Non-HDL cholesterol and LDL cholesterol in the dyslipidemic classification in patients with nonalcoholic fatty liver disease
Du et al. Lipids in Health and Disease
Non-HDL cholesterol and LDL cholesterol in the dyslipidemic classification in patients with nonalcoholic fatty liver disease
Tingting Du 0
Xingxing Sun 1
Xuefeng Yu 0
0 Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430030 , China
1 Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430030 , China
Background: Low-density lipoprotein cholesterol (LDL-C) always underestimates the true cholesterol burden in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to compare LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) in the identification of high-risk dyslipidemic phenotypes in those with NAFLD. Methods: We conducted a cross-sectional analysis using a cohort of 9560 apparently healthy Chinese adults who underwent comprehensive health checkups including abdominal ultrasonography. Results: Among 3709 patients with NAFLD, the prevalence of abnormal LDL using LDL-C was 68.5%, whereas the prevalence was relatively lower when using non-HDL-C (55.9%). The concordance between non-HDL-C- and LDL-Cbased diagnoses of abnormal LDL was similar in the hypertriglyceridemic (ҝ = 0.56; 95% CI 0.52-0.60) and normotriglyceridemic subgroups (ҝ = 0.47; 95% CI 0.44-0.51). Non-HDL-C detected fewer patients with abnormal LDL than LDL-C in normotriglyceridemic patients. However, non-HDL-C detected more patients with abnormal LDL than LDL-C in hypertriglyceridemic patients: 114 of the 1662 patients considered as abnormal LDL according to LDL-C fell into the normonon-HDL-C phenotype, whereas 204 of the 1662 patients considered as abnormal LDL according to non-HDL-C fell into the normoLDL-C phenotype. Conclusion: Among patients with NAFLD, LDL-C is superior to non-HDL-C in the detection of high-risk phenotypes in normotriglyceridemic patients, whereas non-HDL-C seems to be superior in hypertriglyceridemic patients.
Nonalcoholic fatty liver disease; LDL-cholesterol; Non-HDL-cholesterol
The worldwide prevalence of nonalcoholic fatty liver
disease (NAFLD) is increasing rapidly, affecting between
15%–40% of adults [
]. Dyslipidemia that frequently
coexist with NAFLD  has been identified as a major
modifiable risk factor for the accelerated development of
cardiovascular disease (CVD) [
]. Although no licensed
pharmacological lipid-lowering strategy in patients with
NAFLD exists, it is widely accepted that the
lipidlowering strategies for NAFLD and CVD are similar,
aimed primarily at reducing low-density lipoprotein
cholesterol (LDL-C) [
]. Nevertheless, the major
features of dyslipidemia in patients with NAFLD are an
atherogenic lipid profile, consisting of high triglyceride
(TG) levels, low high-density lipoprotein cholesterol
(HDL-C), and an increase in TG-rich lipoproteins
(including very-low-density lipoprotein [VLDL] and
intermediate-density lipoprotein [IDL]), and small dense
LDL particles) . LDL-C concentrations have generally
been reported to be at normal levels in the setting of
]. Thus, LDL-C underestimates the true
cholesterol burden in NAFLD as its concentrations do
not fully capture the whole mass of lipoprotein particles
. Non-high-density lipoprotein cholesterol
(non-HDLC) represents a composite measure that encompasses
the total cholesterol content within all VLDL, IDL and
small dense LDL particles. A growing body of evidence
has highlighted that non-HDL-C levels are at least
moderately increased in NAFLD [
]. Furthermore, a
recent study has demonstrated that non-HDL-C is
stronger than other lipoproteins in predicting the onset
of NAFLD [
]. In addition, emerging data have indicated
that non-HDL-C is a better predictor of CVD than
]. Therefore, measuring non-HDL-C may better
identify lipid abnormalities in patients with NAFLD.
However, no comparison has been made between
nonHDL-C and LDL-C in the classification of patients with
NAFLD into dyslipidemic phenotypes. Hence, we aimed
to compare the classification of a group of patients with
NAFLD into dyslipidemic phenotypes using non-HDL-C
The study participants were Chinese employees and
retired workers aged 20–100 years from the Wuhan
Iron and Steel Company (WISCO), which is one of
the largest iron and steel companies in China. Full
details of the study have been described elsewhere
]. The present cohort included employees and
retired workers free of known CVD who received a
comprehensive health examination (including
abdominal ultrasonography) at the Healthcare system,
WISCO general Hospital, between June 2008 and
December 2010 (n = 15,199).
All subjects were asked to complete a standard
questionnaire that gathered information on alcohol
consumption habits, histories of current and previous
illness, and medical treatments. We excluded 5639
participants from this study, comprising 1271 with
alcohol consumption in amounts >70 g/week for women
(73) and >140 g/week for men (1198), 857 participants
with hepatitis B surface antigen (HBsAg) positivity, and
1467 missing information on age, sex, anthropometric
assessment, lipid measurements, test results for HBsAg,
or liver ultrasound scans. In addition, to avoid the effects
of lipid-lowering on all lipid parameters, 933 participants
with lipid-lowering medication use were excluded.
Furthermore, 1111 individuals with diabetes (defined using
the 2015 American Diabetes Association (ADA) criteria
] of a fasting plasma glucose ≥126 mg/dl or taking
anti-diabetic medications for diabetes) were also
excluded as diabetes has a strong independent relationship
with increased levels of TG, decreased levels of HDL-C,
and increased risk of NAFLD. The remaining available
9560 participants (6022 men and 3538 women) were
included in our data analysis (Fig. 1). The fact that men
accounted for 63% of total participants was in consistent
with the proportion of male employees at WISCO.
According to the Private Information Protection Law,
information that might identify subjects was safeguarded
by the Health Examination Center. This study was
approved by the institutional review board of WISCO
general Hospital. Because we only retrospectively accessed a
de-identified database for purposes of analysis, informed
consent requirement was exempted by the institutional
review board. The procedures followed were in
accordance with the ethical standards of the responsible
committee on human experimentation and with the
Helsinki declaration of 1975, as revised in 1983.
Anthropometric and biochemical measurements
Anthropometric measurements, including weight,
height, and systolic/diastolic blood pressure (BP) were
measured following standardized protocols from the
World Health Organization (WHO). Body mass index
(BMI) was calculated as weight (in kilograms) divided by
the square of height (in meters). Participants’ seated BP
was measured twice for every 5 min on the right arm
after 5 min of rest by trained nurses with a
sphygmomanometer. The mean of the two readings was used in
Overnight fasting (at least 8 h) blood samples were
collected from the antecubital vein of each individual.
Biochemical measurements, including assessment of
fasting plasma glucose, total cholesterol (TC), TG,
LDLC, HDL-C, alanine aminotransferase, uric acid, and
hepatitis viral antigen/antibody, were measured
enzymatically on an autoanalyzer (Hitachi 7600, Ltd., Tokyo,
Japan). Non-HDL-C was calculated as TC minus
HDLC. All the blood measurements were followed the same
Assessment of NAFLD
Ultrasound tests were performed by trained
sonographers using a high-resolution, real-time scanner (model
SSD-2000; Aloka Co., Ltd., Tokyo Japan). One
experienced radiologists used standard criteria in evaluating
the images for the presence or absence of hepatic fat
]. Generally, the diagnoses of fatty liver was based on
the presence of stronger echoes in the hepatic
parenchyma compared with echoes in the kidney or spleen
According to the current Adult Treatment Panel III of
the National Cholesterol Education Program (NECP/
ATP III) guidelines [
], elevated TG is defined as
According to the ADA and the American College of
Cardiology Foundation (ACC) report [
nonHDL-C is defined as ≥130 mg/dl.
All statistical analyses were performed using SPSS
software (version 12.0 for windows; SPSS, Chicago, IL,
USA). Continuous variables were presented as medians
and interquartile ranges (IQR) due to their skewed
distribution. Categorical variables were presented as
percentages. Kruskal-Wallis analysis of median test was
used followed by the Mann-Whitney U test for pairwise
comparisons. Bonferroni correction was applied to
adjust P-values for multiple comparisons. Chi-square
test was performed to assess differences in proportions
across groups. Of the 9560 participants studied, 3709
patients were identified as NAFLD. The NAFLD patients
were divided into four mutually exclusive groups by the
presence or absence of TG ≥150 mg/dl and
non-HDLC ≥ 130 mg/dl. For comparison, patients were also
categorized by the conventional approach based on TG and
LDL-C cut points. For these analyses, levels of 150 mg/
dl for TG and 100 mg/dl for LDL-C were chosen.
LDLC values corresponding to non-HDL-C concentrations
are not available, a value of 100 mg/dl for LDL-C was
chosen for identification of patients as dyslipidemic
phenotypes per consensus report from the ADA/ACC panel
]. Spearman correlation was adopted to assess
coefficients between non-HDL-C and LDL-C. The kappa (ҝ)
statistic was calculated to test for an agreement between
non-HDL-C- and LDL-C-based identification of
dyslipidemic phenotypes. Values for ҝ value can be between 0 and
1, with a value of ≥0.75 signifies perfect agreement,
whereas with a value of <0.40 indicating poor agreement.
Venn diagram was constructed as a visual display of
concordance/discordance among TG-, LDL-C and
non-HDLC-based classification of participants. Significance was
accepted at a two-tailed p < 0.05.
Characteristics of subjects with and without NAFLD
were described elsewhere [
]. Using the conventional
classification, 16.0% were identified as normal, 15.5%
as hypertriglyceride-normoLDL-C, 39.2% as
normoTG-increased LDL-C, and 29.3% as
hypertriglyceride-increased LDL-C (Fig. 2a). Hence,
68.5% had abnormal LDL, as evidenced by increased
Fig. 2 Lipid phenotype distributions of the 3709 patients with
nonalcoholic fatty liver disease according to triglycerides and LDL
cholesterol levels (a), triglycerides and non-HDL-cholesterol levels (b)
LDL-C. When using TG and non-HDL-C to identify
dyslipidemic phenotypes, 31.0% were identified as
normal, 13.1% as
hypertriglyceridemic-normononHDL-C, 24.1% as normoTG-hyper-non-HDL-C, and
31.8% as hypertriglyceridemic-hyper-non-HDL-C. (Fig.
2b). In total, 55.9% of the patients with NAFLD had
abnormal LDL particle number and therefore
abnormal LDL, as evidenced by increased non-HDL-C.
The characteristics of the four groups in Fig. 2a were
showed in Table 1. Individuals with dislipidemia,
irrespective of hypertriglyceridemia or increased LDL-C or
by both, had higher levels of systolic BP, and manifested
more worse lipid profile. Table 2 showed the
characteristics of the four groups in Fig. 2b. Individuals with
dislipidemia, irrespective of hypertriglyceridemia or increased
non-HDL-C or by both, had higher levels of systolic BP
and alanine aminotransferase, and manifested more
worse lipid profile.
When using non-HDL-C and LDL-C to identify
patients with abnormal LDL, discordant classifications
occurred for 18.3% of participants who had an LDL-C ≥
100 mg/dl and non-HDL-C < 130 mg/dl, and for 5.6%
who had an non-HDL-C ≥ 130 mg/dl and LDL-C <
The correlations of non-HDL-C with LDL-C
according to NAFLD status and TG levels were
displayed in Table 3. In the NAFLD state, the
correlation between non-HDL-C and LDL-C is similar
in the hypertriglyceridemic (r = 0.561, P < 0.01) and
normotriglyceridemic subgroups (r = 0.553, P < 0.01).
We then evaluated the discordance between
classifications based on LDL-C and non-HDL-C according to
TG levels (TG < 150 mg/dl and TG ≥ 150 mg/dl)
(Fig. 3). The concordance between non-HDL-C- and
LDL-C-based diagnoses of abnormal LDL was
moderate in both the hypertriglyceridemic ( = 0.56; 95%
CI 0.52–0.60) and normotriglyceridemic ( = 0.47;
95% CI 0.44–0.51) subgroups. Non-HDL-C detected
fewer patients with abnormal LDL than LDL-C in
normotriglyceridemic patients: 563 of the 2047
patients considered as abnormal LDL according to
LDLC fell into the normonon-HDL-C phenotype, whereas
only 5 of the 2047 patients considered as abnormal
LDL according to non-HDL-C fell into the
normoLDL-C phenotype (Fig. 3). However,
non-HDLC detected more patients with abnormal LDL than
LDL-C in hypertriglyceridemic patients: 114 of the
1662 patients considered as abnormal LDL according
to LDL-C fell into the normonon-HDL-C phenotype,
whereas 204 of the 1662 patients considered as
abnormal LDL according to non-HDL-C fell into the
To our knowledge, this is the first study to report a
comparison between LDL-C and non-HDL-C for the
classification of patients with NAFLD into
We noted that the prevalence of discordance defined
according to LDL-C and non-HDL-C cut points was
common, reaching 23.9%. Although fewer proportions of
abnormal LDL were identified by non-HDL-C,
nonHDL-C identified high-risk phenotypes that are not
detected by standard lipid profile in hypertriglyceridemic
patients, indicating that non-HDL-C identifies patients
Data are medians (interquartile range)
*P < 0.008 compared with individuals with normal-TG normal-LDL-C
‡† PP << 00..000088 ccoommppaarreedd wwiitthh iinnddiivviidduuaallss wwiitthh hnyoprmera-Tl-GTGnhorympearl--LLDDLL--CC
Data are medians (interquartile range)
*P < 0.008 compared with individuals with normal-TG normal-non-HDL-C
† P < 0.008 compared with individuals with hyper-TG normal-non-HDL-C
‡ P < 0.008 compared with individuals with normal-TG hyper-non-HDL-C
at risk better than LDL-C in hypertriglyceridemic
Although LDL-C and non-HDL-C are closely
correlated, they assess different elements of lipid metabolism.
LDL-C is the amount of cholesterol contained in LDL
particles, whereas non-HDL-C is the total amount of
cholesterol carried by LDL, IDL, and VLDL particles.
Mechanistically, the cholesterol content within LDL
particles can vary substantially as cholesterol ester within
LDL particles can be exchanged for triglyceride
molecules within VLDL particles [
]. The considerable
discordance between LDL-C- and non-HDL-C-based
identification of dyslipidemia phenotypes supported this
notion. In the hypertriglyceridemic state, a triglyceride
molecule from VLDL particles is exchanged for a
cholesterol ester in LDL particles, producing relatively
triglyceride-enriched LDL particles and relatively
cholesterol-enriched VLDL particles [
]. Hence, LDL-C
underestimates the concentrations of non-HDL-C in the
setting of hypertriglyceridemia.
It is already established that hypertriglyceridemia,
which was typically observed in NAFLD, accounted for
the hepatic over-production of VLDL particles and the
increased VLDL size [
]. The increased VLDL particles
and VLDL size prevent lipoprotein lipase-mediated
clearance of triglyceride molecules within VLDL, thereby
producing triglyceride-rich lipoprotein remnants.
Hepatic lipases can hydrolyze these remnant particles,
producing small dense lipoprotein particles and
imparting increased CVD risk, suggesting that normal LDL-C
but hyper- non-HDL-C generally reflects increased
concentrations of smaller, cholesterol-depleted LDL particles
among those with hypertriglyceridemia. All these
support the notion that the dysregulation of cholesterol
played a vital role in the pathogenesis of NAFLD [
A recent prospective study observed that the increased
non-HDL-C levels precedes the onset of NAFLD ,
which further highlighted a causal relationship between
the impairment of cholesterol regulation and the
In the present study, non-HDL-C identifies a subgroup
of patients with normoLDL-C who had
hyper-non-HDLC. The identification of this subgroup is noteworthy as
the core lipid composition of LDL is altered in a
proatherogenic direction. Multiple mechanistic,
observational and experimental trials have shown that
alterations in VLDL, LDL and IDL synthesis and release may
play a role in the pathogenesis of NAFLD [
explain the observed increased CVD risk among those
with NAFLD. Emerging evidence revealed that
cholesterol-lowering therapy was effective in reducing
CVD events and improving liver damage among those
with NAFLD [
]. Hence, detection and treatment of
dyslipidemia by incorporating non-HDL-C is therefore
of importance among patients with NAFLD and for
preventing and treating CVD, especially in
hypertriglyceridemic patients. Furthermore, accumulating prospective
studies indicate the superiority of non-HDL-C over
LDL-C in predicting CVD [
]. Our present data
supports the currently applicable guidelines that
recommend non-HDL-C as alternative targets of therapy to
LDL-C for the management of dyslipidemias in
individuals with hypertriglyceridemia [
The present study has several limitations. First,
lipoproteins were not measured by the more sophisticated
method nuclear magnetic resonance spectroscopy.
However, increasing evidence suggested that the association
of coronary artery calcification with nuclear magnetic
resonance-measured lipoproteins was comparable to
that with standard lipids [
]. Second, we studied a
cohort of Chinese patients with NAFLD, thus, the present
results may not be generalizable to other racial or ethnic
patients. Third, the cross-sectional nature of this study
makes it difficult to infer causality between different
lipid phenotypes and the relative CVD risk among
patients with NAFLD. Nevertheless, the analysis of the
dyslipidemic classification based on LDL-related
measures was not influenced by this particular design. At
last, NAFLD was diagnosed by ultrasonography, which is
a reasonably accurate technique for detecting modest
amounts of liver fat (>30% liver fat in filtration),
participants with minor amounts of fatty infiltration might not
have been captured.
In conclusion, among patients with NAFLD, LDL-C is
superior to non-HDL-C in the detection of high-risk
phenotypes in normotriglyceridemic patients, whereas
non-HDL-C seems to be superior in
hypertriglyceridemic patients. Our findings together with the logistical
advantages of non-HDL-C (a cost-free test, and can
provide an important value in CVD risk stratification)
may support it as a first-line component to be evaluated
in dyslipidemic classification and for diagnostic and even
therapeutic purposes among those with NAFLD in the
setting of hypertriglyceridemia.
ACC: American College of Cardiology Foundation; ADA: American Diabetes
Association; BMI: body mass index; BP: blood pressure; CVD: cardiovascular
disease; HDL-C: high-density lipoprotein cholesterol; IDL: intermediate-density
lipoprotein; IQR: interquartile range; LDL-C: low-density lipoprotein-cholesterol;
NAFLD: nonalcoholic fatty liver disease; non-HDL-C: non-high-density
lipoprotein cholesterol; TC: total cholesterol; TG: triglyceride; VLDL:
very-lowdensity lipoprotein; WHO: World Health Organization; WISCO: Wuhan Iron and
The authors thank all study participants for their cooperation.
Availability of data and materials
The data are available from the corresponding author upon reasonable
TTD conceived the study design, wrote the first draft of the manuscript,
analyzed the data, contributed to interpretation of results, commented on
drafts, and approved the final version. XXS contributed to interpretation of
results, commented on drafts, and approved the final version. XFY is the
guarantor of this work, and had full access to all the data in the study and
takes responsibility for the integrity of the data and the accuracy of the data
Ethics approval and consent to participate
This study was approved by the institutional review board of WISCO general
Hospital. Because we only retrospectively accessed a de-identified database
for purposes of analysis, informed consent requirement was exempted by
the institutional review board. All procedures followed were performed in
accordance with the ethical standards of the responsible committee on human
experimentation and with the 1975 Helsinki Declaration and its later
Consent for publication
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