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To the Editor:

We would like to comment on the paper by Cammà et al.,1 who report on gender differences in hepatitis C virus (HCV)-related steatosis and on elevated gamma-glutamyl transferase (GGT) values as a predictor of poor response to antiviral treatment.1 In our opinion, these data could be better understood taking into account that HCV genotype 1-related steatosis closely resembles non-alcoholic fatty liver disease (NAFLD).2

Interestingly, in unselected consecutive subjects referred by General Practitioners for the evaluation of a “bright” liver at ultrasound scanning and enrolled in the POLISTENA study, NAFLD also displays a gender-dimorphic pattern. Indeed, in the majority of studies published in the 2000-2005 literature,3 it occurs more frequently in the male gender.4 It is amazing that our results, which were collected in a series recruited in the GPs offices in Modena,4 closely mirror those by Marchesini et al. in Bologna and Turin,5 in the context of metabolic and liver Units (Table 1). These data indicate that male patients with NAFLD are approximately 10 years younger than women with this condition. Women, though, tend to have a higher prevalence of metabolic derangements evaluated according to Adult Treatment Panel III.

Table 1. Demographic, Anthropometric and Metabolic Features of NAFLD Patients According to Gender in the Modena and in the Bologna/Turin Study4, 5
VariablesStudyOverallMalesFemalesP values
  • NOTE. The studies included 161 NAFLD patients (96 males, 65 females) in Modena and 304 (252 males and 52 females) in Bologna/Turin. Data are presented as means ± SE4 or ± SD5 or as prevalence.

  • Abbreviations: M, male; F, female; NS, not significant.

  • *

    Metabolic Syndrome was evaluated in agreement with Adult Treatment Panel III criteria.

  • P refers to the comparison between males and females.

Age (yrs)Modena48.6 ± 1.043.3 ± 1.256.5 ± 1.1.001
 Bologna/Turin42.1 ± 12.139.5 ± 1154.7 ± 9.8<.001
Waist circumference >102 cm (M), >88 cm (F) (%)Modena49.632.474.5<.01
 Bologna/Turin44.139.765.4<.01
Aterial pressure ⩾ 130/85 mm Hg (%)Modena57.245.067.2.039
 Bologna/Turin59.255.676.9.005
Fasting glucose ⩾ 110mg/dL (%)Modena25.222.129.7NS
 Bologna/Turin14.111.128.8.002
HDL cholesterol <40 (M), <50 (F) (%)Modena45.541.850.8NS
 Bologna/Turin35.231.055.8.001
Triglycerides ⩾ 150 mg/dL (%)Modena45.944.148.4NS
 Bologna/Turin47.446.053.8NS
Metabolic Syndrome* (%)Modena36.326.350.8.002
 Bologna/Turin35.630.659.6<.0001

It is tempting to speculate that the circulating levels of estrogens within a physiological range might be responsible for a “protective” effect on the development of steatosis (due to both NAFLD and, presumably, HCV genotype 1). This would imply that women in the fertile age are relatively spared from the development of steatosis and that this protection vanes after menopause similar to what happens for cardiovascular disease. These findings are also supported by the association of NAFLD with the use of the anti-estrogen tamoxifen,6 by the better profile of liver function enzymes in post-menopausal women taking hormone replacement therapy,7 and finally by the finding that estradiol improves insulin sensitivity,8 possibly preventing or reducing fat accumulation. In our opinion, gender differences in steatosis might also mirror derangements of other endocrine hormones, notably insulin, growth and thyroid hormones and cytokines, particularly adiponectin and leptin in NAFLD patients.3

As far as GGT is concerned, this enzyme might be a simple and reliable marker of insulin resistance both in obesity9 and in patients with NAFLD or HCV-related steatosis.10 It is well known that both alanine aminotransferase and, more closely, GGT predict the onset of type 2 diabetes in the general population.10 These observations fit with the finding that insulin resistance impairs the response to antiviral treatment,1 and lead us to conclude that elevated GGT, insulin resistance, and impaired response to antiviral treatment form an ominous triangle in the context of chronic HCV infection.

In conclusion, advances in the pathogenesis of NAFLD made over the past few years might give new clues to the understanding and, possibly, the treatment of HCV-associated steatosis.2

References

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  • 1
    Cammà C, Bruno S, Di Marco V, Di Bona D, Rumi M, Vinci M, et al. Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C. HEPATOLOGY 2006; 43: 6471.
  • 2
    Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004; 126: 586597.
  • 3
    Lonardo A, Carani C, Carulli N, Loria P. Endocrine NAFLD. A hormonocentric perspective of Non-Alcoholic Fatty Liver Disease pathogenesis. J Hepatol 2006; 44: 11961207.
  • 4
    Carulli L, Lombardini S, Lonardo A, Leonardi F, Bertolotti M, Ricchi M, et al. Non-alcoholic fatty liver (NAFLD). Is female sex safer? [Abstract]. J Hepatol 2004; 40(Suppl): 168A.
  • 5
    Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. HEPATOLOGY 2003; 37: 917923.
  • 6
    Bruno S, Maisonneuve P, Castellana P, Rotmensz N, Rossi S, Maggioni M, et al. Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. BMJ 2005; 330: 932937.
  • 7
    Johnson CL, Rifkind BM, Sempos CT, Carroll MD, Bachorik PS, Briefel RR, et al. Declining serum total cholesterol levels among US adults. The National Health and Nutrition Examination Surveys. JAMA 1993; 269: 30023008.
  • 8
    McKenzie J, Jaap AJ, Gallacher S, Kelly A, Crawford L, Greer IA, et al. Metabolic, inflammatory and haemostatic effects of a low-dose continuous combined HRT in women with type 2 diabetes: potentially safer with respect to vascular risk? Clin Endocrinol (Oxf) 2003; 59: 682689.
  • 9
    Marchesini G, Avagnina S, Barantani EG, Ciccarone AM, Corica F, Dall'Aglio E, et al. Aminotransferase and gamma-glutamyltranspeptidase levels in obesity are associated with insulin resistance and the metabolic syndrome. J Endocrinol Invest 2005; 28; 333339.
  • 10
    Lonardo A, Lombardini S, Scaglioni F, Carulli L, Ricchi M, Ganazzi D, et al. Hepatic steatosis and insulin resistance: Does etiology make a difference? J Hepatol 2006; 44: 190196.

Lucia Carulli*, Amedeo Lonardo*, Silvia Lombardini*, Giulio Marchesini†, Paola Loria*, * Department of Internal Medicine, University of Modena, Modena, Italy, † “Alma Mater Studiorum”, Department of Internal Medicine & Gastroenterology, University of Bologna, Bologna, Italy.