CASE REPORT

Clinical Trial of LowDensity Lipoprotein-Apheresis
for Treatment of Diabetic Gangrene
Takashi Iizuka, Haruyo Takeda, Hiromi Inoue, Terukazu Miyamoto, Hiroko Ito,
Masao Omura, Hiroyuki Tsuji, Shyozo Chiba and Tetsuo Nishikawa
A 68-year-old man with a 28-year history ofnon-insulin dependent diabetes mellitus (NIDDM)
was admitted to our hospital because of foot gangrene. He had previously suffered from cerebral
infarction resulting in right hemiplegia and his right foot was amputated because of right femoral

lesion presenting diabetic foot gangrene 5 years previously. The diabetic foot gangrene gradually

becameworse, although he had received various medications. Then, we attempted to treat the
patient with low density lipoprotein (LDL)-apheresis ten times a month. The foot gangrene itself
and the local circulation around the gangrene lesion were remarkably improved after treatment
with LDL-apheresis. Wepresent here the first case of diabetic foot gangrene improved by LDLapheresis. LDL-apheresis therapy is anticipated to be a newtherapeutic approach for treatment
of fatal foot gangrene associated with diabetes mellitus.
(Internal Medicine 36: 898-902, 1997)

Key words: low density lipoprotein

(LDL)-apheresis,

(NIDDM), foot gangrene
Introduction

non-insulin

dependent diabetes mellitus

Case Report

Diabetes mellitus is one of the most commonand serious
metabolic disorders characterized by various complications
involving diabetic micro- and macroangiopathy (1-3). The
diabetic complications which typically develop due to poor
control of diabetes sometimes induce diabetic foot gangrene.
As it is very difficult to successfully treat diabetic foot gangrene

A 68-year-old man was admitted to YokohamaRosai Hospital due to foot gangrene in January 1996. He was first noticed
to have diabetes mellitus and hypertension by a regular health
check-up examination when he was 40 years old. However, he
did not visit any hospitals. He was started on insulin therapy
from March 1991 due to poor control of blood sugar levels. He
and achieve complete healing, sometimes it is necessary to suffered from cerebral infarction in October 199 1 , resulting in
perform amputation. However, lowering of the serum low right hemiplegia. In November1991, his right foot was ampudensity lipoprotein (LDL) by a variety of techniques such as tated because of a right femoral lesion presenting diabetic foot
LDL-apheresis and medications, has beneficial effects for pre- gangrene. He smoked 15 to 20 cigarettes a day for42 years until
vention and regression of atherosclerosis
in patients with
he stopped smoking in November 1991.
hypercholesterolemia
(4). Moreover, LDL-apheresis is also
On admission, his height was 160 cm andbody weight45 kg.
well knownto be beneficial for improving peripheral circula- His temperature was 36.5°C, radial pulse rate 72/min, andblood
pressure 120/70 mmHg.The visual acuity was normal. No
tory insufficiency such as foot gangrene induced by arteriosclerosis obliterance. On the other hand, there have never been any abnormal heart sounds were heard. A chest roentgenogram
reports describing whether or not the treatment with LDL- disclosed marked elongation of the aorta with calcification in
apheresis improves diabetic foot gangrene. Thus, we attempted the aortic arch and an abdominal roentgenogram showed disto examine the effect of LDL-apheresis therapy on diabetic foot tension of the small and large bowels due to a large volume of
gangrene in a patient with non-insulin dependent diabetes air. His right thigh was amputated at one-third lower femoral
mellitus (NIDDM).
lesion. Pulsation was absent at the peripheral arteries in the left
lower extremity, especially at the dorsalis pedis, the tibialis and
popliteal arteries. His tendon jerk reflex was absent at the left
From the Department of Medicine, Yokohama Rosai Hospital, Yokohama
Received for publication November 28, 1996; Accepted for publication August 6, 1997
Reprint requests should be addressed to Dr. Takashi Iizuka, the Department of Medicine, YokohamaRosai Hospital, Yokohama,Kanagawa222
898

Internal

Medicine Vol. 36, No. 12 (December 1997)

LDL-Apheresis and Diabetic Gangrene
lower extremity.

He injected insulin (6 units/day of Novolin 30R) by himself
every morning and had a 1,400 kcal-diet; the laboratory data
during this treatment is shown in Table 1. The levels offasting
plasma glucose and HbAlc were 126 mg/dl and 6.0%, respectively. The serum concentrations of total cholesterol, LDLcholesterol, triglyceride and high density lipoprotein (HDL)cholesterol were 179 mg/dl, 105 mg/dl, 65 mg/dl, and 61.2
mg/dl,

respectively.

Clinical course
Although the patient underwent various types of treatment
such as hyperbaric oxygen therapy and, drip infusion of PGEj
and antibiotics, the lesion of gangrene gradually became worse.
Then, we attempted to treat the patient with LDL-apheresisten
times a month in March 1996. The gangrene improved gradually after LDL-apheresis therapy as shown in Fig. 1A and B. As
shown in Fig. 2, thermography of his left lower extremity
demonstrated a remarkable improvement in the local circula-

tion around the gangrene lesion after the treatment with LDLapheresis. His laboratory data including the serum concentration of lipids, apolipoproteins, fibrinogen and thrombin-antithrombin three complex (TAT) before and after LDL-apheresis
therapy are shown in Table 2. The serum concentrations of total
cholesterol, triglyceride, apolipoprotein B , fibrinogen and TAT
were markedly decreased after LDL-apheresis therapy, although the serum levels of HDL-cholesterol, and apolipoprotein Al, A2 and E were not changed. Clinical course of
blood glucose and hemoglobin A1C (HbAlc) levels during his
admission is shown in Fig. 3, and the blood glucose level was
well controlled by insulin with restriction of calorie intake. In

October 1996, the lesion of the foot gangrene was nearly
completely cured by treatments with LDL-apheresis and
various types of supportive therapies and he was discharged
from our hospital.

Table 1. Laboratory Data on Admission
(N o rm al ra n g e )
W B C
RBC
Hb
H t
P its
CRP

(3 ,5 0 0 ‑ 8 ,7 0 0 )
6 ,3 0 0 /u l
(40 0‑ 570 xl O)
428 x 10
(13. 0‑17. 0)
12.8 g/dl
(3 8 .0 ‑ 5 0 .0 )
3 8 .1 %
( 1 5 .0 ‑ 3 5 .O x l O )
1 7 .1x l O
(0. 0‑ 0.4 ) 0.0 5 mg/ dl

PT
(8 0 ‑ 1 0 0 )
87 %
A PT T
(3 0 ‑4 5 ) 3 5 ,8 se c o n d s
F bg
( 20 0‑4 00 )
30 8 m g/ dl
U rin a ly s is
P r ot e i n
( ‑)
(‑ )
G lu c o se
(‑ )
(‑ )
K e t o n e
( ‑)
( ‑ )
Se d. WBC
(1 ‑2/Fs)
O‑1 /Fs
RB C
( 1 ‑2/F s)
O ‑1/F s
Ep it h.
( 1 ‑2 /F s)
O‑ 1 /F s
C cr
(8 0 ‑ 1 2 0 )
1 6 8 .4 m l/d l
U ri n a r y C P R
(4 0 ‑ 14 5 ) 2 8 . 7 u g /d a y
Al b .
( 0 ‑ 2 1 .6 ) 1 5 .6 m g / d ay
O cc u lt b lo o d
( ‑ )
( ‑)
FB G
(7 0‑1 00)
1 26 mg/d l
H b A IC
(3 .5 ‑ 5 .5 )
6 .0 %
TSH
(0.24‑3.70) 3.23 ulU/ml
F‑T 3
( 2.4‑ 4.3)
2.6 pg/m l
F‑ T4
( 0.8‑ 2.1)
1.4 ng/d l

(N o rm a l ra n g e )
T . P .
A lb .
U . A .
B U N
C r
A m y.
A ST
A LT
A LP
L D H
C h ‑E
G ‑G T P
N a
K
c ¥
T ‑c h o l.
L D L ‑c h o l.
T G
H D L ‑c h o l.
A p o .A l
A p o .A 2
A p o .B
A p o .C 2
A p o .C 3
A p o .E

(6 .5 ‑ 8 .0 )
(4 .0 ‑ 5 .3 )
(2 .9 ‑ 5 .9 )
(9 .0 ‑ 2 2 .0 )
(0 .4 ‑ 0 .8
(3 2 ‑ 8 8 )
( 1 1‑ 2 9 )
(9 ‑ 3 6 )
(9 8 ‑ 2 6 7 )
(2 2 6 ^ 0 6 )
(3 .8‑ 7 .4 )
(5 ‑ 6 5 )
( 1 3 9 ‑ 14 6 )
(3 .6 ‑ 4 .7 )
( 10 3 ‑ 1 1 0 )
(1 3 0‑ 22 0 )
( 40 ‑1 5 0 )
(3 6 ‑ 15 0 )
(4 0 ‑ 8 0 )
( 10 5 ‑ 1 8 0 )
(2 8 ^ 9 )
( 55 ‑1 2 0 )
(2 .2 ‑ 5 .9 )
(5 .7 ‑ 1 3 .1)
(2 .8 ‑ 5 .8 )

6 .8 g/ dl
4 . 1 g /d l
4 .0 m g/ d l
15 . 4 m g / dl
0 . 4 m g /d l
5 4 IU / Z
l l I U /Z
1 5 IU /Z
1 76 IU /7
2 5 4 I U /Z
4 .1 IU /m l
20 IU / 7
141 mEq/Z
4 . 6 mE q / Z
101 mEq//
179 mg/dl
105 mg/dl
65 mg/dl
6 1 . 2 mg / d l
12 7 m g / d l
21.4 mg/dl
69 mg/dl
3 .4 m g/ d l
6. 4 mg / d l
3 .2 m g/ d l

PT: Prothrombin time, APTT: Activated partial thromboplastin time, Fbg: Fibrinogen, Ccr: Creatinine
clearance, HbAlc: Hemoglobin A l e, TSH: Thyroid stimulating hormone, F-T3 : Free triiodothyronine,
F-T4: Free thyroxin, LDH: Lactate dehydrogenase, G-GTP: y glutamyltranspeptidase,
LDL-choL:
Low density lipoprotein-cholesterol,
HDL-choL: High density lipoprotein-cholesterol,
T.P.: Total
protein, Alb.: Albumin, U.A.: Uric acid, BUN: blood urea nitrogen,
AST: Aspartate aminotransferase, ALT: Alanine aminotransferase,
T-chol. : Total cholesterol, TG: Triglyceride, Apo. : Apolipoprotein.
Internal

Medicine Vol. 36, No. 12 (December 1997)

Cr: Creatinine, Amy.: Amylase,
ALP: Leucine aminopeptidase,

899

Iizuka et al

Figure 1. Photographs of his left heel. (A) Diabetic gangrene
on the left heel associated with skin cyanosis around the gangrene Figure 2. Thermographical examination of his lower extremlesion before LDL-apheresis therapy. (B) Improved diabetic gan- ity. Thermography before (A) and after (B) treatment with LDLgrene on the left heel after LDL-apheresis therapy for nine times. apheresis.

Discussion

Table 2. Serum Lipids, Apolipoproteins,
Fibrinogen and TAT
before and after the LDL-Apheresis Therapy
before LDL-apheresis after LDL-apheresis
Total-ch.
Triglyceride
HDL-ch.

Apolipoprotein-A
Apolipoprotein-A2 1
Apolipoprotein-B
Apoli
poprotein -E
Fibrinogen
TAT

176 (mg/dl)
78 (mg/dl)
61.2
(mg/dl)
1 25 (mg/dl)
21.0
(mg/dl)
68 (mg/dl)
3.3 (mg/dl)
300 (mg/dl)
8.3 dig//)

93 (mg/dl)
30 (mg/dl)
61.0
(mg/dl)
122 (mg/dl)
20.1
(mg/dl)
30 (mg/dl)
1.6 (mg/dl)
1 83 (mg/dl)
7.3 (|ig//)

TAT: thrombin-antithrombin

900

three complex.

The present study clearly demonstrated that the lesion of
diabetic foot gangrene was almost completely cured by treatment with LDL-apheresisand various supportive therapies,
although it has never been reported that LDL-apheresis therapy
improves diabetic foot gangrene. It is well known that one of the
most severe complications of diabetes mellitus is the loss of a
limb. It has been suggested that three major factors leading to
tissue necrosis in the diabetic foot are peripheral neuropathy,
infection and ischemia. Peripheral ischemia in patients with
diabetes mellitus is believed to be induced by micro- and
macroangiopathy. It is, however, unlikely that the micro- and
macrovascular diseases

are a direct cause of diabetic

foot

gangrene, since almost all patients with diabetic gangrene have
peripheral neuropathy which may induce an impairment in
protective mechanismsagainst trauma such as burning. Furthermore, infections with anaerobic bacteria coexisting with
Internal

Medicine Vol. 36, No. 12 (December 1997)

LDL-Apheresis and Diabetic Gangrene
(mg/dl)

6 units/day
1,400

140

of Novolin 30R

kcal-diet

1

-

HbAlc

-à"-

120-

FBG

\

(%)

-7.0

§
"m 80-

O

-.

|

6.0

bo
à"S

S

60^HL

g

«^5.9

5.9
5.8

5.8

5.8^«.

å

^^^\5.7

^
40-

å

V

0
20-

§

^

"55

a>»

0-I

1996Jan

.

Feb

^Jiil

5.4

-8

S

2

5.4

^

1

-6.0
<

Q

§
9

So
S

å

.

.

å

Mar Apr May Jun

Jul

.

Aug

1

Sep

h

5.0

Oct

Figure 3. Clinical course of blood glucose and HbAlc levels during admission.

aerobic bacteria are usually observed in most gangrene tissues
of the diabetic foot, suggesting that local infection is also an
important factor for inducing and worsening gangrene. On the
other hand, LDLplays a crucial role in the development of
atherosclerosis (7). In the present case, serum lipid levels such
as total cholesterol, LDL-cholesterol and apolipoprotein B
were not high, compared with the normal range of those lipids,
while diabetic foot gangrene became severe and the possibility
of remission was thought to be very low whentreated by usual
therapy.

circulation in patients with arteriosclerotic
obliterance (ASO)
(1 1). The present study suggests that LDL-apheresis may affect
anticoagulant factors, and improve the local blood flow in

patients with diabetic foot gangrene. Although the mechanism

of LDL-apheresis therapy improving diabetic foot gangrene is

not fully understood, it is speculated that the treatment with
LDL-apheresis may induce new collagen synthesis around the

lesion of gangrene. Therefore, it is suggested that aggressive
treatment of local gangrene tissue induced by diabetes mellitus,
such as LDL-apheresis therapy, seems to promote enhancement in local oxygenation of gangrenous tissues.
This study demonstrated that LDL-apheresis therapy may be

Manyreports have described that LDL-apheresis has a direct
effect on removing LDL-cholesterol, finally resulting in regression of atherosclerosis (4, 8-12). It is also believed that LDL- a new therapeutic approach for improvement in fatal foot
apheresis may improve abnormalities in lipid metabolism (8, gangrene induced by diabetes mellitus.
9), peripheral circulation and blood viscosity (10), local imReferences
mune functions (4), circulating coagulation factors (1 1), and
kallikrein-kinin systems and serum level of NO(12). A previFW, Coffman JD. Current concepts. Vascular and microvascuous study suggested that the decreased levels of peri-wound 1)lar LoGerfo
disease
of the1984.foot in diabetes. Implications for foot care. N Engl J Med
311:
1615,
cutaneous per fusion and oxygenation maycontribute to the
development of diabetic foot gangrene (5). In the present study, 2) Debridge L, Appleberg M, Reeve TS. Factors associated with developthe local circulation around the gangrene lesion was remarkably ment offoot lesions in the diabetic. Surgery 93: 78, 1980.
McMillan DE. Plasma protein changes, blood viscosity, and diabetic
improved after LDL-apheresis. Rubba et al reported that peak 3)microangiopathy.
Diabetes 25: 858, 1976.
blood flow significantly increased in the leg, and blood viscos- 4) Uno H, Ueki Y, MurashitaJ,
Miyake S, TominagaY, Eguchi K, Yano K.
ity was significantly reduced after LDL-apheresis in ten pa- RemovalofLDLfrom plasma by adsorption reduces adhesion molecules
tients with hypercholesterolemia ( 1 0). This study also reported on mononuclearcells in patients with arteriosclerotic obliterans. Atherosclerosis
116: 93, 1995.
that removal of serum fibrinogen was observed after LDL5)
Pecoraro
RE,
Ahroni JH, Boyko EJ, Stensel VL. Chronology and deterapheresis therapy (from 300 mg/dl to 183 mg/dl). Tasaki et al
minants
of
tissue
repair in diabetic lower-extremity ulcers. Diabetes 40:
reported that LDL-apheresis therapy could remove fibrinogen
1305,
1991.
by LDL-adsorption and lead to an improvement in the local 6) Steinberg D, Parhasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond
Internal

Medicine Vol. 36, No. 12 (December 1997)

901

Iizuka et al
cholesterol.

Modifications of low density lipoprotein that increase its

atherogenicity.
N Engl J Med 320: 915, 1989.
Ross R. The pathogenesis of atherosclerosis:
a perspective
Nature

362: 801, 1993.

for the 1990s.

Bambauer R, Schiel R, KellerHE, Latza R. LDL-apheresis in two patients
with 1995.
extremely elevated lipoprotein (a) levels. Int J Artif Organs 18: 286,
Kritz H, Sinzinger H. Atherosclerotic lesions in humans-plaque
stabilization and regression. Wien Klin Wochenschr 107: 555, 1995.
Rubba P, Iannuzzi A, Postiglione A, Scarpato N, Montefusco S, Gnasso

902

A, Nappi G, Cortese C, Mancini M. Hemodynamicchange in the
peripheral circulation after repeat low density lipoprotein apheresis in
familial hypercholesterolemia.
Circulation 81: 610, 1990.
ll) Tasaki H, Tsuda Y, Yamashita K, Toyokawa T. Removal of plasma
fibrinogen by LDL apheresis. Jpn J Apheresis 15 Suppl: S55, 1996
(Abstract).

12) Ueki Y, Murashima J, Matsunaga Y, Tominaga Y, Miyake S. Generated
bradykinin by LDLadsorption induces serum NOin patients with
atherosclerotic obliterance. Jpn J Apheresis 15 Suppl: S56, 1996 (Abstract).

Internal

Medicine Vol. 36, No. 12 (December 1997)