Association between fatty liver disease and carotid atherosclerosis in patients with uncomplicated type 2 diabetes mellitus.
ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a clinic-pathological syndrome closely associated with obesity, dyslipidemia, diabetes and atherosclerosis. Some authors suggest that NAFLD is, in fact, another component of the metabolic syndrome.
To determine the prevalence of NAFLD in diabetes mellitus (DM) patients, and to evaluate the carotid artery status in these patients.
Fifty six patients with uncomplicated type 2 DM were enrolled. Hepatic steatosis (HS) and carotid atherosclerosis (intima-media thickness - IMT) were evaluated by ultrasonography. Plasma liver function tests and other biochemical blood measurements were determined.
HS was found in 38 patients (67.8%) with DM. Subjects with HS had higher values for body mass index, diastolic blood pressure, mean blood pressure and triglycerides, and lower HDL cholesterol concentration, but there were no differences regarding IMT between DM patients with or without HS. Behavioral variables (smoking, diet, and sedentarism), fasting plasma glucose, and LDL cholesterol levels, also, did not significantly differ between subjects with and without HS.
DM patients with HS in our study showed a cluster of cardiovascular risk factors but non-significant carotid atherosclerosis. The detection of HS by abdominal ultrasound should alert to the existence of a higher cardiovascular risk, but in DM this is still under discussion, the results being still unconfirmed.
Journal of gastrointestinal and liver diseases: JGLD 07/2007; 16(2):167-9. · 1.81 Impact Factor
Article: Systemic oxidative alterations are associated with visceral adiposity and liver steatosis in patients with metabolic syndrome.[show abstract] [hide abstract]
ABSTRACT: Although evidence suggests the link between chronic inflammation and oxidative stress as the main mechanism responsible for endothelial dysfunction and cardiovascular complications in patients with metabolic syndrome, little is known about the determining role of each metabolic syndrome component in such alterations. This study investigated the relation between systemic oxidative alterations and metabolic syndrome features in 41 patients. Compared with control subjects, serum vitamin C and alpha-tocopherol concentrations were lower and those of lipid peroxides [thiobarbituric acid reactive substances (TBARs)] were higher in metabolic syndrome patients (P < 0.001). A linear relation was observed between visceral fat thickness and serum TBARs:cholesterol ratio (r = 0.541, P < 0.001), whereas negative correlations were found between alpha-tocopherol and BMI (r = -0.212, P < 0.05) and the grade of liver steatosis (r = -0.263, P < 0.02). Patients with metabolic syndrome and liver steatosis had higher serum hyaluronate (HA) concentrations (P < 0.001). Serum HA was positively correlated with serum alanine amino transferase (r = 0.715, P < 0.001) and the homeostasis monitoring assessment index (r = 0.248, P < 0.03). The presence of metabolic syndrome was predicted from a linear combination of visceral fat and all oxidative variables. In metabolic syndrome patients, serum nitrosothiols and vitamin C concentrations, which were lower (P < 0.001) than in control subjects, were inversely related to the grade of hypertension (r = -0.645, P < 0.001 and r = -0.415, P < 0.007, respectively). In conclusion, metabolic syndrome patients exhibited decreased antioxidant protection and increased lipid peroxidation. Our results indicate a strong association between increased abdominal fat storage, liver steatosis, and systemic oxidative alterations in metabolic syndrome patients and diminished nitrosothiols and vitamin C concentrations as important factors associated with hypertension in these patients.Journal of Nutrition 12/2006; 136(12):3022-6. · 3.92 Impact Factor
Journal of Clinical Endocrinology & Metabolism 08/2002; 87(7):3019-22. · 6.50 Impact Factor
2011, Vol. 13, no. 3, 215-219
Background: Nonalcoholic fatty liver disease (NAFLD) is a clinic-pathological syndrome closely associated with obesity,
dyslipidemia, diabetes and atherosclerosis. Some authors suggest that NAFLD is, in fact, another component of the metabolic
syndrome. Aim: To determine the prevalence of NAFLD in diabetes mellitus (DM) patients, and to evaluate the carotid
artery status in these patients. Methods: Fifty six patients with uncomplicated type 2 DM were enrolled. Hepatic steatosis
(HS) and carotid atherosclerosis (intima-media thickness - IMT) were evaluated by ultrasonography. Plasma liver function
tests and other biochemical blood measurements were determined. Results: HS was found in 38 patients (67.8%) with DM.
Subjects with HS had higher values for body mass index, diastolic blood pressure, mean blood pressure and triglycerides, and
lower HDL cholesterol concentration, but there were no differences regarding IMT between DM patients with or without
HS. Behavioral variables (smoking, diet, and sedentarism), fasting plasma glucose, and LDL cholesterol levels, also, did not
significantly differ between subjects with and without HS. Conclusion: DM patients with HS in our study showed a cluster
of cardiovascular risk factors but non-significant carotid atherosclerosis. The detection of HS by abdominal ultrasound should
alert to the existence of a higher cardiovascular risk, but in DM this is still under discussion, the results being still unconfirmed.
Keywords: nonalcoholic fatty liver disease, diabetes mellitus, intima-media thickness, ultrasonography
Premise: Steatohepatita nonalcoolică este o condiţie clinico-patologică puternic asociată cu obezitatea, dislipidemia, dia-
betul zaharat (DZ) şi ateroscleroza. Unii autori sugerează că SHNA ar fi, de fapt, o altă componentă a sindromului metabolic.
Scop: De a determina prevalenţa SHNA la pacienţii cu DZ şi de a evalua statusul carotidelor la aceşti pacienţi. Metode:
Cincizeci şi şase de pacienţi cu DZ tip 2 necomplicat au fost înrolaţi în studiu. Au fost evaluate ecografic steatoza hepatică
(SH) şi ateroscleroza carotidiană (cu ajutorul grosimii intimă-medie – GIM). Au fost măsurate, de asemenea, testele hepatice
şi alte constante biochimice. Rezultate: SH a fost diagnosticată la 38 de pacienţi (67,8%). Subiecţii cu SH au avut valori mai
mari ale indicelui de masă corporală, tensiunii arteriale diastolice şi a celei medii, ale trigliceridelor, şi valori mai mici ale
HDL-colesterolului. Nu s-au găsit diferenţe semnificatice ale GIM la pacienţii cu SH versus cei fără SH. Fumatul, obiceiurile
alimentare, sedentarismul, glicemia a jeun şi LDL-colesteolul nu au avut diferenţe semnificative la cele două subgrupuri de
pacienţi. Concluzii: Pacienţii diabetici cu SH, în lotul nostru, a avut un cluster de factori de risc cardiovasculari, dar atero-
scleroza carotidiană nu a fost semnificativ diferită la pacientii cu sau fără SH. Detecţia SH prin ecografie abdominală este un
semnal de alarmă pentru riscul cardiovascular crescut, însă la pacienţii cu DZ discuţia rămîne deschisă, rezultatele fiind încă
Cuvinte cheie: steatohepatita nonalcoolică, diabet zaharat, grosimea intimă-medie, ecografie
Association between fatty liver disease and carotid atherosclerosis in
patients with uncomplicated type 2 diabetes mellitus
Laura I. Poanta, Adriana Albu, Daniela Fodor
2nd Internal Medicine Clinic, University of Medicine Iuliu Haţieganu, Cluj Napoca, Romania
Received 05.06.2011 Accepted 01.07.2011
2011, Vol. 13, No 3, 215-219
Corresponding author: Laura Irina Poanta
Nicolae Pascaly 9/16 str
400431, Cluj Napoca, Romania
For a long time, fatty liver disease or hepatic steatosis
(HS) was considered as a benign manifestation. How-
ever, recent data indicate a wide spectrum of clinical and
pathological manifestations that subjects with nonalco-
holic hepatic steatosis develop, termed as nonalcoholic
fatty liver disease (NAFLD) [1-3]. NAFLD is a form of
216Laura I. Poanta et al
liver disease resembling the histological changes of al-
coholic liver disease, but found in subjects who do not
abuse alcohol. Subjects have often associated metabolic
conditions such as insulin resistance, overweight, obes-
ity, dyslipidemia, and diabetes [3-6].
Carotid intima-media thickness (IMT) is a known
marker for early atherosclerosis, and its progression. IMT
is increased in subjects with several risk factors and is a
predictor of cardiovascular events and end-organ dam-
age. The first clinical manifestation of cardiovascular
disease often arises in a stage of well-advanced athero-
sclerosis. However, arterial vessel wall changes occur
during a long subclinical phase characterized by gradual
thickening of intima-media. IMT of large peripheral ar-
teries, especially carotid, can be assessed by B-mode ul-
trasound in a relatively simple way .
Cholesterol intake, body mass index and smoking are
significantly related to the annual progression of carotid
IMT [7,8]. Of all the traditional risk factors, hypertension
appears to have the greatest effect on IMT.
Accordingly, the metabolic syndrome (MS), including
also NAFLD, can be considered the link to the presence of
vascular diseases in patients with NAFLD. In NHANES
III, the authors demonstrated that the presence of MS was
associated with increased risk of myocardial infarction,
stroke or both [9-11]. The association between NAFLD
and carotid IMT was discussed in previous studies as a
possible direct relationship between atherosclerosis and
hepatic steatosis . However, in subjects with type 2 dia-
betes, the link between fatty liver and atherosclerosis is less
clear, and different studies give conflicting results [12-14].
We examined the prevalence of NAFLD in a group
of patients with uncomplicated type 2 DM, and whether
NAFLD associates with carotid atherosclerosis.
Association between fatty liver disease and carotid atherosclerosis
Material and methods
The study protocol conformed to the ethical guide-
lines of the Declaration of Helsinki. All the patients
signed the informed consent.
Carotid atherosclerosis, cardiovascular risk factors,
and the presence of HS were analyzed in 56 patients (34
males and 22 females) under 65 years old with uncompli-
cated DM admitted in our clinic. Diabetes was defined as
self-reported physician diagnosis of diabetes or according
to the WHO and guidelines definition .A control group
of 52 subjects, age and sex matched, was also analyzed.
The patients that reported more than 20 g/day alcohol
drinking were excluded from the study. Hepatic steato-
sis (HS) and carotid IMT were diagnosed by ultrasound
examination. Plasma liver function tests (e.g. aspartate
aminotransferase-ASAT, and alanine aminotransferase-
ALAT) and other biochemical blood measurements were
Ultrasound examination of the liver was performed
after 12 hours fasting. Each subject was examined in the
supine and left lateral positions during quiet inspiration
and asked to stop breathing during inspiration. The pres-
ence or absence and grading of fatty infiltration of the
liver were recorded.
Hepatic steatosis was defined as the presence of an ul-
trasonographic pattern of: parenchymal brightness (from
normal to severe increased), liver-kidney contrast (ab-
sent = 0/present = 1), deep beam attenuation (diaphragm
bright and clear = 0/diaphragm blurred = 1) and bright
vessels wall into parenchyma (present = 0/absent = 1)
. The final findings were classified as normal liver,
and intermediate, moderate or severe HS.
In all subjects, carotid IMT was measured by high-
resolution real-time B mode ultrasonography with a
7.5-MHz linear transducer (Aloka Prosound Alpha 10).
Each subject was examined in the supine position. The
carotid arteries were investigated bilaterally in longitudi-
nal scans. The examination included sections of approxi-
mately 2–3 cm of common carotid artery just below the
carotid bulb. IMT was defined as the distance between
the leading edge of the first echogenic line (lumen-intima
interface) and the second echogenic line (media-adventi-
tia interface) of the far wall. A carotid plaque was defined
as a focal thickening ≥1.2 mm at the level of carotid ar-
tery; none of the study participants had clinically relevant
carotid stenosis (i.e. ≥60%). The variability of ultrasono-
graphic measurement was assessed by performing two
measurements in 15 volunteers over a one week period.
The reproducibility of IMT measurement was 10% .
Overweight was defined as a BMI 25 kg/m². Systolic
and diastolic blood pressure was measured and hyperten-
sion was defined as an average systolic blood pressure 140
mmHg, an average diastolic blood pressure 90 mmHg, or
self-reported use of antihypertensive medication .
Statistical analysis. Data on quantitative character-
istics are expressed as mean ± standard deviation (SD).
Data on qualitative characteristics are expressed as per-
centage values or absolute numbers as indicated. Par-
ticipants were divided into two groups according to the
presence or absence of hepatic steatosis. Comparisons
between groups were made using ANOVA (continuous
data) and χ²-test (nominal data). A p value under 0.05 was
considered statistically significant.
Demographic data of the study group are shown in
the table I.
Medical Ultrasonography 2011; 13(3): 215-219
Thirty-eight out to fifty six patients had HS (67.8%).
Patients with HS had higher values for body mass index,
borderline significant (p = 0.045), diastolic and mean
blood pressure and triglycerides (p = 0.020, p = 0.028,
respectively), and lower HDL cholesterol concentration
(p = 0.04). There was a strong correlation between liver
enzymes and HS (r = 0.71 for ALAT and r = 0.59 for
ASAT), but 18 of the patients with HS had normal levels
Behavioral variables (smoking, diet, and seden-
tarism), fasting plasma glucose, HbA1c, and LDL choles-
terol levels did not significantly differ between subjects
with and without HS. Hepatic steatosis did not correlate
with IMT (r = −0.03; p = 0.75) in our study, but there is
a positive, although non-significant correlation, between
grade of HS and IMT value (r = 0.28, p = 0.06).
There is a mild positive correlation between IMT and
triglycerides levels (r = 0.54, r = 0.04), total cholesterol
(r = 0.049, p = 0.039) and a negative but non-significant
correlation with HDL c levels (r = - 0.18, p = 0.02).
Measures of glucose or HbA1c did not correlate with
Older age and disease duration were independent pre-
dictors of an increased IMT (r = 0.44, p = 0.03; r = 0.41,
p = 0.029, respectively), but not of the presence of HS.
In our study, we could not demonstrate the correlation
between HS and IMT in uncomplicated DM patients; this
is in concordance with other studies in which the correla-
tion between HS and IMT was non-significant , as
opposed to non-diabetic patients and patients with meta-
bolic syndrome, where this connection was well estab-
Increased carotid IMT is a mirror of atherosclerotic
burden and a predictor of subsequent events . Carotid
IMT measurement is more and more frequently used in
clinical trials to follow the harmful effects of risk fac-
tors on vessel walls and, more importantly, the effect
of treating risk factors that cause reduction or prevent
the progression of the IMT, paralleled by a decrease in
cardiovascular risk and events [10,11]. Therefore, IMT
measurements may be used in addition to classical risk
factors of individual risk assessment. Measurement of
carotid IMT could influence a clinician to intervene with
medication and to use more aggressive treatments of
risk factors in primary prevention, and in patients with
atherosclerotic disease in whom there is evidence of ex-
tension of atherosclerosis on carotid arteries.
Fatty liver infiltration can be determined by many dif-
ferent methods. Although the direct measurement of he-
patic fat using a biopsy is considered the “gold standard,”
its use is limited due to risks involved (as it is an inva-
sive method) and the availability of a very small sample
of which, in the case of inhomogeneous fat distribution,
may not provide an accurate estimate [3,15]. Ultrasound,
computerized tomography (CT), magnetic resonance im-
aging (MRI), and 1H magnetic resonance spectroscopy
(1H MRS) are noninvasive and should be used instead.
However, the best method for frequent, repetitive, and
highly specific estimation of hepatic fat in vivo seems to
be localized 1H MRS . This fact is the main limita-
tion of our study since our method for determining fatty
Table 1: baseline characteristics of DM patients with and with-
out hepatic steatosis
Patients with HS
Patients without HS
Age (years) 59.4 ± 3.5 61.5 ± 2.9
IMT (mm) 1.09 ± 0.770.98 ± 0.68
BMI (kg/m2)*33.2 ± 6 28.1 ± 9.2
DBP (mmHg)*105 ± 4.491 ± 8.2
SBP (mmHg)166 ± 10.1148 ± 9.9
MBP (mmHg)*134 ± 8120 ± 7.7
TC (mg/dl)240 ± 128 228 ± 117
TGL (mg/dl)* 388 ± 107 202 ± 98
HDLc (mg/dl)* 38 ± 2555 ± 16
LDLc (mg/dl)131 ± 18127 ± 25
FPG (mg %)120 ± 28104 ± 19
HbA1c (%)7.9 ± 2.27.5 ± 2.1
(for DM) (years)
13 ± 4 11 ± 6
31 (95%)16 (89%)
27 (71%)12 (67%)
HS = hepatic steatosis, IMT = intima media thickness, BMI = body
mass index, DBP = diastolic blood pressure, SBP = systolic blood
pressure, MBP = mean blood pressure, TC = total cholesterol, TGL
= triglycerides, HDLc = high density lipoprotein, LDLc = low den-
sity lipoprotein, FPG = fasting plasma glucose.
218Laura I. Poanta et al
liver infiltration was ultrasound, which is known to be an
operator dependent technique. Another limitation of the
study was the small number of patients
In our study patients with HS showed a cluster of
cardiovascular risk factors, but non-significant carotid
atherosclerosis. In recent studies, it seems that subjects
with ultrasound-diagnosed steatosis have an increased
incidence of cardiovascular events that is independent
of components of the metabolic syndrome [20, 21]. In
diabetic patients, the presence of hepatic steatosis was
associated with elevated serum triglycerides, LDL c, and
reduced HDL which is also evidenced in our study (with
one exception LDL c) . However, almost all of the
studies in which independent associations between fatty
liver and atherosclerosis were found in non-diabetic sub-
jects did not adequately evaluate the impact of visceral
adipose tissue and insulin sensitivity . Moreover, in
the majority of these studies, the diagnosis of fatty liver
was based on ultrasonography.
For patients with type 2 DM, there are conflicting
conclusions . Targher et al  showed that fatty
liver evaluated by patient history and liver ultrasound
was associated with a higher prevalence of cardiovas-
cular disease in people with type 2 DM. A limitation of
this study was that the diagnosis of NAFLD was based
only on ultrasonography, like in our study, a method that
allows the detection of steatosis only when fat on liver
biopsy exceeds 33% .
In contrast, McKimmie et al  demonstrated that
fatty liver evaluated by computed tomography was not
associated with carotid IMT in people with type 2 dia-
betes mellitus. In this study, the authors suggested that
hepatic steatosis was less likely to be a direct mediator
of subclinical cardiovascular disease and may instead be
an epiphenomenon . Our study, although using ultra-
sound, is in agreement with this work.
In conclusion, this study suggests that in patients
with type 2 DM, fatty liver is not associated with carotid
IMT, maybe due to more complex mechanisms involved.
In a diabetic population, it seems that fatty liver is not
a determinant factor associated with cardiovascular dis-
ease expressed by IMT. Future studies will have to ana-
lyze these conflicting data.
Association between fatty liver disease and carotid atherosclerosis
Conflict of interest: none
Research supported by the CNCSIS project number
1277 of the Romanian Ministry of Education and Re-
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