
80 years of age and about one-fourth of those in men more than 80 years old
are the result of diabetes.
4. Approximately 80 per cent of atherosclerotic gangrene in women results
from diabetes.
5. The development of gangrene in a diabetic person is not related to the
requirement of insulin or to the known duration of the diabetes.
July 1957
ATHEROSCLEROTIC GANGRENE
35
6. The gangrene was unilateral in 74 per cent of the diabetic and 79 per cent
of the nondiabetic persons. Infection plays an important role in diabetic gangrene, but it is of minor importance in nondiabetic patients.
7. The average period of survival after amputation is longer in the diabetic
than in the nondiabetic patients.
8. Hyalinization of the juxtaglomerular segment of the afferent glomerular
arteriole was found in 87.3 per cent of the diabetic, but in only 10 per cent of
the nondiabetic persons.
9. It is suggested that advanced hyalinization of the juxtaglomerular segment
of the afferent arteriole, such as that illustrated in Figures 1 and 2, indicates
either frank diabetes or a prediabetic state.
10. With the presence of intercapillary glomerulosclerosis, 48 per cent of the
diabetic persons with gangrene may be recognized as diabetic, by means of
microscopic examination of the kidneys. If we accept advanced hyalinization
of the juxtaglomerular segment of the afferent arteriole as diagnostic of diabetes, the number of positive diagnoses becomes 71 per cent.
STJMMARIO IN INTERLINGUA
1. In un studio del necropsias de 50,184 non-diabeticos e de 1878 diabeticos de
plus que 40 annos de etate al tempore de lor morte, 186 casos de gangrena atherosclerotic de un o ambe extremitates inferior esseva trovate inter le non-diabeticos
e 393 casos inter le diabeticos.
2. Gangrena atherosclerotic es 53 vices plus frequente in diabeticos mascule de
plus que 40 annos de etate que in non-diabeticos mascule del mesme gruppo de
etates. In feminas le proportion correspondente es 71 a 1.
3. Circa duo tertios del casos de gangrena atherosclerotic in homines de minus
que 80 annos de etate e circa un quarto de tal casos in homines de plus que 80
annos de etate es le resultato de diabete.
4. Circa 80 pro cento delcasos de gangrena atherosclerotic in feminas resulta
de diabete.
5. Le disveloppamento de gangrena in un diabetico non es relationate al requirimento de insulinao al cognoscite duration del diabete.
6. Le gangrena esseva unilateral in 74 pro cento del diabeticos e in 79 pro cento
del non-diabeticos. Infection ha un rolo importante in gangrena diabetic sed illo
es de importantia minor in patientes nondiabetic.
7. Le periodo medie del superviventia post amputation es plus longe in diabeticos que in nondiabeticos.
8. Hyalinisation del segmento juxtaglomerular del afferente arteriola glomerular esseva constatate in 87.3 pro cento del diabeticos sed in solmente 10 pro cento
del nondiabeticos.
9. On pote concluder que hyalinisation avantiate del segmento juxtaglomerular
del arteriola afferente (tal como illo es illustrate in figuras 1 e 2) indica (a) diabete
franc o (b) un stato prediabetic.
10. Super le base del presentia de glomerulosclerosis intercapillar, 48 pro cento
del casos de diabete con gangrena poterea esser recognoscite como diabetic per
medio de examines microscopic del renes. Si on accepta hyalinisation avantiate
36
BELL
Vol. 28
del segmento juxtoglomerular del arteriola affereiite como diagnostic pro diabete,
le proportion de diagnoses positive deveni 71 pro cento.
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persons. Arch. P a t h . , 49: 469-473, 1950.
2. B E L L , E . T . : Renal vascular disease in diabetes mellitus. Diabetes, 2: 376-389, 1953.
3. BLUMBERG, N . , AND' ZISSERMANN, L.: Twenty year hospital survey of diabetic deaths.
New England J . Med., 214: 833-837, 1951.
4. C R U N B E R G , A., D A V I E S , H . L., AND B L A I R , J. L . : Diabetic gangrene.
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Brit. M . J., 2:
1254-1257, 1951.
MANDELBERG, A., AND SCHEINFELD, W . : Diabetic a m p u t a t i o n s ; amputation of the lower
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M C K I T T R I C K , J. B . : Diabetic and arteriosclerotic gangrene. New York State J . Med.,
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PERLOW, S., AND R O T H , H . A.: Amputation for gangrene due to occlusive arterial disease.
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SILBERT, S., AND HAIMOVICI, H . : Results of midleg amputations for gangrene in diabetics. J. A. M. A., 144: 454-458, 1950.