Keywords
ultrasound 2D - arteriosclerosis - health policy and practice
Introduction
Ultrasonography has become a widespread diagnostic tool available to most general
practitioners and internists. Whether used for a specific diagnostic or a preventive
workup, it may yield information that goes beyond the specific question asked. One
example of great impact is the chance finding of atherosclerosis which may be a sign
of developing cardiovascular disease. In recent years an increasing prevalence of
hepatic steatosis has been noticed. It is well established that hepatic steatosis
is associated with risk factors for atherosclerosis, particularly type 2 diabetes
and the components of the metabolic syndrome [1]
[2]. In several studies and various populations an association between non-alcoholic
fatty liver disease (NAFLD) and surrogates of cardiovascular disease has been observed
[3].
In this context a strong correlation between hepatic steatosis diagnosed by ultrasonography
or liver histology and intima media thickness has been documented [4]
[5]. Targher et al. found a significantly increased intima media thickness in patients
with type 2 diabetes with a sonographically diagnosed non-alcoholic fatty liver as
compared to diabetic patients with a normal liver [6]. Also, Ramilli et al. [4] demonstrated a correlation between hepatic steatosis detected by ultrasound with
increased body mass index, arterial hypertension, and elevated intima media thickness
and the presence of carotid plaques in Italian outpatients referred for an abdominal
ultrasound for any reason. In Korea Choi et al. [7] found a strong association of hepatic steatosis with carotid plaques by ultrasound
in randomly consecutive patients, even after adjustment for age, sex, BMI, and the
individual factors of a metabolic syndrome. Targher et al. went even one step further
and showed an increased risk for future cardiovascular events in patients with hepatic
steatosis [5]
[8].
This study intends to investigate into the potential of abdominal ultrasound to predict
the prevalence of atherosclerosis in primarily healthy subjects. This may add to the
question of whether it is justified and advisable to recommend a cardiovascular workup
to patients with hepatic steatosis, despite no cardiovascular problems. For this purpose,
the data of 820 primarily healthy individuals presenting with no acute symptoms in
a preventive medical check-up setting were retrospectively analysed, and the association
of hepatic steatosis diagnosed by ultrasonography with risk factors for atherosclerosis
and increased carotid intima media thickness or plaques was evaluated.
Materials and Methods
The Center for Preventive Medicine Hamburg at the University Hospital Hamburg-Eppendorf
offers medical check-ups for preventive medical advice, but no workups of acute diseases.
Thus, primarily individuals in a healthy state are seen who may have long-standing
medication for stable chronic diseases, though. Between March 2006 and July 2007 consecutively
259 women and 561 men aged 19–93 years free of acute symptoms or diseases were included
in this retrospective explorative analysis.
The check-up included a physical examination, measurements of blood pressure and body
mass index (BMI), and routine laboratory values determined by standard procedures
including total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides and lipoprotein(a),
fasting glucose, HbA1c, and liver enzymes (aspartate aminotransferase (ASAT), alanine
aminotransferase (ALAT), and gammaglutamyl transferase (GGT)). Hypertension was defined
by a systolic blood pressure≥140 mmHg or diastolic of ≥90 mmHg or being on antihypertensive
therapy.
Ultrasonographic investigations were performed by a single experienced and certified
internist certified by the German association of ultrasound in medicine (DEGUM) level
III using a high end device (Siemens Acuson Antares premium edition, Siemens, Erlangen,
Germany) with a curved 2–6 MHz array for the abdominal organs and a linear 5–9 MHz
array for the examination of the extracranial vessels and taking the maximum intima
media thickness of the distal wall of one of the common carotid arteries.
The diagnosis of hepatic steatosis by ultrasound was graded according to the criteria
established by Joseph et al. 1991 [9]: “mild steatosis”: slightly hyperechoic, but homogenous echo structure; “moderate
steatosis”: hyperechoic structure, dorsal diminishing of echo signal and beginning
rarefication of hepatic vessels; “severe steatosis”: hyperechoic and irregular parenchym
structure, suspected fibrocirrhotic change, irregular margin and reduced elasticity.
An abnormal intima media thickening refers to a maximal intima media thickness of
>0.8 mm of the far wall of the common carotid artery [10]
[11]
[12]. Plaques were defined as atheromatous, calcificated or mixed circumscribed wall
thickenings, and stenoses were defined as wall irregularities taking more than 60%
of the vessel lumen graded according to Hennerici et al. [13] and Touboul et al. 2012 [14].
Statistical analyses were performed using the XLSTAT software 2012 (Addinsoft Germany).
For comparing the prevalence of characteristics of individuals with (cases) or without
(controls) a fatty liver, the Mann-Whitney test was applied for continuous parameters
and the Chi-square test for discontinuous data. Multivariate analyses were performed
by logistic regression. P-values of <0.05 were regarded significant.
Results
Data of 820 patients were analysed. The basic characteristics of 561 men and 259 women
with (cases) or without (controls) hepatic steatosis as diagnosed by abdominal ultrasound
are given in [Table 1]. In 154 men (28.3%) and 20 women (7.7%) hepatic steatosis was diagnosed by abdominal
ultrasound. 88% of these patients had mild steatosis [9]. Only 2 women and 18 men were judged to have moderate steatosis, and 1 man with
severe hepatic steatosis was suspected to have fibrocirrhosis.
Table 1 Characteristics of individuals with and without hepatic steatosis diagnosed by ultrasonography
and the significance of differences of the means.
|
Men
|
Controls
|
Cases with hepatic steatosis
|
Significance
|
|
n=561
|
n=407
|
n=154
|
|
|
Mean
|
Median
|
1 SD
|
Mean
|
Median
|
1 SD
|
p-value
|
|
Age [years]
|
56.6
|
57.0
|
12.0
|
55.7
|
55.5
|
10.1
|
n.s.
|
|
BMI [kg/m2]
|
25.5
|
25.2
|
2.8
|
28.0
|
27.3
|
3.6
|
<0.0001
|
|
Fasting blood sugar [mg/dl]
|
89.1
|
87.0
|
15.2
|
94.4
|
91.5
|
19.5
|
0.0004
|
|
Hemoglobin A1c [%]
|
5.5
|
5.5
|
0.5
|
5.7
|
5.6
|
0.6
|
0.004
|
|
Total cholesterol [mg/dl]
|
206.3
|
203.0
|
37.6
|
207.0
|
208.0
|
37.7
|
n.s.
|
|
LDL-cholesterol [mg/dl]
|
122.2
|
118.5
|
34.1
|
124.3
|
124.0
|
35.4
|
n.s.
|
|
HDL-cholesterol [mg/dl]
|
63.4
|
61.0
|
16.3
|
54.8
|
53.0
|
14.1
|
<0.0001
|
|
Triglycerides [mg/dl]
|
104.1
|
86.0
|
63.1
|
152.5
|
129.0
|
77.0
|
<0.0001
|
|
ASAT (GOT) [IU/l]
|
27.9
|
27.0
|
7.0
|
33.8
|
30.0
|
13.3
|
<0.0001
|
|
ALAT (GPT) [IU/l]
|
27.8
|
25.0
|
11.3
|
43.7
|
37.0
|
26.5
|
<0.0001
|
|
GGT [IU/l]
|
33.4
|
25.0
|
28.2
|
47.1
|
37.5
|
34.8
|
<0.0001
|
|
Women
|
Controls
|
Cases with hepatic steatosis
|
Significance
|
|
n=259
|
n=239
|
n=20
|
|
|
Mean
|
Median
|
1 SD
|
Mean
|
Median
|
1 SD
|
p-value
|
|
Age [years]
|
57.0
|
57.0
|
12.3
|
61.0
|
60.0
|
5.1
|
n.s.
|
|
BMI [kg/m2]
|
23.2
|
23.0
|
3.5
|
29.2
|
29.5
|
3.1
|
<0.0001
|
|
Fasting glucose [mg/dl]
|
84.6
|
84.0
|
11.5
|
100.1
|
97.0
|
15.2
|
<0.0001
|
|
Hemoglobin A1c [%]
|
5.5
|
5.5
|
0.4
|
5.7
|
5.7
|
0.4
|
0.005
|
|
Total cholesterol [mg/dl]
|
217.5
|
216.0
|
36.3
|
228.1
|
233.0
|
35.4
|
n.s.
|
|
LDL-cholesterol [mg/dl]
|
115.5
|
112.0
|
34.6
|
128.1
|
137.0
|
43.2
|
n.s.
|
|
HDL-cholesterol [mg/dl]
|
84.5
|
83.0
|
20.9
|
67.1
|
61.0
|
25.9
|
<0.0001
|
|
Triglycerides [mg/dl]
|
84.4
|
76.0
|
36.3
|
164.6
|
143.0
|
83.0
|
<0.0001
|
|
ASAT (GOT) [IU/l]
|
25.5
|
24.0
|
8.2
|
27.7
|
24.0
|
7.6
|
n.s.
|
|
ALAT (GPT) [IU/l]
|
21.2
|
19.0
|
9.3
|
34.1
|
28.0
|
16.9
|
<0.0001
|
|
GGT [IU/l]
|
24.8
|
18.0
|
23.5
|
36.0
|
31.0
|
39.7
|
0.018
|
Cases and controls were of comparable age ([Table 1]). In line with the higher ultrasonographic classification of hepatic steatosis in
cases, ALAT and GGT were also on average higher in both male and female cases than
in controls ([Table 1]). Correspondingly, the percentage of those with ALAT or GGT above the upper limit
of normal was higher in cases of both genders.
Male and female cases also differed significantly from controls in their BMI, fasting
blood sugar, HbA1c, triglycerides and HDL cholesterol, while LDL cholesterol was not
significantly different in both sexes ([Table 1]). The mean BMI was 2.5 and 5.9 kg/m2 higher in male and female cases, respectively, compared to that of controls. 55.8%
of male cases were overweight (BMI≥25 kg/m2) and 26.0% obese (BMI≥30 kg/m2) in contrast to 42.2% and 12.6% of controls, respectively. Of female cases 52.6%
were overweight and 36.8% obese, compared to 22.1% and 4.4% controls, respectively.
The 2 women with moderately fatty liver were obese, as were 13 of the 20 men with
moderately to severe fatty liver. Only 2 men with moderately fatty liver were of normal
weight according to the conventional BMI classification.
In line with differences in weight, cases were characterized more often by components
of the metabolic syndrome as defined by the International Diabetes Federation [15], i. e., elevated triglycerides>150 mg/dl, and HDL cholesterol<50 or 40 mg/dl for
women and men, respectively ([Table 2]). Fasting glucose≥100 mg/dl and hypertension were more prevalent in cases, though
only in women the differences reached significance.
Table 2 Frequency of pathological clinical and ultrasonographic parameters and the significance
of their differences in individuals with and without hepatic steatosis diagnosed by
ultrasonography.
|
Controls
|
Cases with hepatic steatosis
|
Significance
|
|
Men
|
[%]
|
[%]
|
p-value
|
|
BMI≥25 [kg/m2]
|
54.9
|
81.8
|
<0.0001
|
|
Hypertension [%]
|
35.0
|
42.2
|
0.113
|
|
Fasting glucose≥100 mg/dl]
|
19.0
|
26.3
|
0.06
|
|
LDL-cholesterol≥130 mg/dl
|
39.1
|
41.1
|
0.673
|
|
HDL-cholesterol<50 mg/dl
|
20.8
|
36.8
|
0.0001
|
|
HDL-cholesterol<40 mg/dl
|
2.3
|
11.8
|
<0.0001
|
|
Triglycerides>150 mg/dl
|
16.5
|
38.6
|
<0.0001
|
|
ALAT (GPT)>45 IU/l
|
7.6
|
30.3
|
<0.0001
|
|
GGT>55 IU/l
|
10.4
|
22.4
|
0.00025
|
|
IMT>0.8 mm
|
29.0
|
36.4
|
0.092
|
|
Carotid plaque
|
24.1
|
31.2
|
0.088
|
|
IMT>0.8 mm or carotid plaque
|
33.7
|
41.6
|
0.082
|
|
Women
|
[%]
|
[%]
|
p-value
|
|
BMI≥25 [kg/m2]
|
10.5
|
26.4
|
<0.0001
|
|
Hypertension [%]
|
31.6
|
68.4
|
0.001
|
|
Fasting blood sugar≥100 mg/dl]
|
7.8
|
42.1
|
<0.0001
|
|
LDL-cholesterol≥130 mg/dl
|
16.8
|
52.6
|
0.0002
|
|
HDL-cholesterol<50 mg/dl
|
3.4
|
21.1
|
0.001
|
|
HDL-cholesterol<40 mg/dl
|
0.4
|
0.0
|
0.774
|
|
Triglycerides>150 mg/dl
|
6.5
|
47.4
|
<0.0001
|
|
ALAT (GPT)>34 IU/l
|
7.8
|
42.1
|
<0.0001
|
|
GGT>38 IU/l
|
13.8
|
21.1
|
0.385
|
|
IMT>0.8 mm
|
16.7
|
40.0
|
0.01
|
|
Carotid plaque
|
18.0
|
25.0
|
0.438
|
|
IMT>0.8 mm or carotid plaque
|
23.0
|
55.0
|
0.004
|
An IMT of >0.8 mm or plaques in the common carotid arteries were more prevalent in
male cases (36.4%) than in controls (29.0%) (p=0.092), yet the difference between
cases (40.0%) and controls (16.7%) reached only significance in women (p=0.001). Also,
plaques in the common carotid arteries or bulbi were numerically more frequent in
male cases (31.2%) than in controls (24.1%) (p=0.088), and in female cases (40.0%)
and controls (16.7%) (p=0.438), which, however, did not reach significance in both
genders. Even though elevated IMT has often been associated with fatty liver especially
in men, it frequently occurred also in individuals without a fatty liver as well.
Still, the logistic regression analysis revealed male sex and hepatic steatosis besides
age as highly significant predictors of an IMT+> 0.8 mm or the manifestation of carotid
plaques detected by ultrasound. Excluding BMI from the analysis did not materially
alter the results. In a multivariate analysis including major cardiovascular risk
factors, besides age only hepatic steatosis and elevated lipoprotein(a) proved to
be statistically significant predictors of the presence of elevated IMT or carotid
plaques in both genders despite multiple adjustments ([Table 3]).
Table 3 Logistic regression of clinical parameters as to prediction of an intima media thickness>0.8 mm
in the common carotid arteries or plaques in the common carotid arteries or bulbi.
|
Logistic regression
|
|
Parameter
|
p-value
|
Odds ratio
|
lower (95%)
|
upper (95%)
|
|
IMT >0.8 mm
|
Age [years]
|
<0.0001
|
1.080
|
1.062
|
1.099
|
|
Male sex
|
0.001
|
1.995
|
1.326
|
3.001
|
|
BMI [kg/m2]
|
0.197
|
1.034
|
0.983
|
1.088
|
|
Steatosis
|
0.031
|
1.583
|
1.042
|
2.403
|
|
Carotid plaque
|
Age [years]
|
<0.0001
|
1.108
|
1.087
|
1.131
|
|
Male sex
|
0.018
|
1.669
|
1.091
|
2.554
|
|
BMI [kg/m2]
|
0.907
|
1.003
|
0.950
|
1.059
|
|
Steatosis
|
0.019
|
1.714
|
1.094
|
2.684
|
|
IMT >0.8 mm
|
Age [years]
|
<0.0001
|
1.087
|
1.069
|
1.105
|
|
or plaque
|
Male sex
|
0.009
|
1.659
|
0.134
|
2.427
|
|
BMI [kg/m2]
|
0.502
|
1.017
|
0.968
|
1.069
|
|
Steatosis
|
0.009
|
1.730
|
1.149
|
2.605
|
|
IMT >0.8 mm
|
Age [years]
|
<0.0001
|
1.089
|
1.068
|
1.111
|
|
or plaque
|
Male sex
|
0.369
|
1.252
|
0.766
|
2.046
|
|
BMI [kg/m2]
|
0.177
|
0.951
|
0.883
|
1.023
|
|
BZ [mg/dl]
|
0.150
|
1.011
|
0.996
|
1.025
|
|
HbA1c [%]
|
0.759
|
0.929
|
0.582
|
1.484
|
|
TG [mg/dl]
|
0.113
|
1.003
|
0.999
|
1.006
|
|
HDL-C [mg/dl]
|
0.192
|
0.992
|
0.981
|
1.004
|
|
LDL-C [mg/dl]
|
0.061
|
1.005
|
1.000
|
1.011
|
|
Lipoprotein(a) [mg/dl]
|
0.009
|
1.007
|
1.002
|
1.012
|
|
Hypertension
|
0.573
|
1.144
|
0.717
|
1.826
|
|
Steatosis
|
0.021
|
1.773
|
1.092
|
2.880
|
Discussion
The results of this study clearly indicate that hepatic steatosis as diagnosed by
abdominal ultrasonography is a valid marker of developing atherosclerosis in otherwise
healthy people in a preventive check-up setup: to our knowledge, this is the first
study demonstrating this correlation in an outpatient population of otherwise healthy
individuals. The multivariate analysis even implies that hepatic steatosis adds to
the effects of the major cardiovascular risk factors. It has been suggested that cardiovascular
disease is the most important factor of outcome in patients with non alcoholic fatty
liver disease and determinates the life expectancy much more than the progression
of liver disease itself. Not only intima media thickness is increased, but there is
also an impairment of flow-mediated vasodilation [16].
It has been shown that the presence of non-alcoholic fatty liver disease diagnosed
by ultrasound is independently associated with an increased prevalence of ischemic
heart disease [17]
[18]. The SHIP study, a large population based study in Northern Germany, showed in a
5- and 10-year follow-up that patients with a fatty liver had a significant higher
morbidity and mortality than patients without this condition [19]
[20].
Certainly, the cohort under investigation is not a representative population. However,
this has been judged not to be necessary to answer the very practical question, whether
it is sensible to recommend cardiovascular diagnostics based on the finding of hepatic
steatosis in a thus far healthy population. Also, the accuracy of ultrasound for the
detection of steatosis is not crucial in this respect, although it has been found
reasonably specific [9]
[21]
[22]. The strength of this study is the retrospective design, since no study objective
could have possibly prejudiced the results of the ultrasonographic investigation and
examination bias is omitted. Furthermore, the scheduling in the center does not allow
sharing knowledge with the investigator regarding results of laboratory values, cardiac
echo or ECG at the time of the abdominal ultrasound.
In our study, hepatic steatosis diagnosed by abdominal ultrasound turned out to be
stronger than any individual major cardiovascular risk factor, but for lipoprotein(a)
to predict subclinical atherosclerosis of the carotid arteries. This is probably due
to the fact that ectopic fat is a major causal factor for the components of the metabolic
syndrome; thus, hepatic steatosis subsumes the effects of these factors similar to
the definition of the metabolic syndrome [1]
[2].
Moreover, ultrasound demonstrates the risk pattern to the patient in real time, not
only by visualizing the fatty liver, but also displaying the developing atherosclerosis
of abdominal vessels.
Ultrasound is also very well-suited for follow-up exams to monitor the therapeutic
success. Weight loss and physical exercise may induce normalization of liver tissue
[23]. This is visually more impressive than the reduction of intima media thickness by
0.1 mm. So, based on this study and previous experience [24], we think abdominal ultrasound to be appropriate in medical prevention, not only
to evaluate the abdominal organs, but also to assess patients who are at a higher
risk for cardiovascular diseases.
In summary, detecting hepatic steatosis has a diagnostic impact on the choice of therapeutic
measures for the prevention of cardiovascular disease by itself, though it seems appropriate
to take hepatic steatosis as a call for further classification of the induced risk
factors and the impact on the arterial wall. In conclusion, this study demonstrates
that the incidental finding of hepatic steatosis is an appropriate indication for
further cardiovascular work-ups in times of individualized medicine and prevention,
especially in men.
