This article has been corrected. See "Corrigendum: Clinical Correlation between Serum Cytokeratin-18 and Metabolic Parameters in Patients with Sonographic Non-alcoholic Fatty Liver Disease" in Volume 64 on page 315.
PDF
ePub
Citation
Print
Abstract
Background/Aims
The serum cytokeratin-18 (CK-18) has been suggested to be a surrogate marker of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the correlation between CK-18 and metabolic parameter in NAFLD patients. Correlation between CK-18 and macronutrient composition was also assessed.
Methods
A total of 212 subjects were recruited. Blood chemistry including fasting glucose, cholesterol level, AST, ALT, and CK-18 were compared. Data on calorie intake and carbohydrate consumption were acquired by five-day-diet diary using 24 hour recall method.
Results
Plasma CK-18 were markedly increased in patient with NAFLD compared with control group (420.4±282.3 vs. 313.6±179, p<0.001). Plasma CK-18 were positively correlated with systolic blood pressure (r=0.130), ALT (r=0.503) and negatively correlated with HDL cholesterol (r=−0.246). NAFLD patients with metabolic syndrome had higher CK-18 level than those without metabolic syndrome (484.0 vs. 372.1 U/L, p=0.021). When NAFLD patients were subdivided into two groups with CK-18 cutoff value of 400 U/L, patients with CK-18 level over 400 U/L showed higher body mass index (28.0±4.5 vs. 25.5±4.3), subcutaneous abdominal fat (283.5±172.2 vs. 195.7±147.8), AST (52.7±26.3 vs. 40.7±23.5) and ALT (102.0±52.6 vs. 61.2±32.2). Calorie intake (r=0.301) and carbohydrate intake (r=0.305) also showed positive correlation with CK-18.
References
1. Jeong EH, Jun DW, Cho YK, et al. Regional prevalence of nonalcoholic fatty liver disease in Seoul and Gyeonggi-do, Korea. Clin Mol Hepatol. 2013; 19:266–272.
2. Park YJ, Lim JH, Kwon ER, et al. Development and validation of a simple index system to predict nonalcoholic fatty liver disease. Korean J Hepatol. 2011; 17:19–26.
3. Ekstedt M, Franzén LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006; 44:865–873.
4. Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology. 2006; 44:27–33.
5. Feldstein AE, Werneburg NW, Canbay A, et al. Free fatty acids pro-mote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology. 2004; 40:185–194.
6. Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006; 18:21–29.
7. Papatheodoridis GV, Hadziyannis E, Tsochatzis E, et al. Serum apoptotic caspase activity as a marker of severity in HBeAg-negative chronic hepatitis B virus infection. Gut. 2008; 57:500–506.
8. Abdel Haleem H, Zayed N, Abdel Hafez H, et al. Evaluation of the diagnostic value of serum and tissue apoptotic cytokeratin-18 in patients with chronic hepatitis C. Arab J Gastroenterol. 2013; 14:68–72.
9. Gonzalez-Quintela A, García J, Campos J, et al. Serum cytoker-atins in alcoholic liver disease: contrasting levels of cytoker-atin-18 and cytokeratin-19. Alcohol. 2006; 38:45–49.
10. Zeng MD, Fan JG, Lu LG, et al. Chinese National Consensus Workshop on Nonalcoholic Fatty Liver Disease. Guidelines for the diagnosis and treatment of nonalcoholic fatty liver diseases. J Dig Dis. 2008; 9:108–112.
11. Han JM, Jo AN, Lee SM, et al. Associations between intakes of individual nutrients or whole food groups and nonalcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol. 2014; 29:1265–1272.
12. Alberti KG, Eckel RH, Grundy SM, et al. International Diabetes Federation Task Force on Epidemiology and Prevention; Hational Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009; 120:1640–1645.
13. Shim YJ, Paik HY. Reanalysis of 2007 Korean national health and nutrition examination survey (2007 KNHANES) results by CAN-Pro 3.0 nutrient database. Korean J Nutr. 2009; 42:577–595.
14. The Korean Dietetic Assocation. Guessing food amount by picture. Seoul: KDA;1999.
15. Hyun WJ, Song GH, Choi MK, Son SM. Food enegy and nutrient composition table easy to understand. Seoul: The Korean Society of Community Nutrition;2007.
16. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005; 129:113–121.
17. Kim YS, Jung ES, Hur W, et al. Noninvasive predictors of nonalcoholic steatohepatitis in Korean patients with histologically proven nonalcoholic fatty liver disease. Clin Mol Hepatol. 2013; 19:120–130.
18. Kwok R, Tse YK, Wong GL, et al. Systematic review with meta-analysis: noninvasive assessment of nonalcoholic fatty liver disease–the role of transient elastography and plasma cy-tokeratin-18 fragments. Aliment Pharmacol Ther. 2014; 39:254–269.
19. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012; 142:1592–1609.
20. Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol. 2013; 19:325–348.
21. Miyasato M, Murase-Mishiba Y, Bessho M, et al. The cytoker-atin-18 fragment level as a biomarker of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Clin Chim Acta. 2014; 433:184–189.
22. Cusi K, Chang Z, Harrison S, et al. Limited value of plasma cyto-keratin-18 as a biomarker for NASH and fibrosis in patients with nonalcoholic fatty liver disease. J Hepatol. 2014; 60:167–174.
23. Hession M, Rolland C, Kulkarni U, Wise A, Broom J. Systematic review of randomized controlled trials of low-carbohydrate vs. low-fat/low-calorie diets in the management of obesity and its comorbidities. Obes Rev. 2009; 10:36–50.
Fig. 1.
Serum cytokeratin-18 (CK-18) level according to disease subgroups. Serum CK-18 level of nonalcoholic fatty liver disease (NAFLD) group was higher than that of control group. Presence of metabolic syndrome (MS) further increased serum CK-18 level in patients with nonalcoholic fatty liver disease. p<0.05 by ANOVA test.
Table 1.
Baseline Characteristic of Nonalcoholic Fatty Liver Disease (NAFLD) and Healthy Control
| Characteristic | Control (n=106) | NAFLD (n=106) | p-value |
|---|---|---|---|
| Age (yr) | 42.54 | 43.01 | 0.590 |
| Sex (male) | 71 (66.9) | 63 (59.4) | 0.221 |
| Systolic blood pressure (mmHg) | 120.5±12.7 | 126.4±14.1 | 0.001∗ |
| Diastolic blood pressure (mmHg) | 75.2±8.0 | 76.9±10.5 | 0.135 |
| AST (U/L) | 32.5±22.4 | 51.6±27.8 | <0.001∗ |
| ALT (U/L) | 48.9±44.9 | 87.4±43.4 | <0.001∗ |
| Fasting glucose (mg/dL) | 94.7±15.4 | 103.3±19.2 | <0.001∗ |
| Total cholesterol (mg/dL) | 182.5±34.8 | 199.0±35.0 | <0.001∗ |
| Triglyceride (mg/dL) | 127.3±83.0 | 182.6±130.0 | <0.001∗ |
| HDL-cholesterol (mg/dL) | 52.6±13.9 | 44.5±8.7 | <0.001∗ |
| LDL-cholesterol (mg/dL) | 105.9±30.8 | 129.3±58.8 | <0.001∗ |
| Cytokeratin-18 (U/L) | 313.6±179.3 | 420.4±282.3 | <0.001∗ |
Table 2.
Relationship between Serum Cytokeratin-18 and Clinical Parameters
| Clinical parameter | r | p-value |
|---|---|---|
| Age | −0.246 | 0.020∗ |
| Systolic blood pressure | 0.130 | 0.036∗ |
| Diastolic blood pressure | 0.073 | 0.236 |
| AST | 0.361 | <0.001∗ |
| ALT | 0.503 | <0.001∗ |
| Fasting glucose | 0.108 | 0.085 |
| Total cholesterol | −0.10 | 0.878 |
| Triglyceride | 0.105 | 0.096 |
| HDL-cholesterol | −0.249 | <0.001∗ |
| LDL-cholesterol | 0.043 | 0.502 |
Table 3.
Clinical Characteristics according to Serum Cytokeratin-18 (CK-18) Level in Patients with Nonalcoholic Fatty Liver Disease
| Variable | CK-18≤400 (n=72) | CK-18>400 (n=34) | p-value |
|---|---|---|---|
| BMI (kg/m2) | 25.5±4.3 | 28.0±4.5 | 0.002∗ |
| Age (yr) | 44.5±10.4 | 40.4±12.7 | 0.025∗ |
| AST (U/L) | 40.7±23.5 | 52.7±26.3 | 0.003∗ |
| ALT (U/L) | 61.2±32.2 | 102.0±52.6 | <0.001∗ |
| Insulin | 13.0±13.7 | 19.9±20.1 | 0.020∗ |
| Glucose (mg/dL) | 104.6±18.0 | 102.4±15.8 | 0.438 |
| Cholesterol (mg/dL) | 201.2±33.5 | 189.0±34.8 | 0.030∗ |
| Waist (cm) | 88.6±10.2 | 95.6±12.2 | <0.001∗ |
| Visceral fat (HU) | 136.9±60.4 | 158.9±55.0 | 0.024∗ |
| Subcutaneous abdominal fat (HU) | 195.7±147.8 | 283.5±172.2 | 0.001∗ |
| Total abdominal fat (HU) | 332.6±193.3 | 442.5±208.7 | 0.001∗ |
| Liver (HU) | 47.8±10.8 | 41.5±14.1 | 0.001∗ |
| Liver/spleen HU ratio | 0.94±0.22 | 0.80±0.29 | 0.001∗ |
Table 4.
Relationship between Serum Cytokeratin-18 and Dietary Habit
Table 5.
Relationship between Serum Cytokeratin-18 (CK-18) and Macronutrients
| Macronutrients composition | CK-18≤400 (n=72) | CK-18>400 (n=34) | p-value |
|---|---|---|---|
| Energy intake (kcal) | 1,772.8±359.5 | 1,962.8±553.3 | 0.009∗ |
| Carbohydrate intake (g) | 260.2±55.7 | 287.1±80.4 | 0.014∗ |
| Fat intake (g) | 47.5±16.7 | 55.6±24.9 | 0.015∗ |
| Protein intake (g) | 70.9±17.7 | 78.0±23.0 | 0.033∗ |
| Natrium intake (mg) | 3,724.7±1,147.3 | 4,181.3±1483.0 | 0.032∗ |
| Natrium intake/total intake amount | 301.0±84.6 | 330.7±101.9 | 0.051 |
XML Download