Elevated lipid induced complications are significantly higher in North America and worldwide. Higher lipid levels are known to cause complications without sparing any organs including central nervous system, cardiovascular and endocrine systems, and even hepatic and renal systems [
Approximately 30% of Americans are living with fatty liver disease, an epidemic that is rising in geometric proportions because of the calorie rich diet, lack of physical activity, and diabetes [
Even though there are published studies that have investigated the effect of lipids on cardiovascular system [
We analyzed the sample of adults 20 years and older who participated in NHANES, an ongoing population-based statistical survey to estimate the health status of the noninstitutionalized civilian US population, based on interview, examination, and laboratory information from representative samples of US households. In-person interviews were conducted in sampled households, and subjects were invited to participate in medical examinations. Participants were selected using a stratified multistage probability design with oversampling of certain age and ethnic groups. We extracted data on individuals with age equal or above 20 years old, who participated in NHANES from 1999 through 2012 into a combined dataset (NHANES 1999–2012) to increase sample size for greater estimator reliability (NHANES Analytic Guidelines) [
Covariates included age, gender and ethnicity, blood pressure, cardiovascular disease, alcohol use, and use of lipid-lowering drugs. Age, race, and ethnicity were self-reported by the participants.
Hyperlipidemia was defined in accordance with “National Cholesterol Education Program-Adult Treatment Panel” (NCEP-ATP III) guidelines [
The statistical analyses for this study were performed using STATA, version 14 (STATA Corp, College Station, Texas) a statistical software package that takes into account sample weighting and the complex, multistage probability sample design of NHANES [
Table
Demographic characteristics and lipid and liver enzyme laboratory data.
| |
---|---|
| |
20–29 | 6256 (19) |
30–39 | 5907 (19) |
40–49 | 5754 (21) |
50–59 | 4817 (17) |
≥60 | 11709 (24) |
| |
| |
Male | 16538 (48) |
Female | 17905 (52) |
| |
| |
Mexican American | 6518 (7.9) |
Other Hispanics | 2473 (5.3) |
Non-Hispanic White | 16275 (70) |
Non-Hispanic black | 7107 (11) |
Other | 2070 (5.8) |
| |
| |
<High school | 8530 (18.5) |
High school | 7050 (24) |
Some college degree | 8264 (30) |
Graduate degree and above | 6163 (27) |
| |
Participant with BMI ≥ 30 | 7504 (34.8) |
Participants with Hypertension | 2883 (12.0) |
Told by Doctor of having high cholesterol | 3417 (10.6) |
On lipid lowering drugs | 1123 (7.8) |
Five or more alcohol drinks/day | 2065 (15.0) |
| |
| |
Optimal (<100) | 8514 (41.6) |
Near optimal/above optimal (100–129) | 6338 (30.9) |
Borderline high (130–159) | 3725 (18.2) |
High (160–189) | 1373 (6.7) |
Very high (≥190) | 502 (2.3) |
| |
| |
<40 | 6164 (19) |
≥40 | 28279 (81) |
| |
| |
Normal (<150) | 15846 (74.1) |
Borderline high (150–199) | 2620 (12.3) |
High (200–499) | 2693 (12.6) |
Very high (≥500) | 214 (1.0) |
| |
| |
Desirable (<200) | 17220 (51) |
Borderline high (200–239) | 9878 (29) |
High (≥240) | 7345 (20) |
| |
| |
≤40 | 28828 (84) |
>40 | 5615 (16) |
| |
| |
≤40 | 30200 (89) |
>40 | 4243 (11) |
| |
| |
≤120 | 1047 (3.6) |
>120 | 33396 (96) |
In overall sample, 27% adults had LDL levels > 130 mg/dl (borderline high) and 19% participants had HDL levels < 40 mg/dl (low). However, based on NCEP-ATP recommendation for female, 40% female had HDL levels less than 50 mg/dl. Twenty-six percent had triglycerides levels greater than 150 mg/dl (borderline high) according to NCEP-ATP III guidelines. Sixteen percent adults had ALT > 40 U/L, 11% had AST > 40 U/L, and 96% had ALP > 120 U/L in overall sample (Table
The mean LDL, HDL, and triglyceride levels were 117.3 mg/dl, 45.8 mg/dl in male and 56.1 mg/dl in female, and 126.9 mg/dl, respectively, all within the normal range, with the exception of HDL being little high. Adults had mean body mass index (BMI) of 28.2 and mean waist circumference of 97.5 cm, well within the normal range with the cut-off values of 30 for BMI, 102 cm for men, and 88 cm for women for waist circumference (Table
Mean values of lipid biomarkers and liver enzymes among participants.
Mean (95% CI) | |
---|---|
LDL (mg/dl) | 117.3 (116.5, 118.2) |
HDL (mg/dl) | 50.8 (50.1, 51.5) |
HDL (mg/dl) Male | 45.8 (45.1, 46.5) |
HDL (mg/dl) Female | 56.1 (55.1, 57.1) |
Triglyceride (mg/dl) | 126.9 (124.9, 128.9) |
Total cholesterol (mg/dl) | 202.1 (199.6, 204.6) |
ALT (U/L) | 25.4 (25.0, 25.8) |
ALT (U/L) Male | 29.9 (29.5, 30.4) |
ALT (U/L) Female | 21.5 (21.0, 21.9) |
AST (U/L) | 25.2 (24.8, 25.5) |
AST (U/L) Male | 27.2 (26.9, 27.5) |
AST (U/L) Female | 23.3 (23.0, 23.5) |
ALP (U/L) | 68.9 (68.2, 69.7) |
Waist circumference (cm) | 97.5 (97.1, 98.0) |
BMI | 28.2 (28.0, 28.3) |
SBP (mmHg) | 119.5 (119.0, 119.9) |
DBP (mmHg) | 71.2 (70.9, 71.6) |
ALT: alanine transaminase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; SBP: systolic blood pressure; and DBP: diastolic blood pressure.
Mean lipid biomarkers and liver enzymes.
ALT (U/L) [Mean (SE)] | AST (U/L) [Mean (SE)] | |||||
---|---|---|---|---|---|---|
<40 | >40 | | <40 | >40 | | |
| ||||||
Overall Sample | ||||||
LDL (mg/ml) | 122.3 (0.9) | 130.8 (3.1) | | 123.0 (0.9) | 128.3 (3.9) | |
HDL (mg/dl) | 52.0 (0.4) | 45.4 (1.0) | | 51.4 (0.4) | 50.6 (2.0) | |
Triglyceride (mg/dl) | 129.5 (1.8) | 157.3 (6.8) | | 131.8 (1.8) | 143.9 (9.7) | 0.499 |
| ||||||
<40 | >40 | | <37 | >37 | | |
| ||||||
Male | ||||||
LDL (mg/ml) | 117.3 (0.6) | 124.6 (1.5) | | 118.1 (0.5) | 121.4 (1.8) | |
HDL (mg/dl) | 46.3 (0.4) | 43.3 (0.7) | | 45.6 (0.4) | 48.2 (0.9) | |
Triglyceride (mg/dl) | 147.2 (2.6) | 191.2 (6.9) | | 151.8 (2.5) | 177.9 (9.9) | |
| ||||||
<31 | >31 | | <31 | >31 | | |
| ||||||
Female | ||||||
LDL (mg/ml) | 116.7 (0.5) | 120.9 (1.9) | | 116.7 (0.5) | 121.2 (1.9) | |
HDL (mg/dl) | 56.5 (0.5) | 53.0 (1.2) | | 56.0 (0.4) | 56.7 (1.6) | 0.630 |
Triglyceride (mg/dl) | 123.9 (1.3) | 160.9 (7.5) | | 125.1 (1.3) | 154.7 (8.5) | |
SE = standard error (SE); significant at
We examined the association of demographic characteristics with LDL, HDL, and triglyceride levels using the Chi-square test. Age, gender, and race/ethnicity showed significant association with LDL, HDL, and triglycerides levels. Post hoc analyses showed that >40 years of age and non-Hispanic white and black ethnicity were significantly associated with high LDL and borderline high triglycerides. Age of sixty years and above was also significantly associated with high triglycerides. Female gender was significantly associated with high HDL (>40 mg/dl) and high triglyceride levels (200–499 mg/dl), respectively. Non-Hispanic black ethnicity was significantly associated with borderline high LDL, Mexican American, and non-Hispanic black ethnicity with low HDL and high triglycerides (200–499 mg/dl). Obesity and presence of cardiovascular disease (CVD) were significantly associated with high HDL, whereas being on lipid-lowering drugs demonstrated significant association with low LDL levels. Blood pressure found significantly associated with triglyceride levels; however, LDL and HDL did not show any significant association with blood pressure status (Supplemental Tables
We also examined the association of LDL, HDL, and triglycerides with liver enzymes. LDL, HDL, and triglycerides were found significantly associated with liver enzymes ALT and AST (Table
Association of lipid markers and liver enzymes (overall sample).
ALT (U/L) ( | | AST (U/L) ( | | |||
---|---|---|---|---|---|---|
<40 | >40 | <40 | >40 | |||
LDL (mg/dl) | ||||||
<100 | 4471 (33.3) | 420 (27.6) | | 4595 (32.7) | 296 (33.6) | |
100–129 | 4454 (33.2) | 483 (31.8) | 4654 (33.1) | 283 (32.2) | ||
130–159 | 2969 (22.1) | 378 (24.9) | 3167 (22.5) | 180 (20.5) | ||
160–189 | 1125 (8.3) | 162 (10.7) | 1209 (8.6) | 78 (8.9) | ||
≥190 | 401 (2.9) | 75 (4.9) | 433 (3.0) | 43 (4.9) | ||
| ||||||
HDL (mg/dl) | ||||||
<40 | 5417 (17) | 747 (2.3) | | 5827 (18) | 337 (0.94) | |
≥40 | 23411 (68) | 4868 (14) | 24373 (71) | 3906 (10) | ||
| ||||||
Triglyceride (mg/dl) | ||||||
<150 | 9834 (70.0) | 901 (54.9) | | 10156 (68.9) | 579 (61.2) | |
150–199 | 1976 (14.1) | 290 (17.6) | 2137 (14.5) | 129 (13.6) | ||
200–499 | 2074 (14.8) | 392 (23.9) | 2261 (15.4) | 205 (21.6) | ||
≥500 | 146 (1.0) | 57 (3.5) | 170 (1.2) | 33 (3.5) |
Significant at
We calculated the odds ratio of abnormal ALT (ALT > 40 IU/L), AST (AST > 40 IU/L) using cut-off value of borderline high LDL, low HDL, and borderline high triglycerides. LDL greater than borderline high was associated with over two times higher odds of elevated ALT (OR: 2.33, 95% CI: 2.17, 2.53,
Odds of elevated liver enzymes with lipid biomarkers.
ALT | AST | |||
---|---|---|---|---|
OR (95% CI) | | OR (95% CI) | | |
LDL (mg/dL) | 2.33 (2.17–2.53) | | 2.79 (2.55–3.06) | |
HDL (mg/dL) | 1.51 (1.39–1.64) | | 2.77 (2.47–3.11) | |
Triglyceride (mg/dL) | 2.71 (2.51–2.93) | | 3.21 (2.93–3.52) | |
| ||||
Male | ||||
LDL (mg/dL) | 1.39 (1.18–1.63) | | 1.07 (0.865–1.31) | 0.551 |
HDL (mg/dL) | 1.34 (1.17–1.55) | | 1.19 (0.99–1.44) | 0.055 |
Triglyceride (mg/dL) | 1.83 (1.59–2.09) | | 1.12 (0.93–1.33) | 0.209 |
| ||||
Female | ||||
LDL (mg/dL) | 0.97 (0.88–1.06) | 0.480 | 0.98 (0.87–1.11) | 0.790 |
HDL (mg/dL) | 0.64 (0.49–0.83) | | 0.86 (0.61–1.20) | 0.360 |
Triglyceride (mg/dL) | 1.36 (1.03–1.81) | | 0.96 (0.69–1.34) | 0.080 |
OR = odds ratio; CI = confidence interval; significant at
We modeled the odds of abnormal ALT and AST using LDL, HDL, triglyceride, and other covariates simultaneously and calculated the odds ratio of abnormal ALT (ALT > 40 U/L), AST (AST > 40 U/L) using logistic regression model (Table
Predictors of AST and ALT level on regression (adjusted model).
ALT | AST | |||
---|---|---|---|---|
OR (95% CI) | | OR (95% CI) | | |
Age | 0.87 (0.85, 0.89) | | 0.94 (0.91, 0.97) | |
Gender | 0.49 (0.46, 0.53) | | 0.75 (0.69, 0.82) | |
Ethnicity | 0.93 (0.89, 0.97) | | 1.03 (0.98, 1.08) | 0.134 |
LDL (mg/dl) | 1.07 (1.01, 1.13) | | 1.08 (1.01, 1.16) | 0.057 |
HDL (mg/dl) | 1.59 (1.42, 1.78) | | 2.85 (2.38, 3.42) | |
Triglyceride (mg/dl) | 1.29 (1.21, 1.37) | | 1.43 (1.32–1.55) | |
OR = odds ratio; CI = confidence interval; significant at
Twenty percent male and 11% female had elevated ALT, and 9% male and 10% female had elevated AST according to the gender based cut-off values (data not shown). Mean ALT in male and female was 29.9 U/L and 21.5 U/L, respectively. Similarly, mean AST in male was 27.2 U/L and in female 23.3 U/L (Table
Mean LDL, HDL, and triglycerides among male who had ALT > 40 U/L and AST > 37 was 124.6 mg/dl and 121.4 mg/dl; 43.3 mg/dl and 48.2 mg/dl; and 191.2 mg/dl and 177 9 mg/dl, respectively. In case of female, these values were 120.9 mg/dl and 121.2 mg/dl; 53 mg/dl and 56.7 mg/dl; and 160.9 mg/dl and 154.7 mg/dl, respectively, little higher for HDL and triglycerides. These differences in LDL, HDL, and triglycerides with ALT and AST were significant in both genders with the exception of HDL and AST in female (
LDL greater than borderline high was associated with 39% higher odds (OR: 1.39; 95% CI: 1.18, 1.6,
In the present study, we have expanded the data to include population of 34,443 individuals with age ranging from 20 years and above who are free of hepatitis A, B, C, and D. Also, we have included participants from 1999 to 2012, which is a wider time range than any of the previous studies performed using NHANES. This study helps in drawing the link between high lipid profile and its injurious effect on liver function as measured by AST, ALT, and ALP levels. The mean age of the study population was 46 years old with 62% ranging over 40 years old and 57% of the participants included had a college or graduate level education. Participants of age 60 years and above (2.6%) had normal ALT compared to other age groups; however, no single group found significantly different for AST levels. Similarly, less number of female compared to male (6% versus 9.8%) had elevated ALT and (5.2% versus 5.9%) had elevated AST on Chi-square analyses (data not shown). On the other hand, overall increase in age and female gender appears to be protective to liver health as indicated by the results of regression analysis.
The mean lipid profile and BMI in our study show an interesting pattern, because the mean LDL, HDL, and triglycerides, along with waist circumference and BMI, were all in the upper part of the borderline, with HDL mean value being relatively higher which is 50.8 mg/dl predicted to offer protection. Individuals on lipid-lowering drugs or with BMI < 30 are more likely to have normal liver function than the others with elevated lipid levels. Frequent and excessive consumption of alcoholic drinks can lead to increased AST/ALT functions but potentially without any interference with the lipid levels. Typically, a healthy liver in a subject who is involved with a more sedentary work and life style will metabolize and maintain a normal systemic lipid level in the body, by increasing hepatic reverse cholesterol transport and also uptake of VLDL and LDL by increasing the LDL receptor expression and concentration on the hepatic surface [
Our results suggest that in general there are no gender-specific differences in the systemic LDL and HDL-cholesterol levels; however, the LDL levels were slightly higher in females than males, albeit without any statistical significance. The non-Hispanic whites had a higher limit of both borderline and higher levels of LDL compared to Mexican Americans and Hispanics who had the lowest. In addition, non-Hispanic white had higher HDL levels, which reflect the finding of previous studies, where higher lipid level including HDL-cholesterol was accompanied by an increase in hepatic transaminase expression [
There is a significant rise in hepatic AST and ALT enzymes in proportion to raised LDL, HDL, and triglyceride levels. These findings further strengthen the claims and give a projection about the connection between the etiology and epidemiology of lipid induced hepatic dysfunction. There are substantial scientific evidence that shows how lipids can affect liver function in preclinical and also in clinical setting [
One of the previous studies by Jiang et al. [
Another interesting study by Tsai et al. [
Liver plays a vital role in the biotransformation, detoxification, and excretion of diverse lipophilic agents including medications, dietary substances, and environmental toxicants. In addition to detoxification, the drug metabolizing enzymes also play an important role in converting the prodrugs to their active form. Cytochrome P450 (CYP) and uridine diphosphate (UDP) glucuronosyltransferases (UGT) superfamily metabolizing enzymes primarily execute their functions in liver [
Our study has some limitations. First, we used ALT and AST as a surrogate marker, which is an indirect assessment of liver dysfunction or liver diseases. Second, the proportions of people with LDL, triglycerides, high ALT, and AST were comparatively small. Therefore, despite the large dataset, the power can be limited in these categories, especially when the sample size is reduced for sensitivity analysis. Third, only a single measurement of ALT and AST levels was available for each individual in the NHANES data. Though a small number of participants had CVD, were on lipid-lowering drugs, and reported drinking more than 5 alcoholic drinks per day, perhaps they may have influenced our results. Similarly, missing data and presence of reported/unreported confounding factors such as smoking, cancer/malignancy, diabetes, and presence of liver conditions among participants are the other factors that may have contributed to our results limiting its generalizability.
Both high LDL and HDL were associated with significantly higher odds of elevated liver enzymes in the general US adult population. Age, gender, and race/ethnicity have significant association with LDL, HDL, and triglycerides levels. Our findings raise concerns about potentially unrecognized hepatic dysfunction among people with high LDL or HDL and the underlying hepatic pathophysiology can impact hepatic detoxification of drugs or environmental toxicants.
Low-density lipoprotein
High-density lipoprotein
National Health and Nutrition Examination Survey
Center for Disease Control and Prevention
Alanine amino transferases
Aspartate aminotransferases
Alkaline phosphatase levels
Body mass index
Very low-density lipoprotein
Gamma glutamyl transpeptidase
Cytochrome P450
Uridine diphosphate (UDP) glucuronosyltransferases
Nonalcoholic fatty liver disease.
The authors of this manuscript do not have any conflicts of interest in relation to the data and conclusions presented here.
The Supplemental Tables