Abstract
Hypothyroidism is associated with the risk of development of the metabolic syndrome (MS) and hypercholesterolemia. Direct evidence that hypothyroidism might be associated with advanced chronic liver disease via nonalcoholic steatohepatitis (NASH) is limited. We studied the relationship between thyroid hormones, thyroid stimulating hormone (TSH), cholesterol, and NASH. In consecutive euthyroid patients with biopsy-proven nonalcoholic fatty liver disease, TSH and thyroid hormone (FT3 and FT4) concentrations were compared in 25 patients with steatosis and 44 non-cirrhotic NASH patients featuring concurrent ballooning, lobular inflammation and steatosis. The MS was diagnosed according to ATP III criteria. A meta-analysis of previously published studies was performed to evaluate whether NASH, compared to simple steatosis, is associated with lower cholesterol levels. At univariate analysis, compared to those with steatosis, patients with NASH have a wider waist, elevated levels of BMI, ALT, AST, fasting insulin, HOMA-IR, ferritin, TSH and a lower serum cholesterol. At stepwise multivariable logistic regression analysis, the independent predictors of NASH are high HOMA and TSH and lower total cholesterol (Model 1); MS and high TSH (Model 2). At meta-analysis, serum total cholesterol levels are significantly lower in predominantly non-cirrhotic NASH than in simple steatosis. This study provides cross-sectional and meta-analytic evidence that, in euthyroid patients, high-though-normal TSH values are independently associated with NASH. Further work is needed to ascertain the role, if any, of lower cholesterol serum levels in assisting in the diagnosis of NASH.
Similar content being viewed by others
Abbreviations
- Apo:
-
Apolipoprotein
- ALT:
-
Alanine aminotransferase
- AST:
-
Aspartate aminotransferase
- BMI:
-
Body Mass Index
- HDL:
-
High density lipoprotein
- HOMA-IR:
-
Homeostasis model assessment of insulin resistance
- IR:
-
Insulin resistance
- LDL:
-
Low density lipoprotein
- MS:
-
Metabolic syndrome
- NAFLD:
-
Nonalcoholic fatty liver disease
- NASH:
-
Nonalcoholic steatohepatitis
- TSH:
-
Thyroid stimulating hormone
- FT3:
-
Free thyroxine
- FT4:
-
Free triiodothyronine
References
Loria P, Carulli L, Bertolotti M, Lonardo A (2009) Endocrine and liver interaction: the role of endocrine pathways in NASH. Nat Rev Gastroenterol Hepatol 6:236–247
Vuppalanchi R, Chalasani N (2009) Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management. Hepatology 49:306–317
Eckel RH, Grundy SM, Zimmet PZ (2005) The metabolic syndrome. Lancet 365:1415–1428
Lin SY, Wang YY, Liu PH, Lai WA, Sheu WH (2005) Lower serum free thyroxine levels are associated with metabolic syndrome in a Chinese population. Metabolism 54:1524–1528
Baxter JD, Webb P (2009) Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov 8:308–320
George J, Liddle C (2008) Nonalcoholic fatty liver disease: pathogenesis and potential for nuclear receptors as therapeutic targets. Mol Pharm 5:49–59
Arrese M (2009) Burning hepatic fat: therapeutic potential for liver-specific thyromimetics in the treatment of nonalcoholic fatty liver disease. Hepatology 49:348–351
Wartofsky L, Dickey RA (2005) The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab 90:5483–5488
Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ (2004) Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 291:228–238
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2002) American Diabetes Association: clinical practice recommendations. Diabetes Care 25:S1–147
Mancia G, De Backer G, Dominiczak A et al (2007) 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 28:1462–1536
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2002) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143–3421
Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F, American Heart Association; National Heart, Lung, and Blood Institute (2005) Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 112:2735–2752
Brunt EM, Janney C, Di Bisceglie A et al (1999) Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 94:2467–2474
Dixon JB, Bhathal PS, O’Brien PE (2001) Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 121:91–100
Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M (2003) Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37:917–923
Boza C, Riquelme A, Ibañez L, Duarte I, Norero E, Viviani P, Soza A, Fernandez JI, Raddatz A, Guzman S, Arrese M (2005) Predictors of nonalcoholic steatohepatitis (NASH) in obese patients undergoing gastric bypass. Obes Surg 15:1148–1153
Ong JP, Elariny H, Collantes R, Younoszai A, Chandhoke V, Reines HD, Goodman Z, Younossi ZM (2005) Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes Surg 15:310–315
Harnois F, Msika S, Sabaté JM, Mechler C, Jouet P, Barge J, Coffin B (2006) Prevalence and predictive factors of non-alcoholic steatohepatitis (NASH) in morbidly obese patients undergoing bariatric surgery. Obes Surg 16:183–188
Abiru S, Migita K, Maeda Y, Daikoku M, Ito M, Ohata K, Nagaoka S, Matsumoto T, Takii Y, Kusumoto K, Nakamura M, Komori A, Yano K, Yatsuhashi H, Eguchi K, Ishibashi H (2006) Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis. Liver Int 26:39–45
Liang RJ, Wang HH, Lee WJ, Liew PL, Lin JT, Wu MS (2007) Diagnostic value of ultrasonographic examination for nonalcoholic steatohepatitis in morbidly obese patients undergoing laparoscopic bariatric surgery. Obes Surg 17:45–56
Park JW, Jeong G, Kim SJ, Kim MK, Park SM (2007) Predictors reflecting the pathological severity of non-alcoholic fatty liver disease: comprehensive study of clinical and immunohistochemical findings in younger Asian patients. J Gastroenterol Hepatol 22:491–497
Canbakan B, Senturk H, Tahan V, Hatemi I, Balci H, Toptas T, Sonsuz A, Velet M, Aydin S, Dirican A, Ozgulle S, Ozbay G (2007) Clinical, biochemical and histological correlations in a group of non-drinker subjects with non-alcoholic fatty liver disease. Acta Gastroenterol Belg 70:277–284
Chtioui H, Semela D, Ledermann M, Zimmermann A, Dufour JF (2007) Expression and activity of the cytochrome P450 2E1 in patients with nonalcoholic steatosis and steatohepatitis. Liver Int 27:764–771
García-Galiano D, Sánchez-Garrido MA, Espejo I, Montero JL, Costán G, Marchal T, Membrives A, Gallardo-Valverde JM, Muñoz-Castañeda JR, Arévalo E, De la Mata M, Muntané J (2007) IL-6 and IGF-1 are independent prognostic factors of liver steatosis and non-alcoholic steatohepatitis in morbidly obese patients. Obes Surg 17:493–503
Yamamoto M, Iwasa M, Iwata K, Kaito M, Sugimoto R, Urawa N, Mifuji R, Konishi M, Kobayashi Y, Adachi Y (2007) Restriction of dietary calories, fat and iron improves non-alcoholic fatty liver disease. J Gastroenterol Hepatol 22:498–503
Arvaniti VA, Thomopoulos KC, Tsamandas A, Makri M, Psyrogiannis A, Vafiadis G, Assimakopoulos SF, Labropoulou-Karatza C (2008) Serum adiponectin levels in different types of non alcoholic liver disease. Correlation with steatosis, necroinflammation and fibrosis. Acta Gastroenterol Belg. 71:355–360
Ma H, Gomez V, Lu L, Yang X, Wu X, Xiao SY (2009) Expression of adiponectin and its receptors in livers of morbidly obese patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 24:233–237
Nannipieri M, Cecchetti F, Anselmino M, Mancini E, Marchetti G, Bonotti A, Baldi S, Solito B, Giannetti M, Pinchera A, Santini F, Ferrannini E (2009) Pattern of expression of adiponectin receptors in human liver and its relation to nonalcoholic steatohepatitis. Obes Surg 19:467–474
Sookoian S, Castaño G, Burgueño AL, Gianotti TF, Rosselli MS, Pirola CJ (2009) A diagnostic model to differentiate simple steatosis from nonalcoholic steatohepatitis based on the likelihood ratio form of Bayes theorem. Clin Biochem 42:624–629
Uzunlulu M, Yorulmaz E, Oguz A (2007) Prevalence of subclinical hypothyroidism in patients with metabolic syndrome. Endocr J 54:71–76
Shantha GP, Kumar AA, Jeyachandran V, Rajamanickam D, Rajkumar K, Salim S, Subramanian KK, Natesan S (2009) Association between primary hypothyroidism and metabolic syndrome and the role of C reactive protein: a cross-sectional study from South India. Thyroid Res 2:2
Liangpunsakul S, Chalasani N (2003) Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J Clin Gastroenterol 37:340–343
Reddy A, Dash C, Leerapun A, Mettler TA, Stadheim LM, Lazaridis KN et al (2007) Hypothyroidism: a possible risk factor for liver cancer in patients with no known underlying cause of liver disease. Clin Gastroenterol Hepatol 5:118–123
Hassan MM, Kaseb A, Li D, Patt YZ, Vauthey JN, Thomas MB, Curley SA, Spitz MR, Sherman SI, Abdalla EK, Davila M, Lozano RD, Hassan DM, Chan W, Brown TD, Abbruzzese JL (2009) Association between hypothyroidism and hepatocellular carcinoma: a case–control study in the United States. Hepatology 49:1563–1570
Reinher T (2010) Obesity and thyroid function. Mol Cell Endocrinol 316:165–171
Alberiche M, Boronat M, Saavedra P, Pérez N, Marrero D, López-Plasencia Y, Varillas VF, Ríos M, Nóvoa FJ (2009) Thyrotropin levels and their relationship with cardiovascular risk factors in the island of Gran Canaria, Spain. Implications of lowering the upper reference limit of thyrotropin stimulating hormone. J Endocrinol Invest 32:102–106
Park HT, Cho GJ, Ahn KH, Shin JH, Hong SC, Kim T, Hur JY, Kim YT, Lee KW, Kim SH (2009) Thyroid stimulating hormone is associated with metabolic syndrome in euthyroid postmenopausal women. Maturitas 62:301–305
Mason RL, Hunt HM, Hurxthal L (1930) Blood cholesterol values in hyperthyroidism and hypothyroidism: their significance. New Engl J Med 203:1273–1278
D’Arienzo A, Manguso F, Scaglione G, Vicinanza G, Bennato R, Mazzacca G (1998) Prognostic value of progressive decrease in serum cholesterol in predicting survival in Child-Pugh C viral cirrhosis. Scand J Gastroenterol 33:1213–1218
Bookman ID, Pham J, Guindi M, Heathcote EJ (2006) Distinguishing nonalcoholic steatohepatitis from fatty liver: serum-free fatty acids, insulin resistance, and serum lipoproteins. Liver Int 26:566–571
Tokushige K, Takakura M, Tsuchiya-Matsushita N, Taniai M, Hashimoto E, Shiratori K (2007) Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J Hepatol 46:1104–1110
Acknowledgments
English Editing of the manuscript by courtesy of Jacqueline Mole is gratefully acknowledged.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Carulli, L., Ballestri, S., Lonardo, A. et al. Is nonalcoholic steatohepatitis associated with a high-though-normal thyroid stimulating hormone level and lower cholesterol levels?. Intern Emerg Med 8, 297–305 (2013). https://doi.org/10.1007/s11739-011-0609-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11739-011-0609-4