Skip to main content
×
×
Home

Elevated alanine aminotransferase independently predicts new onset of depression in employees undergoing health screening examinations

  • S. Zelber-Sagi (a1) (a2), S. Toker (a3), G. Armon (a4), S. Melamed (a5) (a6), S. Berliner (a6) (a7), I. Shapira (a6) (a7), Z. Halpern (a1) (a6), E. Santo (a1) (a6) and O. Shibolet (a1) (a6)...
Abstract
Background

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of elevated alanine aminotransferase (ALT). NAFLD is associated with insulin resistance and hepatic inflammation. Similarly, patients with depression exhibit insulin resistance and increased inflammatory markers. However, no study has shown a clear association between elevated ALT and the development of depression. The aim of the study was to test whether elevated ALT, a surrogate marker for NAFLD, predicts the development of depression.

Method

The present prospective cohort study investigated 12 180 employed adults referred for health examinations that included fasting blood tests and anthropometric measurements between 2003 and 2010. Exclusion criteria were: baseline minor/major depression, excessive alcohol consumption and other causes for ALT elevation. Depression was evaluated by the eight-item Patient Health Questionnaire (PHQ-8) score.

Results

The final cohort included 5984 subjects [69.4% men, aged 45.0 (s.d. = 10.24) years]. The incidence rate of minor and major depression was 3.8% and 1.4%, respectively. Elevated ALT was a significant independent predictor for the occurrence of minor [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.40–2.92] and major (OR 3.132, 95% CI 1.81–5.40) depression after adjusting for age, gender, body mass index, education level, serum levels of lipids, glucose, smoking and physical activity. Adding subjective health and affective state parameters (sleep disturbances, self-rated health, anxiety and burnout) as potential mediators only slightly ameliorated the association. Persistently elevated ALT was associated with the greatest risk for minor or major depression as compared with elevation only at baseline or follow-up (p for trend < 0.001).

Conclusions

Elevated ALT was associated with developing depressive symptoms, thus suggesting that NAFLD may represent an independent modifiable risk factor for depression.

Copyright
Corresponding author
*Address for correspondence: O. Shibolet, M.D., Liver Unit, Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel. (Email: orensh@tasmc.health.gov.il)
References
Hide All
Andersen, LB, Harro, M, Sardinha, LB, Froberg, K, Ekelund, U, Brage, S, Anderssen, SA (2006). Physical activity and clustered cardiovascular risk in children: a cross-sectional study (The European Youth Heart Study). Lancet 368, 299304.
Anderson, RJ, Freedland, KE, Clouse, RE, Lustman, PJ (2001). The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 24, 10691078.
Andre, F (2000). Hepatitis B epidemiology in Asia, the Middle East and Africa. Vaccine 18 (Suppl. 1), S20S22.
Anisman, H, Merali, Z, Hayley, S (2008). Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders. Progress in Neurobiology 85, 174.
Armstrong, MJ, Houlihan, DD, Bentham, L, Shaw, JC, Cramb, R, Olliff, S, Gill, PS, Neuberger, JM, Lilford, RJ, Newsome, PN (2012). Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort. Journal of Hepatology 56, 234240.
Ayalon, L, Goldfracht, M, Bech, P (2010). ‘Do you think you suffer from depression?’ Reevaluating the use of a single item question for the screening of depression in older primary care patients. International Journal of Geriatric Psychiatry 25, 497502.
Bar-Shany, S, Green, MS, Slepon, R, Shinar, E (1995). Ethnic differences in the prevalence of anti-hepatitis C antibodies and hepatitis B surface antigen in Israeli blood donors by age, sex, country of birth and origin. Journal of Viral Hepatitis 2, 139144.
Basaranoglu, M, Kayacetin, S, Yilmaz, N, Kayacetin, E, Tarcin, O, Sonsuz, A (2010). Understanding mechanisms of the pathogenesis of nonalcoholic fatty liver disease. World Journal of Gastroenterology 16, 22232226.
Baumeister, SE, Volzke, H, Marschall, P, John, U, Schmidt, CO, Flessa, S, Alte, D (2008). Impact of fatty liver disease on health care utilization and costs in a general population: a 5-year observation. Gastroenterology 134, 8594.
Bedogni, G, Miglioli, L, Masutti, F, Tiribelli, C, Marchesini, G, Bellentani, S (2005). Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 42, 4452.
Bellentani, S, Saccoccio, G, Masutti, F, Croce, LS, Brandi, G, Sasso, F, Cristanini, G, Tiribelli, C (2000). Prevalence of and risk factors for hepatic steatosis in Northern Italy. Annals of Internal Medicine 132, 112117.
Brown, ES, Varghese, FP, McEwen, BS (2004). Association of depression with medical illness: does cortisol play a role? Biological Psychiatry 55, 19.
Browning, JD, Szczepaniak, LS, Dobbins, R, Nuremberg, P, Horton, JD, Cohen, JC, Grundy, SM, Hobbs, HH (2004). Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 13871395.
Bugianesi, E, Moscatiello, S, Ciaravella, MF, Marchesini, G (2010). Insulin resistance in nonalcoholic fatty liver disease. Current Pharmaceutical Design 16, 19411951.
Chen, PH, Chen, JD, Lin, YC (2009). A better parameter in predicting insulin resistance: obesity plus elevated alanine aminotransferase. World Journal of Gastroenterology 15, 55985603.
Clark, JM, Diehl, AM (2003). Defining nonalcoholic fatty liver disease: implications for epidemiologic studies. Gastroenterology 124, 248250.
Cowen, PJ (2010). Editorial: not fade away: the HPA axis and depression. Psychological Medicine 40, 14.
Dan, AA, Kallman, JB, Wheeler, A, Younoszai, Z, Collantes, R, Bondini, S, Gerber, L, Younossi, ZM (2007). Health-related quality of life in patients with non-alcoholic fatty liver disease. Alimentary Pharmacology and Therapeutics 26, 815820.
Dantzer, R, O'Connor, JC, Freund, GG, Johnson, RW, Kelley, KW (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews Neuroscience 9, 4656.
Dantzer, R, O'Connor, JC, Lawson, MA, Kelley, KW (2011). Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology 36, 426436.
David, K, Kowdley, KV, Unalp, A, Kanwal, F, Brunt, EM, Schwimmer, JB (2009). Quality of life in adults with nonalcoholic fatty liver disease: baseline data from the nonalcoholic steatohepatitis clinical research network. Hepatology 49, 19041912.
DeSalvo, KB, Bloser, N, Reynolds, K, He, J, Muntner, P (2006). Mortality prediction with a single general self-rated health question. A meta-analysis. Journal of General Internal Medicine 21, 267275.
Elwing, JE, Lustman, PJ, Wang, HL, Clouse, RE (2006). Depression, anxiety, and nonalcoholic steatohepatitis. Psychosomatic Medicine 68, 563569.
Fracanzani, AL, Valenti, L, Bugianesi, E, Andreoletti, M, Colli, A, Vanni, E, Bertelli, C, Fatta, E, Bignamini, D, Marchesini, G, Fargion, S (2008). Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology 48, 792798.
Fracanzani, AL, Valenti, L, Bugianesi, E, Vanni, E, Grieco, A, Miele, L, Consonni, D, Fatta, E, Lombardi, R, Marchesini, G, Fargion, S (2011). Risk of nonalcoholic steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease and low visceral adiposity. Journal of Hepatology 54, 12441249.
French, JRP, Caplan, RD, Harrison, RV (1982). The Mechanisms of Job Stress and Strain. John Wiley and Sons: Chichester.
Fujii, H, Kawada, N (2012). Inflammation and fibrogenesis in steatohepatitis. Journal of Gastroenterology 47, 215225.
Green, RM, Flamm, S (2002). AGA technical review on the evaluation of liver chemistry tests. Gastroenterology 123, 13671384.
Gutteling, JJ, de Man, RA, van der Plas, SM, Schalm, SW, Busschbach, JJ, Darlington, AS (2006). Determinants of quality of life in chronic liver patients. Alimentary Pharmacology and Therapeutics 23, 16291635.
Herrera-Marquez, R, Hernandez-Rodriguez, J, Medina-Serrano, J, Boyzo-Montes de Oca, A, Manjarrez-Gutierrez, G (2011). Association of metabolic syndrome with reduced central serotonergic activity. Metabolic Brain Disease 26, 2935.
Hobfoll, SE, Canetti, D, Hall, BJ, Brom, D, Palmieri, PA, Johnson, RJ, Pat-Horenczyk, R, Galea, S (2011). Are community studies of psychological trauma's impact accurate? A study among Jews and Palestinians. Psychological Assessment 23, 599605.
Hobfoll, SE, Canetti-Nisim, D, Johnson, RJ (2006). Exposure to terrorism, stress-related mental health symptoms, and defensive coping among Jews and Arabs in Israel. Journal of Consulting and Clinical Psychology 74, 207218.
Insel, TR, Charney, DS (2003). Research on major depression: strategies and priorities. Journal of the American Medical Association 289, 31673168.
Kariv, R, Leshno, M, Beth-Or, A, Strul, H, Blendis, L, Kokia, E, Noff, D, Zelber-Sagie, S, Sheinberg, B, Oren, R, Halpern, Z (2006). Re-evaluation of serum alanine aminotransferase upper normal limit and its modulating factors in a large-scale population study. Liver International 26, 445450.
Kashyap, SR, Diab, DL, Baker, AR, Yerian, L, Bajaj, H, Gray-McGuire, C, Schauer, PR, Gupta, M, Feldstein, AE, Hazen, SL, Stein, CM (2009). Triglyceride levels and not adipokine concentrations are closely related to severity of nonalcoholic fatty liver disease in an obesity surgery cohort. Obesity (Silver Spring) 17, 16961701.
Kerkar, N, D'Urso, C, Van Nostrand, K, Kochin, I, Gault, A, Suchy, F, Miloh, T, Arnon, R, Chu, J, Annunziato, R (2013). Psychosocial outcomes for children with nonalcoholic fatty liver disease over time and compared to obese controls. Journal of Pediatric Gastroenterology and Nutrition 56, 7782.
Kroenke, K, Spitzer, RL, Williams, JBW, Löwe, B (2010). The Patient Health Questionnaire Somatic, Anxiety, and Depressive Symptom Scales: a systematic review. General Hospital Psychiatry 32, 345359.
Kroenke, K, Strine, TW, Spitzer, RL, Williams, JB, Berry, JT, Mokdad, AH (2009). The PHQ-8 as a measure of current depression in the general population. Journal of Affective Disorders 114, 163173.
Lee, CK, Jonas, MM (2007). High prevalence of psychiatric and attention-deficit/hyperactivity disorders in children with NAFLD at children's hospital Boston 1995–2005: a retrospective study. Gastroenterology 132, A738A739.
Lett, HS, Blumenthal, JA, Babyak, MA, Sherwood, A, Strauman, T, Robins, C, Newman, MF (2004). Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosomatic Medicine 66, 305315.
Lotrich, FE, El-Gabalawy, H, Guenther, LC, Ware, CF (2011). The role of inflammation in the pathophysiology of depression: different treatments and their effects. Journal of Rheumatology Supplement 88, 4854.
Marchesini, G, Brizi, M, Bianchi, G, Tomassetti, S, Bugianesi, E, Lenzi, M, McCullough, AJ, Natale, S, Forlani, G, Melchionda, N (2001). Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50, 18441850.
Milaneschi, Y, Corsi, AM, Penninx, BW, Bandinelli, S, Guralnik, JM, Ferrucci, L (2009). Interleukin-1 receptor antagonist and incident depressive symptoms over 6 years in older persons: the InCHIANTI study. Biological Psychiatry 65, 973978.
Miller, AH (2009). Norman Cousins Lecture. Mechanisms of cytokine-induced behavioral changes: psychoneuroimmunology at the translational interface. Brain Behavior and Immunity 23, 149158.
Miller, GE, Freedland, KE, Carney, RM, Stetler, CA, Banks, WA (2003). Pathways linking depression, adiposity, and inflammatory markers in healthy young adults. Brain Behavior and Immunity 17, 276285.
Moussavi, S, Chatterji, S, Verdes, E, Tandon, A, Patel, V, Ustun, B (2007). Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet 370, 851858.
Muldoon, MF, Mackey, RH, Korytkowski, MT, Flory, JD, Pollock, BG, Manuck, SB (2006). The metabolic syndrome is associated with reduced central serotonergic responsivity in healthy community volunteers. Journal of Clinical Endocrinology and Metabolism 91, 718721.
Newton, JL, Jones, DE, Henderson, E, Kane, L, Wilton, K, Burt, AD, Day, CP (2008). Fatigue in non-alcoholic fatty liver disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance. Gut 57, 807813.
Nguyen, QM, Srinivasan, SR, Xu, JH, Chen, W, Hassig, S, Rice, J, Berenson, GS (2011). Elevated liver function enzymes are related to the development of prediabetes and type 2 diabetes in younger adults: the Bogalusa Heart Study. Diabetes Care 34, 26032607.
Omagari, K, Takamura, R, Matsutake, S, Ichimura, M, Kato, S, Morikawa, S, Nagaoka, S, Osabe, M (2011). Serum alanine aminotransferase concentration as a predictive factor for the development or regression of fatty liver. Journal of Clinical Biochemisty and Nutrition 49, 200206.
Pearson, S, Schmidt, M, Patton, G, Dwyer, T, Blizzard, L, Otahal, P, Venn, A (2010). Depression and insulin resistance: cross-sectional associations in young adults. Diabetes Care 33, 11281133.
Prati, D, Taioli, E, Zanella, A, Della Torre, E, Butelli, S, Del Vecchio, E, Vianello, L, Zanuso, F, Mozzi, F, Milani, S, Conte, D, Colombo, M, Sirchia, G (2002). Updated definitions of healthy ranges for serum alanine aminotransferase levels. Annals of Internal Medicine 137, 110.
Pratt, DS, Kaplan, MM (2000). Evaluation of abnormal liver-enzyme results in asymptomatic patients. New England Journal of Medicine 342, 12661271.
Pressler, SJ, Subramanian, U, Perkins, SM, Gradus-Pizlo, I, Kareken, D, Kim, J, Ding, Y, Sauvé, MJ, Sloan, R (2011). Measuring depressive symptoms in heart failure: validity and reliability of the Patient Health Questionnaire-8. American Journal of Critical Care 20, 146152.
Raison, CL, Capuron, L, Miller, AH (2006). Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in Immunology 27, 2431.
Richards, D (2011). Prevalence and clinical course of depression: a review. Clinical Psychology Review 31, 11171125.
Richardson, CR, Kriska, AM, Lantz, PM, Hayward, RA (2004). Physical activity and mortality across cardiovascular disease risk groups. Medicine and Science in Sports and Exercise 36, 19231929.
Sayuk, GS, El-Dirani, S, Elwing, JE, Lustman, P, Lisker-Melman, M, Crippin, JS, Clouse, RE (2007). Severity of depression symptoms and transaminase levels are related in non-alcoholic steatohepatitis (NASH) and chronic hepatitis C. Gastroenterology 132, A-813.
Schillinger, M, Exner, M, Amighi, J, Mlekusch, W, Sabeti, S, Rumpold, H, Wagner, O, Minar, E (2003). Joint effects of C-reactive protein and glycated hemoglobin in predicting future cardiovascular events of patients with advanced atherosclerosis. Circulation 108, 23232328.
Sermoneta-Gertel, S, Donchin, M, Adler, R, Baras, M, Perlstein, T, Manny, N, Shouval, D, Galun, E (2001). Hepatitis C virus infection in employees of a large university hospital in Israel. Infection Control and Hospital Epidemiology 22, 754761.
Shirom, A (1989). Burnout in work organizations. In International Review of Industrial and Organizational Psychology (ed. Cooper, C. L. and Robertson, I.), pp. 2548. Wiley: New York.
Shirom, A (2003). Job-related burnout. In Handbook of Occupational Health Psychology (ed. Quick, J. C. and Tetrick, L. E.), pp. 245265. American Psychological Association: Washington, DC.
Silva, N, Atlantis, E, Ismail, K (2011). A review of the association between depression and insulin resistance: pitfalls of secondary analyses or a promising new approach to prevention of type 2 diabetes? Current Psychiatry Reports 14, 814.
Simon, GE, Goldberg, DP, Von Korff, M, Ustun, TB (2002). Understanding cross-national differences in depression prevalence. Psychological Medicine 32, 585594.
Soldatos, CR, Dikeos, DG, Paparrigopoulos, TJ (2000). Athens Insomnia Scale: validation of an instrument based on ICD-10 criteria. Journal of Psychosomatic Research 48, 555560.
Stanca, CM, Bach, N, Krause, C, Tandon, N, Freni, MA, Gutierrez, JA, Bodian, C, Lopez, J, Berk, PD, Bodenheimer, HC Jr, Branch, AD, Odin, JA (2005). Evaluation of fatigue in U.S. patients with primary biliary cirrhosis. American Journal of Gastroenterology 100, 11041109.
Suzuki, A, Binks, M, Wachholtz, A, Diehl, AM (2007). Relationship of psychological issues and sleep disturbance to liver function in obese patients at a residential weight loss program. Gastroenterology 132, A-811.
Swain, MG (2006). Fatigue in liver disease: pathophysiology and clinical management. Canadian Journal of Gastroenterology 20, 181188.
Taylor, VH, Macqueen, GM (2010). The role of adipokines in understanding the associations between obesity and depression. Journal of Obesity 2010, 748048.
Tilg, H (2010). The role of cytokines in non-alcoholic fatty liver disease. Digestive Diseases 28, 179185.
Timonen, M, Laakso, M, Jokelainen, J, Rajala, U, Meyer-Rochow, VB, Keinanen-Kiukaanniemi, S (2005). Insulin resistance and depression: cross sectional study. British Medical Journal 330, 1718.
Toker, S, Biron, M (2012). Job burnout and depression: unraveling their temporal relationship and considering the role of physical activity. Journal of Applied Psychology 97, 699710.
Toker, S, Shirom, A, Melamed, S (2008). Depression and the metabolic syndrome: gender-dependent associations. Depression and Anxiety 25, 661669.
Weinstein, AA, Kallman Price, J, Stepanova, M, Poms, LW, Fang, Y, Moon, J, Nader, F, Younossi, ZM (2011). Depression in patients with nonalcoholic fatty liver disease and chronic viral hepatitis B and C. Psychosomatics 52, 127132.
Wong, VW, Wong, GL, Choi, PC, Chan, AW, Li, MK, Chan, HY, Chim, AM, Yu, J, Sung, JJ, Chan, HL (2010). Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 59, 969974.
Younossi, ZM, Boparai, N, Price, LL, Kiwi, ML, McCormick, M, Guyatt, G (2001). Health-related quality of life in chronic liver disease: the impact of type and severity of disease. American Journal of Gastroenterology 96, 21992205.
Zelber-Sagi, S, Nitzan-Kaluski, D, Halpern, Z, Oren, R (2006). Prevalence of primary non-alcoholic fatty liver disease in a population-based study and its association with biochemical and anthropometric measures. Liver International 26, 856863.
Zelber-Sagi, S, Ratziu, V, Oren, R (2011). Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence. World Journal of Gastroenterology 17, 33773389.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed