Non-alcoholic fatty liver disease in patients infected with human immunodeficiency virus: a systematic review

Pires, Leonardo Bispo; Rocha, Raquel; Vargas, Daniel; Daltro, Carla; Cotrim, Helma P

doi:10.1590/1806-9282.66.1.81

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Revista da Associação Médica Brasileira

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REVIEW ARTICLE • Rev. Assoc. Med. Bras. 66 (1) • 2020 • https://doi.org/10.1590/1806-9282.66.1.81 copy

Non-alcoholic fatty liver disease in patients infected with human immunodeficiency virus: a systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

SUMMARY

OBJECTIVE

To evaluate the prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with HIV/AIDS.

METHODS

The systematic review included articles indexed in MEDLINE (by PubMed), Web of Science, IBECS, and LILACS. Studies eligible included the year of publication, diagnose criteria of NAFLD and HIV, and were published in English, Portuguese, or Spanish from 2006 to 2018. The exclusion criteria were studies with HIV-infection patients and other liver diseases. Two reviewers were involved in the study and applied the same methodology, according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).

RESULTS

One hundred and sixteen papers were selected, including full articles, editorial letters, and reviews. Twenty-seven articles were excluded because they did meet the inclusion criteria. A total of 89 articles were read, and 13 were considered eligible for this review. Four case series used imaging methods to identify NAFLD, and nine included histology. The prevalence of NAFLD in HIV-patients ranged from 30%-100% and, in nonalcoholic steatohepatitis (NASH), from 20% to 89%. A positive association between dyslipidemia, insulin resistance, and body mass index was observed. There was no agreement between the studies that evaluated the relationship between antiretroviral drugs and NAFLD.

CONCLUSION

This systematic review showed a high prevalence of NAFLD in HIV-patients, which was associated with metabolic risk factors. The possible association between antiretroviral therapy and NAFLD needs further studies.

Non-alcoholic fatty liver disease; HIV infections; Acquired Immunodeficiency Syndrome

Reference	Country	Diagnostic Method	N	Prevalence

				NAFLD	NASH
Perez et al., 2018 ¹⁴14. Moreno-Perez O, Reyes-Garcia R, Muñoz-Torres M, Merino E, Boix V, Reus S, et al. High Irisin levels in nondiabetic HIV-infected males are associated with insulin resistance, nonalcoholic fatty liver disease, and subclinical atherosclerosis. Clin Endocrinol (Oxf). 2018;89(4):414-23.	Spain	Magnetic resonance	72	33,3%	-
Morse et al., 2015 ⁸8. Morse CG, McLaughlin M, Matthews L, Proschan M, Thomas F, Gharib AM, et al. Nonalcoholic steatohepatitis and hepatic fibrosis in HIV-1-monoinfected adults with elevated aminotransferase levels on antiretroviral therapy. Clin Infect Dis. 2015;60(10):1569-78.	USA	Biopsy	62	73%	54%
Vodkin et al., 2015 ²2. Vodkin I, Valasek MA, Bettencourt R, Cachay E, Loomba R. Clinical, biochemical and histological differences between HIV- associated NAFLD and primary NAFLD: a case-control study. Aliment Pharmacol Ther. 2015;41(4):368-78.	USA	Biopsy	86	38%	24%
Nishijima et al., 2014 ¹⁵15. Nishijima T, Gatanaga H, Shimbo T, Komatsu H, Nozaki Y, Nagata N, et al. Traditional but not HIV-related factors are associated with nonalcoholic fatty liver disease in Asian patients with HIV-1 infection. PLoS One. 2014;9(1):e87596.	Japan	Ultrasonography	485	31%	-
Rivero-Juarez et al., 2013 ¹⁷17. Rivero-Juárez A, Camacho A, Merchante N, Pérez-Camacho I, Macias J, Ortiz-Garcia C, et al; Grupo para el estudio de las hepatitis vı´ricas (HEPAVIR) de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI). Incidence of liver damage of uncertain origin in HIV patients not co-infected with HCV/HBV. PLoS One. 2013;8(7):e68953.	Spain	Biopsy	10	100%	20%
Sterling et al., 2013 ⁹9. Sterling RK, Smith PG, Brunt EM. Hepatic steatosis in human immunodeficiency virus: a prospective study in patients without viral hepatitis, diabetes, or alcohol abuse. J Clin Gastroenterol. 2013;47(2):182-7.	USA	Biopsy	14	64%	28%
Arendt et al., 2011 ¹⁰10. Arendt BM, Mohammed SS, Ma DW, Aghdassi E, Salit IE, Wong DK, et al. Non-alcoholic fatty liver disease in HIV infection associated with altered hepatic fatty acid composition. Curr HIV Res. 2011;9(2):128-35.	Canada	Biopsy	20	30%	70%
Crum-Cianflone et al., 2009 ¹¹11. Crum-Cianflone N, Dilay A, Collins G, Asher D, Campin R, Medina S, et al. Nonalcoholic fatty liver disease among HIV-infected persons. J Acquir Immune Defic Syndr. 2009;50(5):464-73.	USA	Ultrasonography	216	31%	20%*
Ingiliz et al., 2009 ¹⁸18. Ingiliz P, Valantin MA, Duvivier C, Medja F, Dominguez S, Charlotte F, et al. Liver damage underlying unexplained transaminase elevation in human immunodeficiency virus-1 mono-infected patients on antiretroviral therapy. Hepatology. 2009;49(2):436-42.	France	Biopsy	30	60%	89%
Akhtar et al., 2008 ¹²12. Akhtar MA, Mathieson K, Arey B, Post J, Prevette R, Hillier A, et al. Hepatic histopathology and clinical characteristics associated with antiretroviral therapy in HIV patients without viral hepatitis. Eur J Gastroenterol Hepatol. 2008;20(12):1194-204.	USA	Biopsy	23	56%	39%
Guaraldi et al., 2008 ¹⁶16. Guaraldi G, Squillace N, Stentarelli C, Orlando G, D’Amico R, Ligabue G, et al. Nonalcoholic fatty liver disease in HIV-infected patients referred to a metabolic clinic: prevalence, characteristics, and predictors. Clin Infect Dis. 2008;47(2):250-7.	Italy	Computer Tomography	225	36%	-
Mohammed et al., 2007 ¹³13. Mohammed SS, Aghdassi E, Salit IE, Avand G, Sherman M, Guindi M, et al. HIV-positive patients with nonalcoholic fatty liver disease have a lower body mass index and are more physically active than HIV-negative patients. J Acquir Immune Defic Syndr. 2007;45(4):432-8.	Canada	Biopsy	26	100%	55%

Reference	Country	Diagnostic Method	N	Clinical Conditions and Laboratory changes
Morse et al., 2015 ⁸8. Morse CG, McLaughlin M, Matthews L, Proschan M, Thomas F, Gharib AM, et al. Nonalcoholic steatohepatitis and hepatic fibrosis in HIV-1-monoinfected adults with elevated aminotransferase levels on antiretroviral therapy. Clin Infect Dis. 2015;60(10):1569-78.	USA	Biopsy	62	IR/DM (+); Hepatic steatosis (+); Aminotransferases elevation (+); Polymorphyms PNPLA3.
Vodkin et al., 2015 ²2. Vodkin I, Valasek MA, Bettencourt R, Cachay E, Loomba R. Clinical, biochemical and histological differences between HIV- associated NAFLD and primary NAFLD: a case-control study. Aliment Pharmacol Ther. 2015;41(4):368-78.	USA	Biopsy	86	Dyslipidemia (+); aminotransferases elevation (+); Canalicular enzymes (+); ART (-); HIV (+)
Nishijima et al., 2014 ¹⁵15. Nishijima T, Gatanaga H, Shimbo T, Komatsu H, Nozaki Y, Nagata N, et al. Traditional but not HIV-related factors are associated with nonalcoholic fatty liver disease in Asian patients with HIV-1 infection. PLoS One. 2014;9(1):e87596.	Japan	Ultrasonography	485	IR/DM (-); BMI/WC (+); Dyslipidemia (+), hypertriglyceridemia and elevated LDL levels; aminotransferases elevation (+), elevated ALT; ART (-);Elevated CD4+ (+)
Price et al., 2014 ¹⁹19. Price JC, Seaberg EC, Latanich R, Budoff MJ, Kingsley LA, Palella FJ Jr, et al. Risk factors for fatty liver in the Multicenter AIDS Cohort Study. Am J Gastroenterol. 2014;109(5):695-704.	USA	Computer Tomography	719	IR/DM (+); BMI/WC (+); Elevation of aminotransferases (+), elevated ALT; ART (+), greater cumulative exposure to Dideoxynucleoside analogues (Stavudina, Didanosine, Zalcitabine); HIV (-); CD4+ (-)
Rivero-Juarez et al., 2013 ¹⁷17. Rivero-Juárez A, Camacho A, Merchante N, Pérez-Camacho I, Macias J, Ortiz-Garcia C, et al; Grupo para el estudio de las hepatitis vı´ricas (HEPAVIR) de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI). Incidence of liver damage of uncertain origin in HIV patients not co-infected with HCV/HBV. PLoS One. 2013;8(7):e68953.	Spain	Biopsy	10	IR/DM (+); BMI/WC (+); Dyslipidemia (+), hypertriglyceridemia; Hepatic steatosis (+); ART (-); CD4+ plus hypertriglyceridemia (+)
Sterling et al., 2013 ⁹9. Sterling RK, Smith PG, Brunt EM. Hepatic steatosis in human immunodeficiency virus: a prospective study in patients without viral hepatitis, diabetes, or alcohol abuse. J Clin Gastroenterol. 2013;47(2):182-7.	USA	Biopsy	14	IR/DM (+); Canalicular enzymes (+) plus hypertriglyceridemia
Crum-Cianflone et al., 2009 ¹¹11. Crum-Cianflone N, Dilay A, Collins G, Asher D, Campin R, Medina S, et al. Nonalcoholic fatty liver disease among HIV-infected persons. J Acquir Immune Defic Syndr. 2009;50(5):464-73.	USA	Ultrasonography	216	BMI/WC plus Hypertriglyceridemia (+); Dyslipidemia (+), hypertriglyceridemia and decreased HDL levels; ART (-); HIV (-); CD4+ (-)
Ingiliz et al., 2009 ¹⁸18. Ingiliz P, Valantin MA, Duvivier C, Medja F, Dominguez S, Charlotte F, et al. Liver damage underlying unexplained transaminase elevation in human immunodeficiency virus-1 mono-infected patients on antiretroviral therapy. Hepatology. 2009;49(2):436-42.	France	Biopsy	30	IR/DM (+); BMI/WC (-); Dyslipidemia (-); ART (-); HIV (-)
Akhtar et al., 2008 ¹²12. Akhtar MA, Mathieson K, Arey B, Post J, Prevette R, Hillier A, et al. Hepatic histopathology and clinical characteristics associated with antiretroviral therapy in HIV patients without viral hepatitis. Eur J Gastroenterol Hepatol. 2008;20(12):1194-204.	USA	Biopsy	23	BMI/WC (+); ART (+), all patients who presented DHGNA were exposed to NRTIs; HIV (+)
Guaraldi et al., 2008 ¹⁶16. Guaraldi G, Squillace N, Stentarelli C, Orlando G, D’Amico R, Ligabue G, et al. Nonalcoholic fatty liver disease in HIV-infected patients referred to a metabolic clinic: prevalence, characteristics, and predictors. Clin Infect Dis. 2008;47(2):250-7.	Italy	Computer Tomography	225	IR/DM (+); BMI/WC and Visceral Adipose Tissue (+); Dyslipidemia (+); aminotransferases elevation (+); ART (+), exposure to NRTIs
Mohammed et al., 2007 ¹³13. Mohammed SS, Aghdassi E, Salit IE, Avand G, Sherman M, Guindi M, et al. HIV-positive patients with nonalcoholic fatty liver disease have a lower body mass index and are more physically active than HIV-negative patients. J Acquir Immune Defic Syndr. 2007;45(4):432-8.	Canada	Biopsy	26	BMI/WC (-); Dyslipidemia (+), hypertriglyceridemia;

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[1] CORRESPONDING AUTHOR: Helma Pinchemel Cotrim Programa de Pós-graduação em Medicina e Saúde, Complexo Hospitalar Universitário Professor Edgard Santos – UFBA Rua Augusto Viana, s/n, 5º andar, Canela, Salvador, Bahia - Brasil, CEP 40110-060 Phone/Fax: +55 71 3276-2373 E-mail: helmacotrim@gmail.com