EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN., 2009
El-Akkad et al
MICROVASCULAR COMPLICATIONS IN PATIENTS WITH DIABETES
MELLITUS ASSOCIATED WITH LIVER CIRRHOSIS AS COMPARED
WITH TYPE -2 DIABETES MELLITUS
By
Atef F. El-Akkad*, Ayman G. Ghaberial**,
Ayman Farouk Darwish***
Departments of *Internal Medicine, **Clinical Pathology and ***Rheumatology
Minia Faculty of Medicine
ABSTRACT :
Introduction: Type-2 diabetes mellitus is frequently complicated by microangiopathy, such as diabetic retinopathy and nephropathy (skyler 2006). These vascular
complication greatly affect the prognosis of diabetic patients (WHO study group
1999). Among patients with liver cirrhosis 20-30% have been reported to have
diabetes and if borderline cases are included, over 80% have abnormal glucose
metabolism of hepatic etiology (Giampaolo et al., 1994). In these patients the
incidence of microangiopathy are thought to be low (creed et al., 2004). However, as
far as we know, there have previously been few detailed studies on the incidence,
severity or pathogenesis of vascular complications in patients with cirrhosisassociated diabetes.
Aim of the work: To study the pathogenesis and the risk factors for the development
of vascular complications (microangiopathy) in diabetes secondary to liver disease
versus patients with type- 2 diabetes mellitus.
Patients and Methods: This study was conducted in the period from April 2007 till
October 2007, on 70 patients presented to the internal medicine outpatient clinic and
internal medicine department of El-minia university hospital and were divided into
three groups. Group I (LC-DM)) including thirty (30) patients of liver cirrhosis of
virus C developing diabetes mellitus. Group II (Type2-DM) including thirty (30)
patients of type-2 diabetes mellitus. Group III including (10) apparently normal
healthy volunteers as control. All the groups were compared as regard for the
pathogenesis and risk factors for the development of microvascular complicationts in
diabetes mellitus secondary to liver cirrhosis of virus C (LC-DM) versus patients with
type-2 diabetes mellitus (Type2-DM),also all the groups were compared as regard the
incidence of these microvascular complications including retinopathy, neuropathy and
nephropathy.
Results: Fundus examination (microvascular retinopathy) of the studied groups
showed a significant difference as regard retinopathy between group II as compared
with group I (p<0.02) and group III (p<0.005)and a significant difference of group I
as compared with group III (p<0.02). As regard microvascular nephropathy there
were a significant difference between group I as compared with group II as regard
serum albumin (p<0.003) and a highly significant difference of microalbuminuria
(p<0.001) but no significant difference between group II and group III as regard of
these elements. There were a highly significant difference between group I as
compared with group II as regard F-IRI (P<0.001) and a significant relation of
HOMA-IR (p<0.02). As regard results of sensory nerve conduction velocity
(neuropathy) there were a near significant difference (p<0.06) between group II as
compared with group I as regard sensory nerve conduction velocity in the median
nerve, however, the conduction velocity in the ulnar nerve did not show a significant
difference between the two groups. These results confirm the lower incidence of
microvascular complications in patients with group I (LC-DM) as compared group II
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El-Akkad et al
(Type2-DM) patients, also confirm the more incidence of insulin resistance in patients
of liver cirrhosis associated with diabetes mellitus than patients with diabetes mellitus
without liver cirrhosis .
Conclusion: The risk factors and the incidence of diabetic retinopathy, nephropathy
and neuropathy (microvascular complications)were significantly lower in diabetic
patients associated with liver cirrhosis (LC-DM) than in patients with (type2-DM).
KEY WORDS:
(LC-DM) Liver cirrhosis associated with diabetes mellitus
(Type2-DM) type2 diabetes mellitus
(HOMA-IR) Homeostasis model assessment insulin resistant
(F-IRI) Fasting immune reactive insuline.
INTRODUCTION :
Although it is a well established
phenomena that glucoregulation is
disorderd in chronic liver disease, yet
the prevalence differs much from one
study to another.
related chronic liver disease could be
facilitated by hepatic iron overload and
mitochondrial damage [brischetto R, et
al., 2003].
Type-2 diabetes is a common
and serious disease with chronic
complications, and it constitutes a
substantial burden for both the patient
and the health care system. Type- 2
diabetes is characterized by an asymptomatic phase between the actual onset
of diabetic hyperglycemia and clinical
diagnosis. This phase has been
estimated to last at least 4-7 years, and
consequently 30-50% of type-2 diabetic
patients remain undiagnosed [Harris MI,
et al., 2007].
This seems to be related to the
etiology of chronic liver disease.71% of
patients with liver cirrhosis had
manifest diabetes. 25% had impaired
glucose tolerance. Only 4% had normal
glucose tolerance. In most cases
diabetes was clinically asymptomatic.
only 16% of those patients had family
histoy and 8% had retinopathy [Holstein
A, et al., 2002].
About 80% of patients with
chronic liver disease such as cirrhosis
are glucose intolerance and some 2030% eventually develop diabetes
mellitus [petrides AS, Z Gastroentrol.,
1999].
Microvascular complications in
diabetes contribute to pathologic and
functional changes in many tissues,
including eye, heart, kidney, skin, and
neuronal tissues.
A higher prevalence of diabetes
was observed in patients with HCVrelaled chronic liver disease in
comparison with patient with liver
disease of other etiologies (32.5% VS
15.3%). Patients with HBV had diabetes in only 6.6%.
Based on the tissues affected, these
changes are traditionally known as
diabetic retinopathy, nephropathy, and
neuropathy, respectively.
PATIENTS AND METHODS :Group (1) (LC-DM) 30 patients
presented to the internal medicine
clinic & internal medicine department
It is postulated that type-2
diabetes mellitus in patients with HCV –
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of EL- minia university hospital, who
met the following inclusion criteria:
1) Diabetes mellitus was
diagnosed after liver cirrhosis developed, thus fulfilling the diagnosis of
diabetes secondary to liver cirrhosis
(kuzuya et al., 2002), and who were
being treated with diet and insulin (LCDM group).
2) The patients with cirrhosis
(clinically and ultrasonography confirmed) are due to hepatitis c virus who
diagnosed by Elisa.
Group (2) (Type2 -DM group) 30
patients who met the following:
1) Type 2 diabetes mellitus (T2DM group).
2) Matching for type of therapy,
sex, age, duration of diabetes, degree of
glycemic control and body mass index.
El-Akkad et al
and this confirmed with PCR with
exclusion of other causes of liver cirrhosis as metabolic, autoimmune, history
of alcohol intake or active consumption
of alcohol and hepatic focal lesion or
other neoplastic lesions as metastasis
with liver cirrhosis, Diabetes mellitus
was diagnosed after liver cirrhosis
development without past history or
family history of diabetes mellitus. All
patients of group II were diagnosed as
diabetic according to the diagnostic
criteria with exclusion of other causes
precipitating DM as hyperthyroidism,
drug as thiazide diuretics and corticosteroids.
Ethical aspects: All apatients had given
an informed consent regarding the
participation in the present study and the
right to be withdrawn from it at any
time with receiving aprit from all there
investigations done during the study .
The diagnosis of diabetes was
made according to the diagnostic criteria of WHO (Alberti and Zimmet
1998).
methods:All patients are subjected to the following:
*Careful history taking including:
Data on age, sex, weight, height,
body mass index, blood pressure and
smoking habits (Beks et al., 1995).
Type 2 diabetes was defined as a
mean fasting glucose level of < 7.8
mmol/l and/or a mean 2-h postload
glucose level of < 11.1 mmol/l, based
on two oral glucose tolerance tests, or
treatment with oral blood glucose-lowering agents or insulin (WHO) (Jager et
al., 2001).
Group (3) control, 10 control
patients without cirrhosis or diabetes
mellitus.
*Demographic data:
Patients' weights (kg) and heights (m)
were measured.
Body mass index (BMI) is calculated
according to the following formula:
BMI= body weight (kg)/ [height (m)] 2
The internationally accepted range of
BMI in adult is as following:
 Underweight: <18.5.
 Average weight: 18.5-24.9.
 Overweight: 25-29.9.
 Obesity: 30-39.9.
 Extreme obesity: >40). (Molnar et
al., 2000)
Selection and exclusion criteria: All
patients of group I were liver cirrosis
with hepatitis C antibody positive and
HBsAg negative diagnpsed by ELISA
*Thorough clinical examination.
- Laboratory data:
For all subjects in both groups,
blood was obtained after fasting 12
Duration of diabetes was determined based on the medical record e.g.,
onset of glucosuria or hyperglycemia by
annual medical check up, onset of thirst,
polyuria, polydipsia, or date of
diagnosis.
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El-Akkad et al
hours or longer to measure and compare
the following:
 CBC
 Fasting plasma glucose (FBG) level.
 HbA1c
 Total cholesterol, triglyceride,
HDL, LDL .
 Fasting insulin level (immunoreactive insulin: IRI)
As an index for insulin resistant, the
homeostasis model assessment of
insulin resistant (HOMA-IR)
(HOMA-IR = fasting blood glucose
(mg/dl) X fasting insulin level (mu/ml) /
405) was used (Matthews et al.,. 1985)
neovascularization and/or laser coagulation scars in at least one eye.
All the relevant examinations were
completed by an ophthalmologist and
the patients were categorized according
to the degree of their retinopathy:
1- No retinopathy.
2- Nonproliferative Diabetic Retinopathy (NPDR).
3- Proliferative diabetic retinopathy
(PDR).
*Neuropathy evaluation:
Nerve conduction studies were performed using standard surface stimulation
and recording techniques with a neuroscreen Plus electro-diagnostic machine
*Statistical Analysis:
All data were tabulated by EXCEL
Microsoft program on PC computer.
Statistical analysis was done using
SPSS, (Software Package for Scientific
Statistics) USA, version 11.
*Assessment of nephropathy:
Diabetic nephropathy was diagnosed
based on microalbuminuria of 20mg/
day or greater.
All the measurements were
performed after worming of the fore
arm and lower leg for at least 15 min.
the peak-peak amplitudes were used.
The reference velocities from our own
laboratory were used with the abnormal
values being defined as >2 standard
deviations from the normal mean
values. the motor nerve conduction
velocities were measured in the right
median, tibial and peroneal nerve. The
sensory nerve conduction velocities and
amplitude were measured in the
median, ulnar and sural nerves.
Numerical data were expressed as
mean and standard deviation (SD),
which was compared using t-student
test.
Categorical data were expressed as
number and percent which were
compared using Chi-square test.
P-value was considered to be
significant if less than 0.05.
RESULTS:
Table (1): show the clinical characteristics of the studied groups who
were 70 patients subdivided into 3
groups, group I: including 30 patients
of liver cirrhosis associated with diabetes mellitus (LC-DM). They were 18
males (60%) and 12 females (40%).
The mean age of them was 55.4 ± 6.8.
Group II including 30 patients of type-2
diabetes mellitus (Type2-DM). They
were 12 males (40%) and 18 females
(60%). The mean age of them was 55.2
± 11.7. the third, group III including 10
*Assessment of retinopathy:
Retinopathy was assessed by
direct (60 dioptre) ophthalmoscopy
and/or by fundus photography. Both
findings were graded according to the
modified Arlie House classification
(Klein et al., 2005).
Any retinopathy was defined as the
presence of one or more hemorrhages,
microaneurysms, soft and hard exudates,
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age and sex matched healthy individuals as control .they were 6 males
(60%) and 4 females (40%). The mean
age of them was 54.5 ± 5.6.
El-Akkad et al
highly significant HbA1c (p< 0.0001)
& high significant differences between
group II as compared with group III as
regard FBG (p<0.0001> and HbA1c
(p<0.0001). There were high significant
difference between group I as compared with group II as regard FIRI(p<0.001) and HOMA-IR (P<0.02)
but with no significant difference between group II and III (P<0.95) & 0.08
respectively). Comparing group I & III
as regards fasting F-IRI & HOMA-IR)
there was a significant diff-erence
(P<0.04 & 0.008 respectively) .
Table (2) and figure (1): Show
results of fundus examination of the
studied groups. There was a significant
difference as regard retinopathy between group II as compared with group I
(p<0.02) and group III (p<0.005) and a
significant difference of group I as
compared with group III (p<0.01). The
retinopathy changes in group I was 33%
as compared with 63.3% in group II.
These statistical differences proves the
high incidence of retinopathy in Type-2
diabetes mellitus (Type2-DM) as compared with liver cirrhosis associated
with diabetes mellitus.
These results can be interpretated
by the more incidence of insulin
resistance as indicated by the high mean
value of F-IRI that was 42.7±32 in
group I as compared with 19.8±15.9 in
group II, and high mean value of
HOMA-IR that was 13.27± 8 in group I
in comparison with 8.74±6.18 in group
II. These results proves that liver cirrhosis associated with diabetes mellitus
(LC-DM) can be due to more incidence
of insulin resistance ,as compared with
type2-diabetes mellitus without liver
cirrhosis.
Table (3): show complete blood
count, liver function test and microalbuminuria (as a marker of diabetic
nephropathy changes) of the studied
groups. There were significant differences of hemoglobin level, WBCs,
platelets, RBCs, serum albumin and
ALT (but within normal ranges)
between group I as compared with
group II, III. These statistical differences can be interpretated by the
complications of liver cirrhosis in group
I (LC-DM). As regard microalbuminuria was highly significant in group
II in comparison with group I with
mean value 115.4 ± 109 in group II and
39.67 ± 29.9 in group I that indicate the
higher incidence of nephropathic
changes in type-2 diabetes mellitus
(Type2-DM) when compared with liver
cirrhosis associated with diabetes
mellitus (LC-DM).
Table (5): show lipid profile of the
studied groups, there were significant
differences between group I as compared with group II as regard Cholesterol (p<0.01), Triglyceride (p< 0.02)
and a highly significant difference with
HDL (p<0.005) .but no significant
differences between the three groups as
regard LDL. These results can explain
the lower incidence of retinopathy in
group I (LC-DM) by the protective
effects on vascular complications of
low serum levels of lipids such as
Triglycerides, total Cholesterol, decreased coagulation factors and thrombocytopenia
associated
with
liver
cirrhosis.
Table (4), Fig (2), (3) and (4): show
fasting blood glucose (FBS), HbA1c, FIRI and HOM-IR of the studied groups.
There were a significant differences
between groupies compared with group
II as regared FBG (p< 0.002) and a
Table (6) and Figure (5): show
results of sensory nerve conduction
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velocity of group I and group II. There
were a near significant difference
between group I and group II (p<0.06)
as regard sensory nerve conduction
velocity in the median nerve. However,
the conduction velocity in the ulnar
nerve did not show significant difference between the two groups .
El-Akkad et al
group I as compared with group II as
regard F-IRI (p<0.001) and HOMA-IR
(P<0.02).
There were a near significant
difference between group II (P<0.06) as
regard sensory nerve conduction velocity in the median nerve as diabetic
neuropathy. T summation of these
results confirm the more incidence of
diabetic microvascular complications
(retinopathy, nephropathy and neuropathy) in patients of liver cirrhosis associated with type-2 diabetes mellitus
(Type 2-DM) as compared with patients
of liver cirrhosis associated with
diabetes mellitus .
To summarize our results: there
was a significant difference as regard
retinopathy between group II as compared with group I (p<0.02). There was
significant differences between group I
as compared with group II as regard
serum albumin (p<0.003) and microalbuminuria (p<0.001). There were a
highly significant differences between
RESULTS:
Table (1): Clinical characteristics of the studied groups.
Variable
Group I
(n=30)
Group II
(n=30)
Group III
(n=10)
55.4±6.8
18 (60%)
55.2±11.7
12 (40%)
54.5±5.6
6 (60%)
12 (40%)
Female
8(26.7%)
Smoking
2(6.7%)
Hypertension
Ischemic heart disease 2(6.7%)
27.1±4.1
BMI
4.2±2.1
D.M. Duration
120±15.
SBP
9
73±9
DBP
18 (60%)
3(10%)
6(20%)
4(13.3%)
29.6±5.6
4.3±3.2
120.3±18.
5
74.7±9.6
4 (40%)
3(30%)
0(0%)
0(0%)
27.3±2.5
123.2±12.
7
76±4.7
Age
Sex
Male
P-value
I vs II II vs III I vs III
0.95
0.12
0.84
0.27
0.70
1
0.09
0.12
0.38
0.059
0.88
0.94
0.12
0.12
0.22
0.23
0.64
0.83
0.40
0.40
0.87
0.56
0.48
0.68
0.33
Table (2): Results of fundus examination of the studied groups.
Fundus
examination
Group I
(n=30)
Normal
20(66.7%)
Retinopathy 10(33.3%)
(*: significant).
Group II
(n=30)
11(36.7%)
19(63.3%)
Group III
(n=10)
10(100%)
0(0%)
109
P-value
I vs II II vs III I vs III
0.02*
0.005* 0.01*
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El-Akkad et al
Table (3): Complete blood count, liver function test and microalbuminuria of the studied groups.
Variable
Group I
(n=30)
Hb (g/dl)
10.88±2.3
3
WBCs(x 10 )
6.52±2.76
3
Platelets (x 10 )
159.9±87.6
RBCs (x 106)
4±0.85
Serum albumin (g/dl)3.08±1.14
ALT (U/l)
37.8±21.08
Microalbuinuria
39.67±29.9
(*: significant).
Group II
(n=30)
12.48±1.83
7.94±2.74
256.13±79.1
4.54±0.61
3.78±0.45
28.7±22.7
115.4±109
Group III
(n=10)
13.55±1.73
7.85±2.57
301.6±68
4.9±0.45
4.05±0.54
19.8±11.27
56.7±108.9
P-value
I vs II
II vs III I vs III
0.004*
0.11
0.002*
0.05*
0.92
0.19
0.0001*
0.11
0.0001*
0.007*
0.08
0.003*
0.003*
0.13
0.01*
0.11
0.24
0.01*
0.001*
0.14
0.43
Table (4): Fasting blood glucose (FBG), HbA1c, F-IRI and HOMA-r of the studied groups
Variable
Group I
(n=30)
FBG (mg/dl) 148±68.59
HbA1c
7.53±1.26
F-IRI
42.7±32.8
HOMA-r
13.27±8.94
(*: significant).
Group II
(n=30)
Group III
(n=10)
I vs II
210.26±79.55 97.1±15.9 0.002*
8.73±0.79
6.87±0.67 0.0001*
19.8±15.9
19.5±18.48 0.001*
8.74±6.18
4.84±5.1
0.02*
P-value
II vs III
0.0001*
0.0001*
0.95
0.08
I vs III
0.02*
0.12
0.04*
0.008*
P-value
II vs III
0.19
I vs III
0.61
Table (5): Lipid profile of the studied groups
Variable
Group I
(n=30)
Cholesterol
137.6±53.3
(mg/dl)
Triglyceride
79.8±25.25
(mg/dl)
HDL (mg/dl)
58.46±17.1
LDL (mg/dl)
62.67±48.58
(*: significant).
Group II
(n=30)
Group III
(n=10)
175.3±65.4
146.7±31.5
I vs II
0.01*
95±27.24
100.9±30.5
0.02*
0.56
0.03*
73.13±21.34
82.8±54.51
72.8±19.9
53.7±11.88
0.005*
0.135
0.96
0.10
0.03*
0.57
Table (6): Results of sensory nerve conduction velocity of group I and group II.
Sensory nerve conduction velocity
Median nerve
Ulnar nerve
Delayed DL and low MCV
No delayed DL and normal MCV
Delayed DL and low MCV
No delayed DL and normal MCV
110
Group I
(n=30)
9(30%)
21(70%)
14(46.7%)
16(53.3%)
Group II
(n=30)
16(53.3%)
14(46.7%)
17(56.7%)
13(43.3%)
Pvalue
0.06
0.43
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El-Akkad et al
100
90
80
70
60
50
40
30
20
10
0
no retinopathy
retinopathy
group I
group II
control
group
Fig. 1 : incidence of retinopathy in the studied group
250
200
Percent
150
group I
group II
control group
100
50
0
group I
group II
control
group
Groups
Fig. 2 : Mean fasting blood glucose in the studied groups
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9
8
7
Percent 6
5
El-Akkad et al
group I
group II
control group
4
3
2
1
0
group I group II control
group
Groups
Fig. 3 : Mean HbALc in the studied groups
14
12
10
Percent
8
group I
group II
control group
6
4
2
0
group I group II control
group
Groups
Fig. 4 : Mean HOMA-r in the studied groups
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El-Akkad et al
70
60
50
Percent
40
group I
group II
30
20
10
0
Delayed DL and
No delayed DL
delayed DL and no delayed DL
low MCV
and norm al MCV
low MCV
and norm al MCV
Fig. 5 : Results of sensory nerve conduction velocity of the studied groups .
secretion is observed after glucose
loading in liver cirrhosis (Proietto et
al., 2008) .
DISCUSSION;
The liver plays important roles
in the homeostasis of glucose metabolism since it acts as a major target
organ for insulin and a site for gluconeogenesis and glycogen storage.
Diabetes mellitus (DM) commonly
develops in patients with liver cirrhosis
as the result of hepatocyte dysfunction
and/or inadequate mass (Kim and
Choi, 2006).
Among patients with liver
cirrhosis, 20-30% has been reported to
have diabetes, and if borderline cases
are included, over 80% have abnormal
glucose metabolism of hepatic etiology
(Giampolo et al., 2005).
Glucose
uptake
into
hepatocytes after glucose absorption is
delayed due to decreased hepatocyte
mas in CLD, leading to hyperinsulinemia. Subsequent continuous hyperinsulinemic state could eventually
induce insulin resistance in the patients. Previous reports suggested that
insulin resistance, characterized by
both decreased glucose transport and
decreased non oxidative glucose metabolism in skeletal muscle, could be the
cause of diabetes in liver cirrhosis
(Selberg et al., 2004).
The pathogenesis of diabetes in
liver disease is not fully understood . In
alcoholic liver disease, reduced insuline secretion due to pancreatic damage
could be the cause of impaired glucose
metabolism. However, that may not be
the cause of diabetes in viral liver
disease. Because excess insuline
In addition, glucose effecttiveness, glucose metabolic pathway
independent of insulin secretion, is also
reduced
in
cirrhotic
patients
(kruszynsky et al., 1993). Therefore,
hyperinsulinemia
and
peripheral
insulin resistance contribute to the
development of DM, in patients with
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liver LC, which is more frequently
associated with HCV infection (Kwon,
2003).
El-Akkad et al
These findings agreed with the
published data in literature. In the
study by Marchisini., (1999), the overt
diabetes was reported to affect long
term survival of cirrhotic patients by
increasing the risk of hepatocellular
failure, without increasing the risk of
diabetes-associated
cardiovascular
events, cirrhotic patients, even in the
presence of overt diabetes, are at low
risk of cardiovascular disease. The low
prevalence may be related to shorter
duration of diabetic disease, also in
relation to reduced life expectancy, as
well as to liver disease-induced abnormalities protecting the cardiovascular
system from atherosclerosis.
Hepatogenous diabetes differs
from type- 2 diabetes in that there is
less often a positive family history and
that the cardiovascular and retinopathic
risk is low. The prognosis of cirrhosis
patients with diabetes is more likely to
be negatively affected by the underlying hepatic disease and its complications than by the diabetes (Holstein
et al., 2002).
Accordingly, the present study
evaluated and compared clinical features and microvascular complications
of patients with DM associated with
LC versus patients with type-2 DM.
Also, the recent study by
Tamura et al., (2007) which suggest
that the development of atherosclerosis
in patients with DM is suppressed by
the presence of LC, probably due to
reduced platelet counts and fibrinogen
levels. In that study, there were no
significant differences between the LCDM group and DM group in the
duration of DM, proportion of smokers, arterial blood pressure, fasting
and postbrandial plasma glucose
levels, and CRP, but HbA1, platelet
counts and fibrinogen were signifycantly lower in the LC-DM group than
in the DM group.
The published data in literature
reported that,chronic hyperglycemia,
diabetes duration and hypertension are
predominant risk factors for diabetic
microangiopathy such as retinopathy,
nephropathy and neuropathy (Skyler,
1996), While in addition to these, sex,
age, smoking, insulin resistance and
dyslipidemia are also strong risk
factors of macroangiopathy (Garber,
2008) .
To compare the microvascular
complications, we adjusted the background factors such as sex, age,
diabetes duration between the two
groups. Therfore, there were no
differences in these risk factors as well
as blood pressure between the two
groups of DM.
In the present study, patients
with DM associated with LC had significantly lower incidence of retinopathy
(33.3% vs 63.3% in type-2 diabetes).
Pathophysiology of retinopathy
is well difined in diabetes; however the
pathophysiology involving retinopathy
in cirrhosis is unknown. Increased
estrogen formation may cause hormonal modification in retinopathy.
Shunts in retinal vasculature resembling intrarenal and intrapulmonary
shunts observed in hepatopulmonary
syndrome and hepatorenal syndrome
In the present study, the
incidence of different risk factors
including hypertension and ischemic
heart disease were low with DM
associated with LC but with non
significant statistical difference when
compared to patients with type-2
diabetes.
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EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN., 2009
may be operational in retinal ischemia
and cotton-wool spots.Increased hydrostatic pressure caused by high portal
pressure, hypoalbuminemia in cirrhosis
and resultant decreased oncotic
pressure may also contribute to exudates formation via extravasation of
plasma contents (onder et al., 2005).
El-Akkad et al
complications. Therfore, they concluded that in diabetes associated with
liver cirrhosis, the incidence of diabetic
retinopathy
and
cerebrovascular
disease is lower than in type-2 diabetes
mellitus, probably because of lower
levels of serum Lp(a). In our study
unfortunately we have not done Lp(a)
and also we have not study the
cerebrovascular disease in our patients
as we consider it one of the macrovascular complications of diabetes and
therefore it is outside the scope of our
thesis. Therfore, we recommend
studying the association between
microvascular and macrovascular
complications in LC-DM patients.
A study done by Dittmer et al.,.
(1998) supports our findings in the
present study. In that study, 17 patients
with cirrhosis and portal hypertension,
largely due to alcohol consumption,
had ophthalmic examination before
and after transjugular intrahepatic portosystemic stent shunting. Retinopath
was evident in 11 patients of which5
were exudates in nature. Retinopathy
regressed significantly or disappeared
completely after this procedure which
has hemodynamic contributions to the
systemic circulation. These findings
were attributed to the fact that cirrhosis
leads to decreased retinal perfusion.
As admitted by Vidal et al.,
(2008), the lower prevelance of
retinopathy in cirrhosis individuals
than in type-2 diabetes mellitus
patients can be explained by an understanding duration of diabetes in the
type-2 diabetes mellitus control group.
It is indeed very difficult to quantify
the exact duration of the disease (and
thus that of hyperglycemia) in such
patients with type-2 diabetes mellitus,
since the phenotype (expression of the
genetic defect which is suggested by
the higher prevalence of the disease in
the family history) may appear early
but remain undiagnosed for along
period of time. Another possible
explanation obtained by these authors
may be the lower prevalence of
hypertension in diabetes in patients
with cirrhosis; a known hypotensive
condition contrasting with the hypertension frequently associated with
type-2 diabetes mellitus.
The lower incidence of
retinopathy in our LC-DM group may
be explained by the protective effects
on vascular complications of low
serum level of lipids such as triglycerides, total cholesterol, decreased
coagulation function and thrombocytopenia associated with liver
cirrhosis. Further studies are needed to
address this issue of pathogenesis of
retinopathy in LC-DM in depth.
Similarly, Fujiwara et al.,
(2005) reported that the incidence of
diabetic retinopathy and cerebrovascular disease was significantly lower in
the LC-DM group compared to the
type-2DM group. The results obtained
by those authors indicated that Lp(a)
and the diabetes duration were significant predictors for retinopathy, while
lipoprotein (Lpa) was a significant
predictor for the cerebrovascular
In the present study, hemoglobin, blood counts(red cells, white
cells, and platelets) in patients with
DM associated with LC were signifycantly lower than patients with type-2
diabetes.
116
EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN., 2009
Similarly, Fujiwara et al.,
(2005) reported lower blood counts in
LC-DM group than the type-2 DM
group.
El-Akkad et al
However, the hyperinsulinemia
as a risk for the development of microvascular complications in LC-DM
needs further evaluations in a large
prospective study.
A large number of investigators
(Nygren et al.,; Petrides et al., 1999;
Kruszynska et al.,2000) have,directly
or indirectly, shown that reduced
insulin clearance by the liver cirrhosis,
contributes to hyperinsulinemia, and
this may be the main explanation for
the hyperinsulinemia.
Kruszynska et al., (1991) found
that,insulin secretion was greater in
patients with cirrhosis both in the
fasting state
and
during the
hyperglycemic clamp. After an oral
glucose load, however, the increase in
serum C-peptide concentration was
relatively delayed and the insulin
secretion index was not increased.
Hepatic insulin extraction was reduced
in the fasting state and during the
hyperglycemic
clamp.
Thus,
hypersecretion and decreased insulin
clearance were postulated to result in
increased insulin concentrations in
patients with cirrhosis.
Also, Bianchi et al., (1994)
analysed the prognostic significance of
diabetes in patients with cirrhosis,
which was defined as the presence of
hyperglycemia and overt glycosuria
that in most cases required dietary
restriction of active treatment. Those
authors reported low platelets count in
LC-DM patients.
It has been reported that
increased platelet aggregation in
association with the development of
diabetic complications, and strict blood
sugar control could improve platelet
aggregation and prevent the retinopathy (Ishizuka et al., 1998). In LCDM patients there were thrombocytopenia and/or platelet dysfunction
both of which may be attributed to the
lower incidence of microvascular
complications.
In the present study, fasting
insulin, immunoreactive insulin (IRI)
and HOMA-R of patients with DM
associated with LC were significantly
higher while fasting blood glucose and
HbA1c were significantly lower than
the patients with type-2 diabetes. These
findings reflect an evidence of hyperinsulinemia and insulin resistance in
patients with LC-DM.
In the study by Vidal et al.,
(2008), the C-peptid/immunoreactive
insulin (IRI) molar ratio, an indirect
parameter of hepatic insulin extraction,
was only slightly and not significantly
decreased in the fasting state, and
hence
IRI
slightly
increased.
Surprisingly, C-peptide/ immunoreactive insuli (IRI) molar ratio
appeared to be increased with decreased immunoreactive insulin (IRI)
following a meal in the cirrhotic
patients in comparison with the
corresponding results in the NIDDM
patients. The authors explained this
discrepancy by that, a clear- cut
reduction in insulin clearance resulting
in a lower C-peptide/IRI molar ratio,
would be expected in the presence of
Insulin resistance of cirrhotic
patients may be attributed, at least
partially, to portosystemic shunts
which result in significant hyperglucagonemia and hyperinsulinemia, together with reduced postbrandial liver
glucose extraction (decreased hepatic
first-pass effect) (Letiexhe et al., 1993;
Kruszynska et al., 1993).
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EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN., 2009
portosystemic shunts in cirrhosis
patients and no direct measurement of
insulin sensitivity, using the gold
standard method, the so called glucose
clamp technique, was performed in
there study. Moreover, no information
was provided about possible interference of drugs such as thiazide or
beta-blockers, frequently prescribed in
cirrhotic patients, and which may
further diminish insulin sensitivity.
El-Akkad et al
density lipoprotein cholesterol and
lipoprotein (Lpa) than in LC-DM
group than the type-2 DM group.
These findings and our data
correlate well with the low incidence
of retinopathy, nephropathy, neuropathy and cardiovascular risk factors in
patients with DM associated with LC,
and give an explanation for the low
vascular complications in this category
of patients.
Fujiwara et al., (2005) reported
that group of DM associated with LC
had significantly higher serum insulin
levels and more insulin resistance
calculated by homeostasis model
assessment.
CONCLUSION
The diabetic subjects with liver
cirrhosis were associated with insulin
resistance and hyperinsulinemia. The
hyperinsulinemia observed in cirrhosis
is well recognized by both hepatologists and diabetologists, but the
mechanism for this is unclear.
Kim and Choi, (2006) who
found that, insulin resistance in liver
cirrhosis was higher than the other
type-2 DM, and impaired hepatic
insulin dgradation might be an
important mechanism of hyperinsulinemia in liver cirrhosis.
However risk factors for
vascular complications, the incidence
of diabetic retinopathy and other
microvascular complications were
significantly lower in these patients
than in the patients with type-2
diabetes mellitus in this study.
Furthermore, recent study by
Kuriyama et al., (2007) showed significantly higher level of HOMA-R was
also observed in the group with
diabetic triopathy, suggesting insulin
resistance might have an impact as a
factor for diabetic triopathy. Therfore,
improvement of insulin resistance
would be important to prevent diabetic
angiopathy also in liver disease.
This is probably due to the
lower levels of serum lipids because of
a decreased liver functions.
The prognosis of cirrhotic
patients with diabetes is more likely to
be negatively affected by its complications rather than by the diabetes
itself.
In the present study, serum
levels of cholesterol, triglycerides and
HDL in patients with DM associated
with LC were significantly lower than
patients with type-2 diabetes. This may
be one of the factors implicated in the
pathogenesis of lower microvascular
complications in LC-DM patients.
RECOMMENDATIONS
1) Further studies are needed to
address the pathogenesis of microvascular complications in LC-DM in
depth.
2) We recommend studying the association between microvascular and
macrovascular complications in LCDM patients.
Similarly, Fujiwara et al.,
(2005) reported lower serum levels of
total cholesterol, triglycerides, low
118
EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN., 2009
3) The hyperinsulinemia and its
relation to the development of microvascular complications in LC-DM need
further evaluations in large prospective
studies.
El-Akkad et al
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patients with type 2 diabetes and
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‫معدل اإلصابة بمضاعفات األوعية الدموية الدقيقة فى مرضى البول السكرى‬
‫المقترنين بالتليف الكبدى مقارنة بمرضى البول السكرى النوع الثانى ‪.‬‬
‫عاطف فاروق العقاد* ‪ -‬أيمن جميل غبلاير**‪-‬أيمن فاروق درويش***‬
‫أقسام *الباطنة العامة و**الباثولوجيا األكلينيكية و***األمراض الروماتيزميه‬
‫كلية طب المنيا‬
‫يعتبر مرض البول السكرى النوع الثانى من االمراض التى تصاحبها مضاعفات االوعيه‬
‫الدمويه الدقيقه‪ ,‬مثل االضطرابات فى وظائف الكلى واالضطرابات فى شبكيه العين واالضطرابات‬
‫فى االعصاب خاصة الطرفيه‪.‬‬
‫وتعتبر هذه المضاعفات من اهم عوامل التكهن فى مرضى البول السكرى‪.‬‬
‫وقد لوحظ انه من بين ‪ % 30-20‬من مرضى التليف الكبدى يعانون من مرض البول السكرى‪ .‬بل‬
‫اكثرمن ‪ % 80‬من مرضى التليف الكبدى يعانون من اضطراب فى تسبة السكر بالدم‪.‬‬
‫وقد اعتقد ان مضاعفات االوعيه الدمويه الدقيقه فى هؤالء المرضى اقل من نظيرهم ممن ال‬
‫يعانون من التليف الكبدى‪ ,‬غير ان عدد الدراسات والبحث فى كيفية وطبيعه العوامل المؤثره وحدة‬
‫هذه المضاعفات فى مرضى التليف الكبدى المصاحب بالبول السكرى لم يكن بالشكل الكافى‪.‬‬
‫يهدف البحث الى دراسة العوامل المؤديه وطبيعة هذه العوامل التى تؤدى الى حدوث‬
‫مضاعفات االوعيه الدمويه الدقيقه فى مرضى البول السكرى المصاحب للتليف الكبدى ومقارنتها‬
‫بنظيرها فى مرضى البول السكرى النوع الثانى ‪.‬‬
‫وقد شملت الدراسه ‪ 70‬مريضا ممن يترددون على عيادة االمراض الباطنيه و عيادة‬
‫امراض السكربمستشفى المنيا الجامعى ‪.‬‬
‫وتم التقسييم الى ثالثة مجموعات كما يلى ‪:‬‬
‫‪ )1‬المجموعه االولى‪ :‬مرضى يعانون من مرض البول السكرى وذلك بعد اكتشاف اصابتهم‬
‫بمرض التليف كبدى ‪(.‬سبب التليف الكبدى فى هؤالء المرضى اصابتهم بفيروس الكبدى‬
‫الوبائى سى)‪ .‬وعددهم ‪ 30‬مريضا ‪.‬‬
‫‪ )2‬المجموعه الثانيه‪ :‬مرضى يعانون من مرض البول السكرى النوع الثانى ممن يتوافقون فى‬
‫الفئه العمريه ومده االصابه بمرض البول السكرى مع المجموعه االولى وكلى المجموعتين‬
‫يتم معالجتهم بعقار االنسولين ‪.‬‬
‫‪ )3‬المجموعه الثالثه‪ :‬اشخاص متطوعين للبحث ممن ال يعانون من ال مرض البول السكرى‬
‫وال من التليف الكبدى ‪.‬‬
‫و خضع جميع األشخاص لآلتي‪:‬‬
‫‪ -1‬التاريخ المرضى (السن‪ ,‬النوع‪ ,‬التدخين‪).... ,‬‬
‫‪ -2‬الفحص االكلينيكى الشامل ( الوزن‪ ,‬الطول‪ ,‬ضغط الدم وفحص إكلينيكي شامل‬
‫للمريض)‬
‫‪ -3‬الفحص المعملي والذى شمل ‪:‬‬
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‫‪El-Akkad et al‬‬
‫‪EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN., 2009‬‬
‫‪ ‬صورة دم كامله‬
‫‪ ‬نسبة السكر بالدم (صائم)‬
‫‪ ‬نسبة االنسولين بالدم‬
‫‪ ‬نسبة الهيموجلوبين السكرى‬
‫‪ ‬نسبة الدهون بالدم‬
‫‪ ‬نسبة بيله البيومينيه زهيده‬
‫‪ -4‬فحص قاع العين‬
‫‪ -5‬سرعة التوصيل فى االعصاب الطرفيه‬
‫ولقد تم تحليل النتائج إحصائيا وتم جدولتها إلبراز العالقات المختلفة بين جميع العناصر وذلك‬
‫باستخدام الحاسب اآللي‪.‬‬
‫وكانت أهم النتائج التي توصلت إليها هذه الدراسة ما يلي‪-:‬‬
‫شارك في البحث ‪ 60‬مريضا مقسمين الى ثالث مجموعات‪:‬‬
‫‪ ‬مجموعة (‪ )1‬مرضى مصابون بمرض البول السكرى المصاحب للتليف الكبدى وعددهم ‪30‬‬
‫‪ ‬مجموعة (‪ )2‬مرضى مصابون بمرض البول السكرى النوع الثانى وعددهم ‪30‬‬
‫‪ ‬الى جانب ‪ 10‬من االشخاص المتطوعين ‪ ,‬مجموعة (‪)3‬‬
‫أوضحت النتائج انه ال يوجد اختالف بين المجموعات من حيث العمر اوالنوع او الوزن او‬
‫كونهم مدخنين او مده االصابه بمرض البول السكرى اومتوسط ضغط الدم ( وذ لك بناء على‬
‫تثبيت االختيار)‬
‫بينت النتائج ان المشاركين فى المجموعة االولى حين تم عمل فحص قاع العين‪ ,‬وجد ان‬
‫‪ 33.3%‬منهم يعانون من قصور فى الشبكيه بينما ‪ 63.3%‬من المجموعه الثانيه يعانون من هذا‬
‫القصور وهذا يوضح االختالف الشديد بين المجموعتين من حيث االصابه بقصور الشبكيه‬
‫الناتجه عن مرض البول السكرى‪.‬‬
‫كشف البحث أن من المشاركين فى المجموعة االولى حين تم عمل صوره دم كامله انهم يعانون‬
‫من انخفاض ملحوظ فى نسبه الهيوجلوبين وعدد الصفائح الدمويه وعدد كرات الدم البيضاء‬
‫وعدد كرات الدم الحمراء حين تم مقارنتهم بمرضى المجموعه الثانيه ومرضى المجموعه‬
‫الثالثه‪.‬‬
‫كشف البحث ايضا ان نسبه االلبيومين فى الدم ونسبه البيله االلبيومينيه الذهيده فى البول‬
‫منخفضين بشكل ملحوظ فى المجموعه االولى مقارنة بالمجموعتين االخريين‪.‬‬
‫وقد اظهر البحث ان نسبه السكر بالدم (صائم) ونسبه الهيوجلوبين السكرى بالدم فى المجموعه‬
‫االولى يعدوا منخفضين بشكل واضح حين تم مقارنتهم بالمجموعه الثانيه‪ ,‬كما انه عند قياس‬
‫نسبه االنسولين بالدم وقياس درجه المقاومه لالنسولين بالدم وجد ان المجموعه االولى تفوق‬
‫المجموعتين الثانيه والثاله بشكل واضح ‪.‬‬
‫كما أوضحت النتائج ان هناك ارتفاع واضح فى نسبة الكوليستيرول ونسبة الدهون الثالثيه‬
‫ونسبه الدهون ذات الكثافه العاليه بالدم فى مرضى المجموعه الثانيه حين تم مقارنتهم‬
‫بالمجموعه االولى والثالثه ‪.‬‬
‫كما أوضحت النتائج ان نسبه الذين يعانون من ضعف فى سرعه التوصيل فى االعصاب الحسيه‬
‫فى المجموعه االولى بلغت ‪ 30%‬بينما وصلت نسبتهم فى المجموعه الثانيه الى ‪. 53.3%‬‬
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