Non-alcoholic fatty liver disease (NAFLD) encompasses the often benign non-alcoholic
fatty liver (NAFL) characterized by hepatic steatosis with or without mild inflammation
and the more complicated non-alcoholic steatohepatitis (NASH) with lobular inflammation
and hepatocellular ballooning which can be complicated by fibrosis.1 Independent associates
for the presence of liver fibrosis in patients with NASH are diabetes mellitus (DM),
insulin resistance, hypertension, weight gain, and increased serum alanine and aspartate
aminotransferase.2 NAFLD patients with fibrosis are at increased risk for liver cirrhosis.
The estimated risks to develop liver cirrhosis are for patients with NASH and patients
with NAFL, 22% and 4%, respectively.3
In the last decade, the prevalence of NAFLD has tremendously increased as a result
of the world-wide raise of patients with DM and obesity (i.e., metabolic syndrome).
This has led to a fivefold increase of NAFLD-related liver transplantation.4 Moreover,
NAFLD is considered to be the hepatic expression of the metabolic syndrome5 with augmented
atherogenesis expressed by increased carotid intima-media thickness (CIMT), endothelial
dysfunction, arterial stiffness, impaired left ventricular function, and coronary
calcification. As a result, patients with NAFLD have an increased risk for cardiovascular
(CV) disease and mortality.6-8
Among others, Adams et al demonstrated that the 10-year survival of patients with
NAFLD was significantly lower compared with the general population (77 vs 87%, P[log-rank] = 0.005),
due to higher frequency of fatal CV disease and malignancy.8 In addition, Targher
et al demonstrated that the presence of NAFLD in asymptomatic patients with DM type
2 was independently associated with an increased risk for myocardial infarction, coronary
revascularization procedures, ischemic stroke, and/or CV death (odds ratio 1.84, 95%
CI 1.4;2.1, P < 0.001).6
Currently, the diagnostic reference standard to diagnose NAFLD is a liver biopsy.9
However, in an asymptomatic population this invasive technique is not practical as
a screening method and not without hazards. Therefore, as an alternative technique,
positron emission tomography (PET)/computed tomography (CT) can be used to detect
hepatic inflammation by means of the glucose tracer fluorine-18 fluoro-2-deoxyglucose
(18F-FDG). 18F-FDG visualizes the importance and utilization of glucose (metabolic
activity) of the cells and is expected to be higher in inflammatory cells.10 The major
drawback of this method is that 18F-FDG PET/CT cannot differentiate between hepatic
histologic subtypes.
Results of studies evaluating the hepatic uptake of 18F-FDG measured with PET or PET/CT
in NAFLD patients are controversial.11-13 Abikhzer et al demonstrated in patients
with hepatic steatosis a small global decrease in hepatic metabolic activity corrected
for lean body mass in comparison with controls.12 However, there was no difference
when the hepatic standard uptake value (SUV) of 18F-FDG was corrected for body weight.
In addition, Lin et al demonstrated a significantly negative correlation in the degree
of fatty liver and the maximum hepatic SUV of 18F-FDG on PET.11 In contrast, Bural
et al showed higher maximum hepatic SUVs on PET in subjects with diffuse hepatic steatosis
compared to those in the control group.13 A part of the differences in results of
the hepatic SUV of 18F-FDG in patients with NAFLD can be explained by the fact that
some studies did not take into account lean body mass, glucose levels, and 18F-FDG
dose.
Recently, Hong et al demonstrated in 331 asymptomatic men with NAFLD a significantly
increased mean hepatic 18F-FDG SUV of 2.40 ± 0.25 in comparison with a mean hepatic
18F-FDG SUV of 2.28 ± 0.26 in 349 controls. In addition, the increased uptake was
closely correlated with serum γ-glutamyl transpeptidase and triglycerides, markers
for hepatic inflammation and injury.14
In this issue of the journal, the same group addressed the role of hepatic 18F-FDG
uptake for predicting future CV and cardio-cerebrovascular events and evaluated its
prognostic value in comparison with other CV risk factors including the Framingham
risk score and CIMT.15 In a recent study, 815 asymptomatic participants underwent
a health screening program that consisted of 18F-FDG PET/CT, abdominal ultrasonography,
and CIMT measurements. The primary endpoint consisted of CV events including myocardial
infarction, coronary intervention for significant coronary stenosis, and angina requiring
an emergency room visit with demonstration of significant coronary stenosis. Additional
analysis evaluated the combined endpoint cerebrovascular (consisting of stroke, transient
ischemic attacks, and deaths) and cardiovascular events. Moon et al demonstrated that
the only independent factor for future CV events in this asymptomatic population was
the combination of high hepatic FDG uptake and NAFLD (determined by abdominal sonography
and questionnaire about alcohol intake). This remained after including cerebrovascular
events. In the NAFLD subgroup, high hepatic FDG uptake and male were independently
associated with future CV events. For the combined endpoint cardio-cerebrovascular
events, only high hepatic FDG uptake was an independent factor in the NAFLD subgroup.
However, the conclusions of the authors should be placed in a broader perspective.
First, the study results might not be representative for the general population since
the study population comprised a high percentage of male (>90%). Second, there were
some small differences in the procedure of patients’ preparation for 18F-FDG PET/CT
in comparison with the guidelines which might influence the implementation.16 The
cut-off value of blood glucose levels at the time of FDG injection was higher (<200 mg/dl
instead of an upper plasma level range between 126 and 150 mg/dl which is nowadays
recommended in a research population). Third, evaluation of CV and cardio-cerebrovascular
events in an asymptomatic cohort is challenging since event rates are low. In line
with expected, the CV event rates were indeed low, in the control group as well as
in the NAFLD group, 0.7% (3/421) and 1.5% (6/394), respectively. Therefore, conclusions
on differences in CV event rates between patients with and without NAFLD are based
on an absolute difference of 3 events. In the additional analysis after inclusion
of cerebrovascular events, the absolute difference in events between the groups was
even smaller, only 2 events (1.2% (5/421) vs 1.8% (7/394), respectively). Although
independently associated in multivariate analyses, the additive value of screening
asymptomatic patients for NAFLD in combination with increased hepatic 18F-FDG SUV
on PET/CT on top of traditional risk scores is limited given the small absolute numbers.
As well, the radiation exposure of PET/CT should be taken into account. The effective
dose from 18F-FDG in adults is about 7 mSv for an administrated activity of 370 MBq.17
On top, the CT-related radiation dose should be added. This radiation dose differs
from patient to patient and ranges from 1 up to 20 mSv, depending on the type of scanner
and body mass index. In conclusion, we have to be aware that patients with NAFLD and
no cardio-cerebrovascular complaints are at increased risk for these events. However,
since we realize that a liver biopsy is not the ideal screening tool, determining
hepatic FDG uptake on PET/CT scan could be a good non-invasive alternative to estimate
the risk of these patients but needs more data and convincing proof.