Hyperferritinemia in patients with nonalcoholic fatty liver disease

In liver diseases, hyperferritinemia (HYF) is related to injured cells in acquired and genetic conditions with or without iron overload. It is frequent in patients with nonalcoholic fatty liver disease (NAFLD), in which it is necessary to define the mean of HYF to establish the better approach for them. The present study evaluated the significance of elevated ferritin in patients with NAFLD and steatohepatitis (NASH).

Method:

The review was performed using search instruments of indexed scientific material, including MEDLINE (by PubMed), Web of Science, IBECS and LILACS, to identify articles published in Portuguese, English and Spanish, from 2005 to May, 2016. Studies eligible included place and year of publication, diagnose criteria to NAFLD, specifications of serum ferritin measurements and/or liver histopathologic study. Exclusion criteria included studies with patients with alcohol consumption ≥ 20 g/day and other liver diseases.

Results:

A total of 11 from 30 articles were selected. It included 3,564 patients and they were cross-sectional, retrospective, case series and case-control. The result's analyses showed in 10 of these studies a relationship between ferritin elevated serum levels and NAFLD/NASH with and without fibrosis and insulin resistance.

Conclusion:

Hyperferritinemia in patients with NAFLD/NASH is associated more frequently with hepatocellular injury than hemochromatosis. These data suggest the relevance to evaluate carefully HYF in patients with NAFLD/NASH to establish appropriate clinical approach.

Keywords:
nonalcoholic fatty liver disease; steatosis; steatohepatitis; hyperferritinemia

Authors	Year	N	Population	HPF/NASH associated
Brudevold et al.¹⁷17 Brudevold R, Hole T, Hammerstrøm J. Hyperferritinemia is associated with insulin resistance and fatty liver in patients without iron overload. PLoS ONE. 2008; 3(10):e3547.	2008	40	Patients with hyperferritinemia	HPF was related to increased levels of C-peptide (p<0.002) and age (p<0.002),as well as IR
Yoneda et al.¹²12 Yoneda M, Nozaki Y, Endo H, Mawatari H, Iida H, Fujita K, et al. Serum ferritin is a clinical biomarker in Japanese patients with nonalcoholic steatohepatitis (NASH) independent of HFE gene mutation. Dig Dis Sci. 2010; 55(3):808-14.	2010	106	Patients with NAFLD	HPF is associated with NASH (p=0.006) and correlated with HOMA-IR (r =0.212,p=0.048). Ideal ferritin cutoff point at 196 ng/mL (95CI 0.596-0.856, p=0.005)
Manousou et al.¹¹11 Manousou P, Kalambokis G, Grillo F, Watkins J, Xirouchakis E, Pleguezuelo M, et al. Serum ferritin is a discriminant marker for both fibrosis and inflammation in histologically proven non-alcoholic fatty liver disease patients. Liver Int. 2011; 31(5):730-9.	2011	111	Patients with NAFLD	HPF is associated with NASH (p=0.0001), portal (p=0.043) and lobular (p=0.009) inflammation, and AST (p=0.002)
Williamson et al.¹⁸18 Williamson RM, Price JF, Glancy S, Perry, E, Nee LD, Hayes PC, et al.; Edinburgh Type 2 Diabetes Study Investigators. Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty liver disease in people with type 2 diabetes: the Edinburgh type 2 diabetes study. Diabetes Care. 2011; 34(5):1139-44.	2011	939	Patients with MetS	Associated features of MetS can be used as screening for NAFLD/NASH
Zimmermann et al.¹⁶16 Zimmermann A, Zimmermann T, Schattenberg J, Pöttgen S, Lotz J, Rossmann H, et al. Alterations in lipid, carbohydrate and iron metabolism in patients with non-alcoholic steatohepatitis (NASH) and metabolic syndrome. Eur J Intern Med. 2011; 22(3):305-10.	2011	37	Patients with MetS	Higher insulinemia, C-peptide and IR in patients with NASH x non-NASH (p=0.034; 0.032 and 0.04)
Adams and Barton¹⁵15 Adams P, Barton J. A diagnostic approach to hyperferritinemia with a non-elevated transferrin saturation. J Hepatol. 2011; 55(2):453-8.	2011	-	Patients with hyperferritinemia	Serum ferritin has widely fluctuating values when associated with NASH/NAFLD
Kowdley et al.⁸8 Kowdley KV, Belt P, Wilson LA, Yeh MM, Neuschwander-Tetri BA, Chalasani N, et al.; NASH Clinical Research Network. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2012; 55(1):77-85.	2012	628	Patients with NAFLD	Ferritin > 1.5 times the ULN was independently associated with advanced hepatic fibrosis (OR 1.66, 95CI 1.05-2.62; p=0.028) and increased NAS score (OR 1.99, 95CI 1.06-3.75, p=0.033)
Nakajima et al.¹⁹19 Nakajima T, Nakashima T, Yamaoka J, Shibuya A, Itoh Y, Yoshikawa T. Age is a negative, and visceral fat accumulation is a contributor to hepatic steatosis, regardless of the progression in non-alcoholic fatty liver disease. J Gastroenterol Hepatol Res. 2012; 1(11):315-9.	2012	60	Patients with NAFLD	Steatosis/NAFLD correlates positively with area of visceral (r=0.321, p=0.0001) and subcutaneous (r=0.349, p<0.01) fat, and negatively with age (r=0.509,p<0.0001)
Chandok et al.³3 Chandok N, Minuk G, Wengiel M, Uhanova J. Serum ferritin levels do not predict the stage of underlying non-alcoholic fatty liver disease. J Gastrointestin Liver Dis. 2012; 21(1):53-8.	2012	482	Patients with NAFLD	Mean serum ferritin was similar in subjects with steatosis, NASH or cirrhosis (223.9 x 240.7 x 271.3, p=0.84)
Angulo et al.¹1 Angulo P, George J, Day CP, Vanni E, Russell L, De la Cruz AC, et al. Serum ferritin levels lack diagnostic accuracy for liver fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014; 12(7):1163-9.	2014	1,014	Patients undergoing liver biopsy	HPF correlates positively with the severity of fibrosis (p<0.001), with less accuracy in patients with NAFLD
Cippà et al.⁷7 Cippà PE, Boucsein I, Adams H, Krayenbuehl PA. Estimating iron overload in patients with suspected liver disease and elevated serum ferritin. Am J Med. 2014; 127(10):1011.e1-3.	2014	147	Patients with hyperferritinemia	Only ferritin > 2,000 mg/L predicts iron overload, and ferritin/AST ratio is a predictor of tissue iron overload with sensitivity of 83.3% and specificity of 78.6%

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[1] *Correspondence: Programa de Pós-Graduação em Medicina e Saúde, Address: Complexo Universitário Professor Edgard Santos, Rua Augusto Viana, 5º andar, Salvador, BA - Brazil, Postal code: 40110-060. helmacotrim@gmail.com