Epidemiology of fatty liver in a hospital-based study in Taiwan.

ABSTRACT

Background. The aim of this study was to assess the epidemiology of fatty liver in Taiwan.

Methods. We retrospectively analyzed the medical records of all patients receiving health examinations at China Medical College Hospital from January through December 2000. A total of 1,012 subjects were included for analysis. Data were analyzed using the t test, chi-square analysis, and multivariate logistic regression.

Results. Our cohort was comprised of 41.8% women and 58.2% men; mean age was 49.2 years. The prevalence of fatty liver was 36.9% in all subjects, and prevalence was higher in men than in women. After controlling for other covariates, the multivariate logistic regression analysis showed that the significant factors related to fatty liver were male sex, obesity, hyperglycemia, hypertriglyceridemia, elevated glutamate pyruvate transaminase level, and hyperuricemia, Elevated glutamate oxaloacetate transaminase level was negatively associated with fatty liver.

Conclusions. The prevalence of fatty liver is high in Taiwan. This study establishes background data for further investigation.

**********

FATTY LIVER, also known as fatty degeneration of the liver or hepatic steatosis, is the most common liver disease, but its clinical significance remains unclear. (1,2) The natural course of this disease is still controversial. When alcoholic hepatitis or other confounding factors do not exist, nonprogressive fatty liver should be a benign clinical condition with little risk of progression. (3-5) If confounding factors such as alcohol consumption or hepatitis C virus infection do coexist, fatty liver can progress steatohepatitis (slowly progressive fatty liver with inflammation), liver cirrhosis, and even liver failure. (6-11) In Western countries, the prevalence of fatty liver is between 16.9% and 19.8% (12,13); in Japan, the prevalence is between 14% and 22% (14-16); and in Taiwan, the prevalence is 25.2%. (17,18) Although the prevalence is high, fatty liver is usually found incidentally in periodic health examinations, life insurance examinations, or as part of screening before blood donation. (5,17)

Although the real mechanism of fatty liver is still elusive, related factors have been widely assessed. As in the current report, obesity, glucose intolerance/diabetes mellitus, dyslipidemia, essential hypertension, transaminase level, gamma-glutamyl transpeptidase level, alcohol consumption, and hepatitis C virus infection were closely associated with fatty liver. (10-23) Little is known about the epidemiology of fatty liver in Taiwan; therefore, we conducted a retrospective, cross-sectional study to assess the epidemiology of fatty liver in Taiwanese people.

MATERIALS AND METHODS

From January through December 2000, we retrospectively analyzed the medical records of all patients receiving periodic health examinations at the Department of Family Medicine of China Medical College Hospital in Taichung City, Taiwan. A total of 1,012 subjects who were grossly healthy and, in most cases, without obvious serious disease, were included for further analysis. Information collected included history of systemic diseases, medications taken, smoking history, and data about alcohol consumption. Complete physical examination was performed by the doctors in the Department of Family Medicine. Subjects were classified as nonsmokers if they had never smoked or had quit smoking. Subjects who had abused alcohol were classified as drinkers, while those who never drank alcohol or only drank occasionally were classified as nondrinkers. Abdominal ultrasonography was performed by the gastroenterologist using a high-resolution real-time machine (TOSHIBA Sonolayer SSA-270A, convex-type 3.5 MHz transducer, Tochigi- Ken, Japan). Fatty liver was diagnosed according to the international criteria. (24,25)

Blood pressure was measured with the patient in a sitting position using a mercury sphygmomanometer. Weight and height were measured. Venous blood samples were obtained in the morning after a 12-hour overnight fast. A number of biochemical markers, such as total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL), fasting glucose, uric acid, glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT) levels were analyzed by a biochemical autoanalyser (Hitachi-735, Tokyo, Japan) at the Department of Clinical Laboratory of China Medical College Hospital within 4 hours of collection. Hepatitis B surface antigen was detected by enzyme-linked immunosorbent assay (ELISA) (Enzygnost, Dade Behring Marburg GmbH, Marburg, Germany). Antibody to hepatitis C virus was detected by electroimmunoassay (EIA) (Abbott HCV EIA 3rd generation). Normal and abnormal values are shown in Table 1 (26-32)

Statistical analysis was done using SAS software (Version 6.12, SAS Institute Inc, Cary, NC). We did t tests, chi-square analysis, and multivariate logistic regressions. P values < .05 were considered statistically significant.

RESULTS

Women comprised 41.8% of our study population, and 58.2% were men The mean age was 49.2 [+ or -] 12.8 years (range, 18 to 87 years). The prevalence of fatty liver was 36.9% in all subjects (Figure). The prevalence was higher in men than in women (43.5% vs 27.7%; P < .01).

Chi-square analysis of correlates of fatty liver is shown in Table 1. Subjects with fatty liver were significantly older than subjects without the condition (P < .05). Other significant factors related to fatty liver were obesity, high systolic blood pressure, high diastolic blood pressure, hyperglycemia, hypercholesterolemia, hypertriglyceridemia, high low-density lipoprotein (LDL) level, low HDL level, hyperuricemia, and elevated levels of GOT, GPT, and GGT.

The results of multivariate logistic regression for fatty liver are shown in Table 2. This analysis showed significant factors for fatty liver to be male sex, obesity, hyperglycemia, hypertriglyceridemia, elevated GPT level, and hyperuricemia. Elevated GOT level was negatively associated with fatty liver.

DISCUSSION

Fatty liver is defined as >5% fat in a dry liver specimen obtained by biopsy. (33) Thus, liver biopsy remains the standard for the diagnosis of fatty liver, but it is an invasive and inconvenient method. (5) Imaging modalities may prove safer and provide convincing evidence of fatty liver. Sensitivity and specificity of ultrasonography in diagnosing fatty liver are 80% to 95% and 90% to 95%, respectively. (24,25)

Similar to previous reports, (19,34-36) our study shows a higher prevalence of fatty liver in men than in women (43.5% vs 27.7%; P .01). The total prevalence of fatty liver in our study is 36.8%, however, which is higher than in previous reports. (12-18)

The frequency of fatty liver in obese adults is 99%. (37) Obesity is considered a predictable factor in the development of fatty liver. (34-38) Body mass index (BMI) is easily measured and is a widely accepted indicator of overall adiposity. (35) We think BMI can be widely used in assessing fatty liver. Galambos and Wills (39) found the main component of fat in the liver was triglyceride. Serum triglyceride level, therefore, may be a more important indicator of fatty liver than cholesterol level. (17) The cause-and-effect relationship between hypertriglyceridemia and fatty liver remains unclear, however.

Daniel et al (40) found the most likely diagnosis of patients with marker-negative elevated liver-function tests was fatty liver. Fat accumulation in the cytoplasm of fatty hepatocytes causes an increase in GPT leakage from hepatocyte cytoplasm into the blood. (41) As a result, elevated serum GPT levels are detected. Therefore, we think that an elevated GPT level is an effect of fatty liver, not the cause. On the other hand, elevated GOT level was negatively associated with fatty liver (ie, subjects with normal GOT levels were more likely to have fatty liver than subjects with elevated GOT levels), which differs from a previous report. (7) The real cause of the difference remains to be determined.

As in previous reports, (15,17) our study showed hyperuricemia to be related to fatty liver. Although the real mechanism remains unclear, the same pathogenesis of metabolic disorders as in hyperinsulinism/insulin resistance has been suggested. (1,15-17,19,23,34,35,42-45)

Alcohol intake is a risk factor for fatty liver in Western countries. (10) In our study, there was no association between alcohol intake and fatty liver. This variable was obtained through patient self-reporting, however, and subjects may not have accurately reported their alcohol consumption. The sample size of subjects reporting alcohol consumption was small, which could explain why alcohol intake was not a statistically significant risk factor of fatty liver. As Lin et al (17) reported, the amount of alcohol consumed by Taiwanese people was relatively small and nutritional deficiency was rare, another reason that alcohol may not be a risk factor of fatty liver in Taiwan.

We conclude that male sex, obesity, hyperglycemia, hypertriglyceridemia, elevated GPT level, and hyperuricemia are the significant factors related to fatty liver. Because this study is hospital-based, the subjects may not be representative of the general population in Taiwan. Thus, a large, detailed survey regarding fatty liver is recommended. We hope our study provides background data for further studies on the epidemiology of fatty liver in Taiwan.

TABLE 1

Correlates of Fatty Liver in Chi-Square Analysis

                                       Non-fatty Liver
Variable                                   No. (%)

Age (years) (mean [+ or -] SD         48.6 [+ or -] 13.8
BMI [greater than or equal to]28
kg/[m.sup.2]
  No                                      605 (68.5)
  Yes                                      34 (26.4)
Systolic blood pressure
[greater than or equal to]140 mm Hg
  No                                      539 (65.5)
  Yes                                     100 (52.9)
Diastolic blood pressure
[greater than or equal to]90 mm Hg
  No                                      567 (65.6)
  Yes                                      72 (48.7)
Fasting glucose level
[greater than or equal to]110 mg/dL
  No                                      573 (68.4)
  Yes                                      66 (37.9)
Total cholesterol level
[greater than or equal to]200 mg/dL
  No                                      377 (70.7)
  Yes                                     262 (54.7)
Triglyceride level
[greater than or equal to]200 mg/dL
  No                                      621 (67.8)
  Yes                                      18 (18.8)
LDL level
[greater than or equal to]130 mg/dL
  No                                      411 (68.7)
  Yes                                     228 (55.1)
HDL level <35 mg/dL
  No                                      609 (64.4)
  Yes                                      30 (45.5)
Uric acid level
(Men [greater than or equal to] 7.0,
women [greater than or equal to]
6.5 mg/dL)
  No                                      502 (72.3)
  Yes                                     137 (43.2)
HBsAg
  No                                      539 (62.0)
  Yes                                     100 (69.9)
HCV ab
  No                                      597 (62.4)
  Yes                                      42 (76.4)
GOT level >34 IU/L
  No                                      544 (65.3)
  Yes                                      95 (53.1)
GPT level >40 IU/L
  No                                      560 (67.0)
  Yes                                      79 (44.9)
ALP level > 126 IU/L
  No                                      629 (63.0)
  Yes                                      10 (71.4)
GGT level > 50 IU/L
  No                                      587 (64.6)
  Yes                                      52 (50.5)
Smoking
  No                                      476 (64.2)
  Yes                                     163 (60.4)
Drinking
  No                                      567 (63.1)
  Yes                                      72 (63.2)

                                         Fatty Liver
Variable                                   No. (%)        P Value

Age (years) (mean [+ or -] SD         50.3 [+ or -] 11.0    .032
BMI [greater than or equal to]28
kg/[m.sup.2]
  No                                      278 (31.5)        .001
  Yes                                      95 (73.6)
Systolic blood pressure
[greater than or equal to]140 mm Hg
  No                                      284 (34.5)        .002
  Yes                                      89 (47.1)
Diastolic blood pressure
[greater than or equal to]90 mm Hg
  No                                      297 (34.4)        .001
  Yes                                      76 (51.3)
Fasting glucose level
[greater than or equal to]110 mg/dL
  No                                      265 (31.6)        .001
  Yes                                     108 (62.1)
Total cholesterol level
[greater than or equal to]200 mg/dL
  No                                      156 (29.3)        .001
  Yes                                     217 (45.3)
Triglyceride level
[greater than or equal to]200 mg/dL
  No                                      295 (32.2)        .001
  Yes                                      78 (81.2)
LDL level
[greater than or equal to]130 mg/dL
  No                                      187 (31.3)        .001
  Yes                                     186 (44.9)
HDL level <35 mg/dL
  No                                      337 (35.6)        .003
  Yes                                      36 (54.5)
Uric acid level
(Men [greater than or equal to] 7.0,
women [greater than or equal to]
6.5 mg/dL)
  No                                      193 (27.7)        .001
  Yes                                     180 (56.8)
HBsAg
  No                                      330 (38.0)        .085
  Yes                                      43 (30.1)
HCV ab
  No                                      360 (37.6)        .052
  Yes                                      13 (23.6)
GOT level >34 IU/L
  No                                      289 (34.7)        .003
  Yes                                      84 (46.9)
GPT level >40 IU/L
  No                                      276 (33.0)        .001
  Yes                                      97 (55.1)
ALP level > 126 IU/L
  No                                      369 (37.0)        .713
  Yes                                       4 (28.6)
GGT level > 50 IU/L
  No                                      322 (35.4)        .007
  Yes                                      51 (49.5)
Smoking
  No                                      266 (35.8)        .303
  Yes                                     107 (39.6)
Drinking
  No                                      331 (36.9)       1.000
  Yes                                      42 (36.8)

LDL = Low-density lipoprotein, HDL = high-density lipoprotein, HBsAg =
hepatitis B surface antigen, HCV Ab = hepatitis C virus antibody, GOT =
glutamate oxaloacetate transaminase, GPT = glutamate pyruvate
transaminase, ALP = alkaline phosphatase, GGT = gamma-glutamyl
transpeptidase.

TABLE 2

Multivariate Logistic Regression Analysis Results for Fatty Liver

Variable (reference)                       EP (SE)       OR   95% CI

Intercept                                -2.0 (0.3)
Sex (women)
  Men                                     0.6 (0.2)      1.8  1.3-2.6 *
Age in years                             -0.003 (0.007)  1.0  0.9-1.0
BMI (<28 kg/[m.sup.2])
  [greater than or equal to]28 kg/
   [m.sup.2]                              1.5 (0.2)      4.7  2.9-7.5 *
Hypertension (normal)
  Yes                                     0.1 (0.2)      1.1  0.8-1.6
Fasting glucose level (<110 mg/dL)
  [greater than or equal to]110 mg/dL     1.1 (0.2)      2.9  1.9-4.3 *
Total cholesterol level (<200 mg/dL)
  [greater than or equal to]200 mg/dL     0.4 (0.2)      1.5  0.95-2.5
Triglyceride level (<200 mg/dL)
  [greater than or equal to]200 mg/dL     1.9 (0.3)      6.8  3.7-12.3 *
LDL level (<130 mg/dL)
  [greater than or equal to]130 mg/dL     0.2 (0.2)      1.2  0.7-1.9
HDL level ([greater than or equal to]35
mg/dL)
  <35 mg/dL                               0.6 (0.3)      1.8  0.97-3.2
Uric acid level (men <7.0 mg/dL,
women <6.5 mg/dL)
   Men [greater than or equal to]7.0,
   women [greater than or equal to]6.5    0.8 (0.2)      2.2  1.6-3.0 *
GOT level ([less than or equal to]34
IU/L)
  >34 IU/L                               -0.6 (0.3)      0.6  0.3-0.9 +
GPT level ([less than or equal to]40
IU/L)
  >40 IU/L                                1.0 (0.3)      2.7  1.6-4.6 *
GGT level ([less than or equal to]50
IU/L)
  >50 IU/L                               -0.4 (0.3)      0.7  0.4-1.1

* P< .001.

+ P< .05.

EP = Estimated parameter, SE = standard error, OR = odds ratio, CI =
confidence interval, LDL = low density lipoproteins, HDL = high-density
lipoproteins, GOT = glutamate oxaloacetate transminase, GPT = glutamate
pyruvate transminase, GGT = gamma-gluatamyl transpeptidase.

Percent of subjects with and without fatty liver by sex.

       Non-fatty liver  Fatty liver

Women       72.3           27.7
Men         56.5           43.5

Total       63.1           36.9

Note: Table made from bar graph

References

(1.) Lonardo A: Fatty liver and nonalcoholic steatohepatitis. where do we stand and where are we going? Dig Dis 1999; 17:80-89

(2.) Bellentani S, Saccoccio G, Masutti F, et al: Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000; 132:112-117.

(3.) Teli MR, James OF, Burt AD, et al: The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995; 22:1714-1719

(4.) Day CP, Yeaman SJ: The biochemistry of alcohol-induced fatty liver. Biochem Biophys Acta 1994; 1215:33-48

(5.) O'Connor BJ, Kathamna B, Tavill AS: Nonalcoholic fatty liver (NASH syndrome). Gastroenterologist 1997; 5:316-329

(6.) Powell EE, Cooksley WG, Hanson R, et al: The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990; 11:74-80

(7.) Assy N, Kaita K, Mymin D, et al: Fatty infiltration of liver in hyperlipidemic patients. Dig Dis Sci 2000; 45:1929-1934

(8.) Wanless IR, Lentz JS: Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990; 12:1106-1110

(9.) Ludwig J, McGill DB, Lindor KD: Review: nonalcoholic steatohepatitis. J Gastroenterol Hepatol 1997; 12:398-403

(10.) Pares A, Tresserras R, Nunez I, et al: Prevalence and factors associated to the presence of fatty liver in apparently healthy adult men. Med Clin (Barc) 2000; 114:561-565

(11.) Lin SC, Shih SC, Kao CR, et al: Prevalence of antibodies to hepatitis C virus in patients with nonalcoholic fatty liver. Chung Hua I Hsueh Tsa Chih (Taipei) 1995; 56:80-85

(12.) Tacikowski T, Milewski B, Dzieniszewski J, et al: Liver steatosis assessed by ultrasonographic examination in patients with hyperlipoproteinemia. Wiad Lek 1994; 47:725-730

(13.) Lonardo A, Bellini M, Tartoni P, et al: The bright liver syndrome. prevalence and determinants of a "bright" liver echo pattern. Ital J Gastroenterol Hepatol 1997; 29:351-356

(14.) Nomura H, Kashiwagi S, Hayashi J, et al: Prevalence of fatty liver in a general population of Okinawa. Jpn J Med 1988; 27:142-149

(15.) Kawai N, Kawai T, Kawai K: Ultrasonic and laboratory studies on fatty liver in white-collar workers. Nippon Shokakibyo Gakkai Zasshi 1995; 92:1058-1065

(16.) Ikai E, Ishizaki M, Suzuki Y, et al: Association between hepatic steatosis, insulin resistance and hyperinsulinaemia as related to hypertension in alcohol consumers and obese people. J Hum Hypertens 1995; 9:101-105

(17.) Lin DY, Sheen IS, Chiu CT, et al: Clinical significance of ultrasonographic fatty liver in asymtomatics: analysis of 1040 check-up subjects. J Med Ultrasound 1993; 1:165-171

(18.) Lu SN, Wang LY, Chang WY, et al: Abdominal sonographic screening in a single community. Gaoxiong Yi Xue Ke Xue Za Zhi 1990; 6:643-646

(19.) Marceau P, Biron S, Hould FS, et al: Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab 1999; 84:1513-1517

(20.) Takeda T, Fujino A, Mizoue T, et al: Relationship between fatty liver and coronary risk factors. Sangyo Eiseigaku Zasshi 2000; 42:24-28

(21.) Knobler H, Schattner A, Zhornicki T, et al: Fatty liver--an additional and treatable feature of the insulin resistance syndrome. QJ Med 1999; 92:73-79

(22.) Umeki S, Hisamoto N, Hara Y: Study on background factors associated with impaired glucose tolerance and/or diabetes mellitus. Acta Endocrinol (Copenh) 1989; 120:729-734

(23.) Cortez-Pinto H, Camilo ME, Baptista A, et al: Non-alcoholic fatty liver: another feature of the metabolic syndrome? Clin Nutr 1999; 18:353-358

(24.) Leung KW, Liu JD, Chen PH, et al: Clinical significance and diagnosis of fatty liver in Taiwan. J Formosan Med Assoc 1986; 85:149-160

(25.) Tam KM, Wu JS: Ultrasonographic diagnosis of fatty liver. J Formosan Med Assoc 1986; 85:45-53

(26.) Huang PC, Yu SL, Lin YM, et al: Body weight of Chinese adults by sex, age and body height and criterion of obesity based on body mass index. J Chin Nutr Soc 1992; 17:157-172

(27.) Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993; 269:3015-3023

(28.) Summary of the national guidelines for the diagnosis and management of lipid disorders in Taiwan, the experts panel. Zhonghua Yi Xue Za Zhi (Taipei) 1995; 55:1-14

(29.) Friedwald WT, Levy RI, Fredrickson DS: Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 1972; 18:499-502

(30.) The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2000; 23:4-19

(31.) Summary of 1993 World Health Organization-International Society of Hypertension guidelines for the management of mild hypertension. Subcommittee of WHO/ISH Mild Hypertension Liaison committee. BMJ 1993; 307:1541-1546

(32.) Saggiani F, Pilati S, Targher G, et al: Serum uric acid and related factors in 500 hospitalized subjects. Metabolism 1996; 45:1557-1561

(33.) Cairns SR, Peters TJ: Biochemical analysis of hepatic lipid in alcoholic, diabetic and control subjects. Clin Sci 1983; 65:645-652

(34.) Luyckx FH, Desaive C, Thiry A, et al: Liver abnormalities in severely obese subjects: effects of drastic weight loss after gastroplasty. Int J Obes Relat Metab Disord 1998; 22:222-226

(35.) Lonardo A, Trande P: Are there any sex differences in fatty liver? a study of glucose metabolism and body fat distribution. J Gastroenterol Hepatol 2000; 15:775-782

(36.) Luyckx FH, Lefebvre PJ, Scheen AJ: Non-alcoholic steatohepatitis: association with obesity and insulin resistance, and influence of weight loss. Diabetes Metab 2000; 26:98-106

(37.) Adler M, Schaffer F: Fatty liver hepatitis and cirrhosis in obese patients. Am J Med 1979; 67:811-816

(38.) Sharabi Y, Eldad A: Nonalcoholic fatty liver disease is associated with hyperlipidemia and obesity. Am J Med 2000; 109:171

(39.) Galambos JT, Wills CE: Relationship between 505 paired liver test and biopsies in 242 obese patients. Gastroenterology 1978; 74:1191-1195

(40.) Daniel S, Ben-Menachem T, Vasudevan G, et al: Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients. Am J Gastroenterol 1999; 94:3010-3014

(41.) Noguchi H, Tazawa Y, Nishinomiya F, et al: The relationship between serum transaminase activities and fatty liver in children with simple obesity. Acta Paediatrica Japonica 1995; 37:621-625

(42.) Lin CC, Li TC, Lai SW, et al: Hypertriglyceridemia and the related factors in middle-aged adults in Taiwan. Mid Taiwan J Med 2001; 6:1-6

(43.) Ng KC, Lin CC, Lai SW, et al: Obesity and the related factors in middle-aged adults in Chung-Hsing village in Taiwan. Mid Taiwan J Med 2001; 6:35-39

(44.) Lai SW, Tan CK, Ng KC: Epidemiology of hyperuricemia in the elderly. Yale J Biol Med 2001; 74:151-157

(45.) Lin CC, Li TC, Lai SW, et al: Epidemiology of obesity in elderly people. Yale J Biol Med 1999; 72:385-391

RELATED ARTICLE: KEY POINTS

* Fatty liver affects about 36.9% of a population receiving periodic health examinations in Taiwan. This exceeds previous estimates (25.2%) and is higher than the prevalence in western countries (16.9% to 19.8%) and in Japan (14% to 22%).

* Men are affected more frequently than women (43.2% vs 27.7%).

* Factors related to fatty liver in Taiwan include male sex, obesity, hyperglycemia, hypertriglyceridemia, elevated glutamate pyruvate transaminase, and hyperuricemia.

* Alcohol intake was not associated with fatty liver disease in the population studied.

* Elevated glutamate oxaloacetate transaminase was negatively associated with fatty liver.

From the Departments of Community Medicine and Emergency Medicine, China Medical College Hospital, Taichung, Taiwan.

Reprint requets to Kim-Choy Ng, China Medical College Hospital, Department of Emergency Medicine, No. 2, Yuh-Der Road, Taichung, 404, Taiwan.