Nonalcoholic Fatty Liver Disease A Risk Factor for Microalbuminuria in

Type 2 Diabetic Patients

F. CASOINIC1, D. SMPELEAN1, CTLINA BDU2, LUCHIANA PRUN3
1

University of Medicine and Pharmacy Cluj-Napoca, IVth Medical Clinic, Department of Diabetology
2
Heart Institute Niculae Stancioiu, Cluj-Napoca
3
County Hospital Baia Mare, Department of Diabetology

The aim of our study was to assess the presence of microalbuminuria in diabetic subjects with
nonalcoholic fatty liver disease (NAFLD) compared with diabetic patients without NAFLD and to
correlate this with inflammatory markers such as high sensitive C- reactive protein (hsCRP).
Material and Methods. The study was conducted on 75 diabetic subjects with ultrasonographical NAFLD, in which alcohol consumption and other causes of chronic liver disease have
been excluded. The exclusion criteria also included smoking, arterial hypertension, known renal
disease. The control group consisted of 70 diabetic patients, matched for age and gender, without
ultrasonographical evidence of NAFLD. In all subjects we measured height, weight, BMI, fasting
glucose, HbA1c, total cholesterol, LDL and HDLcholesterol, triglycerides, serum transaminases,
hsC-reactive protein and microalbuminuria. A p-value<0.05 was considered statistically significant.
Results. Microalbuminuria was significantly more frequent in subjects with NAFLD than in
controls (12.7% vs 7.8%, p<0.05). Microalbuminuria was positively correlated with hsCRP levels.
In conclusion NAFLD is positively correlated with microalbuminuria-marker of early stage
CKD, in diabetic patients. This seems to be related to higher levels of proinflammatory factors
released by the liver, such as hsCRP.
Key words: nonalcoholic fatty liver disease, microalbuminuria, cardiometabolic risk, diabetes
mellitus.

Nonalcoholic fatty liver disease (NAFLD), the

hepatic manifestation of the metabolic syndrome [13],
is associated with obesity, prediabetes, type 2 diabetes
mellitus, dyslipidaemia, insulinresistance and arterial
hypertension [2][3]. In type 2 diabetic patients studies
have shown that NAFLD is correlated with an increase
in total cardiovascular risk independently of the
other components of the metabolic syndrome [47].
Moreover, the presence of endothelial dysfunction in patients with NAFLD has been
demonstrated using the flow mediated vasodilatation
method [8]. Microalbuminuria as an indicator of
endothelial dysfunction is at present the best
documented predictor for the development of diabetic
chronic renal disease. Genetic susceptibility, metabolic
abnormalities, hemodynamic changes, upregulated
growth factors and cytokines may play a part in the
development of diabetic micro-albuminuria [9].
The pathogenetic link between NAFLD in
diabetic patient and microalbuminuria is supposed
to be represented by proinflammatory cytokines
secreted by the liver [10]. The presence of microROM. J. INTERN. MED., 2009, 47, 1, 5559

albuminuria in diabetic patients with NAFLD may

increase the prediction of cardiovascular risk and
that of chronic kidney disease, with concurrent
important therapeutical management implications.
It is thus possible to identify a subgroup of diabetic
patients who require a more intensive treatment to
reduce the risk of future cardiovascular events and
chronic kidney disease [10].
The aim of our study was to determine the
prevalence of microalbuminuria and to correlate it
with chronic inflammation markers such as high
sensitive C reactive protein (hCRP) in diabetic
patients with NAFLD versus diabetic patients
without NAFLD.
MATERIAL AND METHODS
SUBJECTS

The study was conducted on 75 diabetic patients

with ultrasonographically diagnosed NAFLD. The

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F. Casoinic et al.

glutamyltransferase (with reference range of 10

35 IU/L for ASAT, 1040 IU/L ALAT, GT), fasting
glucose, HbA1c, total cholesterol, HDL cholesterol,
hsCRP (reference range <=3 mg/dlL, serum creatinine.
Albumin excretion rate was measured from an
early morning urine sample as the albumin/ creatinine
ratio (ACR). Microalbuminuria was defined as
albumin excretion rate of 30 to 299 g/mg creatinine.
Hepatic ultrasonography was performed by a
single examiner blinded to patient clinical status.
Ultrasonographical criteria for hepatic steatosis
were diffuse echogenicity of liver relative to kidney
and posterior attenuation of ultrasound beam [11].
Statistical analysis was performed using
SPSS 11.0. The data are expressed in means SD.
Unpaired t test for numerical variables and X2 test
for categorical variables were used. A p value
<0.05 was considered statistically significant.

control group included 70 diabetic patients without

ultrasonographical evidence of NAFLD, matched for
age, gender and the time from diagnosis of diabetes.
In both groups the exclusion criteria were:
alcohol consumption, smoking, infection with
hepatitic viruses B and C, more rare causes of chronic
hepatopathy (autoimmune hepatitis, hemochromatosis), known renal disease, urinary infection,
arterial hypertension and severely unbalanced
diabetes mellitus.
CLINICAL MEASUREMENTS AND LABORATORY
PROCEDURES

Both groups were evaluated both clinically

and paraclinically. Information regarding smoking,
alcohol intake and current used medication were
obtained by questionnaire. Body mass index was
measured dividing weight in kilograms by height
squared meters. Abdominal circumference was
measured at the level of the umbilicus. Blood
pressure was measured repeatedly using a mercury
sfigmanometer.
Biochemical parameters were determined using
morning drawn venous blood, after an overnight fast.
We have determined serum transaminases, gamma

RESULTS

The characteristics of patients are shown in

Table I. Diabetic patients with NFLD were more
likely to be men, older than controls, with a tendency
towards obesity and a longer duration of diabetes.

Table I
Clinical and biochemical characteristics of the groups studied
Variables
N
Sex (%males)
Age (years)
BMI (kg/m2)

Diabetes mellitus
with NAFLD
75
65.3
63 5
29.4 2

Diabetes duration (years)

DM
without NAFLD
70
52.2
59 3
27.1 4

P value

>0.05
>0.05
<0.05

92

73

<0.05

Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

133 5
85 5

130 3
80 4

>0.05
>0.05

HbA1c

7.4 1.0

6.8 0.7

<0.05

Triglycerides (mmol/L)

1.51 0.5

1.42 0.4

<0.05

HDL cholesterol (mmol/L)

LDL cholesterol (mmol/L)

1.38 0.4
3.35 0.5

1.42 0.3
3.33 0.4

<0.05
>0.05

ASAT (IU/L)

29 10

22 4

<0.05

ALAT (IU/L)

30 9

23 3

<0.05

GT (UI/L)
Creatinine (mg/dL)
Metabolic syndrome
(IDF criteria 2005)(%)

Biologically the diabetics with NAFLD had a

poorer long term glycemic control, reflected by a

28 10

21 5

<0.05

0.91 0.1

0.87 0.2

>0.05

88

72

<0.05

significantly higher value of HbA1c than controls

(7.4% vs 6.8%). The presence of NAFLD was also

Nonalcoholic fatty liver disease

associated with a more deleterious lipidic profile,

with a tendency towards higher triglycerides and low
HDL cholesterol levels, compared with controls.
Regarding liver enzymes, diabetic patients with
NAFLD had higher levels of both transaminases and
GT, thus reflecting the presence in this group of
patients with steatohepatitis.
The prevalence of microalbuminuria was
significanty higher in diabetic patients with
NAFLD, as shown in Fig. 1 (12 % versus 7.14%).
14

High sensitive C reactive protein levels were

significantly higher in diabetic patients with NAFLD
compared to controls, and were correlated with the
presence of microalbuminuria, as shown in Fig. 3.
8
7
6
5
4
3
2
1
0

7.2
5.9

DM with
NAFLD

12 %

12
10
p <0,01

57

5.5

DM with
NAFLD
with
microA

DM
without
NAFLD
without
microA

4.9

DM
without
NAFLD

5.3

DM
without
NAFLD
with
microA

4.5

DM
without
NAFLD
without
microA

7.14 %
Fig. 3. Mean values of hsCRP in the NAFLD diabetic
patients with and without microalbuminuria, versus non
NAFLD with or without microalbuminuria.

6
4
2

DISCUSSION

DM with NAFLD

DM without NAFLD

Fig. 1. The prevalence of microalbuminuria in diabetic

patients with NAFLD versus controls.

Using the elevated levels of serum transaminases

as surrogate marker of hepatic injury, we subsequently divided the diabetic patients with NAFLD
into two subgroups: simple steatosis (with normal
levels of transaminases) and respectively steatohepatitis
(with elevated serum transaminases). Comparing
these two subgroups we found that patients with steatohepatitis had a higher prevalence of microalbuminuria
than those with simple steatosis (Fig. 2).
15 %

16

12%

14
12

8.57 %

10

7.14 %

8
6
4
2

tr
ol
s
Co
n

s
ep
at
iti
St
ea
to
h

Si
m

pl
e

NA

st
et
os

FL

is

Fig. 2. Prevalence of microalbuminuria in the two

subgroups.

In this study we have found that the presence of

NAFLD in diabetic patients was associated with a
higher prevalence of microalbuminuria and positively
correlated with hsCRP levels. Our findings support
the results reported by Targher et al., that suggested
that the presence of NAFLD in diabetic patients
increases the risk of microvascular complications,
such as nephropaty and retinopathy [10].
Microalbuminuria is at present the best
noninvasive independent predictor for endothelial
dysfunction and also for cardiovascular morbidity
and mortality. In our study the association between
NAFLD and microalbuminuria in diabetic patients
was independent of arterial hypertension.
The mechanism by which NAFLD could
contribute to endothelial dysfunction is poorly
understood. Our data suggest that NAFLD promotes
inflammation, probably by releasing proinflammatory
cytokines from injured hepatocytes, due to reactive
oxygen species derived from steatosis stimulated
fatty liver oxidation. A pathogenetic circle is thus
promoted enhancing consequently both hepatic
injury and subclinical systemic inflammation. In
our study diabetic patients with elevated serum
transaminases had the highest prevalence of
microalbuminuria and the highest hsCRP levels.
Further studies are needed to establish the
exact mechanism by which the deleterious effects
of NAFLD are exercised.

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F. Casoinic et al.

In view of the emerging evidence that

NAFLD is an independent cardiovascular risk factor
(47), our data support the conviction that diabetic
patients with NAFLD require a more attentive
assessment of total cardiovascular risk and thus a
more aggressive approach in order to diminish the
number of future cardiovascular events.
The main limitation of our study is that the
diagnosis of NAFLD was not performed by liver
biopsy, and was based instead on clinical and

ultrasonographical data. Liver biopsy is not easily

applied in epidemiological studies. Ultrasonography
has a good sensitivity and specificity for moderate
and severe steatosis, but a lower sensitivity for
hepatic fat infiltration under 33% [11]. This tends to
underestimate the cases of NAFLD.
In conclusion NAFLD in diabetic patients
increases the risk for microalbuminuria and thus for
future cardiovascular events and chronic kidney disease.

Scopul studiului de fa const din evaluarea prezenei microalbuminuriei la

pacienii diabetici cu FGNA comparativ cu cei fr FGNA i corelarea acesteia cu
markeri ai inflamaiei cum este proteina C reactiv cu sensibilitate nalt.
Material i metod. Studiul a fost desfurat pe un grup de 75 de pacieni
diabetici cu FGNA diagnosticat ultrasonografic, la care s-au exclus consumul de
alcool precum i alte cauze de boal cronic hepatic, fumatul, hipertensiunea
arterial i boala renal preexistent. Grupul de control a fost constituit din 70 de
pacieni diabetici, fr dovezi ecografice de FGNA. La toi pacienii s-au
determinat parametrii antropometrici, glicemia jeun, HbA1c, colesterolul total,
LDL i HDL colesterolul, trigliceridele, transaminazele serice, hs PCR i
microalbuminuria. Analiza statistic a fost efectuat cu SPSS11.0. O valoare a
p<0,05 a fost considerat semnificativ statistic.
Rezultate. Microalbuminuria a fost semnificativ mai frecvent la subiecii cu
FGNA dect la grupul de control (12,7% vs 7,8%, p<0,05). Microalbuminuria s-a
corelat pozitiv cu hsCRP la pacienii diabetici cu FGNA.
In concluzie FGNA la pacienii diabetici, rezervorul cel mai mare de factori
de risc din patologie se coreleaz cu prezena microalbuminuriei-marker de
boal cronic renal nc din stadiu precoce. Nivelele plasmatice crescute de
hsCRP precum i alte cytokine proinflamatorii eliberate de ficat par s joace un
rol patogenetic n acest sens.
Corresponding author: F. Casoinic, MD
IVth Medical Clinic, CF University Hospital, Cluj-Napoca
18, Republicii St., 400015 Cluj-Napoca, Romania
E-mail: fcassoinic@yahoo.com

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