Clinical Syndromes and Consequences of
Marina Nu ´n ˜ez
Highly active antiretroviral therapy (HAART)-related hepatotoxicity complicates the man-
agement of patients infected with human immunodeficiency virus (HIV), increases medical
costs, alters the prescription patterns, and affects the guideline recommendations. Among
the clinical consequences derived from HAART-related liver toxicity, hypersensitivity reac-
tions and lactic acidosis are recognized as acute events with potential to evolve into fatal
cases, whereas there seems to be other syndromes not as well characterized but of equal
concern as possible long-term liver complications. Belonging to the latter category of syn-
drome, HAART-related nonalcoholic steatohepatitis, liver fibrosis, portal hypertension,
and nodular regenerative hyperplasia are discussed in this review. Updated information on
liver toxicity of current antiretroviral drugs, including the most recently licensed, is pro-
vided. Management and prevention of liver toxicity among HIV-infected patients treated
with HAARTare reviewed as well. (HEPATOLOGY 2010;52:1143-1155)
preted and managed. New hepatic problems which
might be related to the use of highly active antiretrovi-
ral therapy (HAART) continue to be revealed. In addi-
tion, new antiretrovirals have been licensed for which
information on liver safety is limited. I refer to past
reviews for previous information on the subject.1-8Af-
ter those publications, prescription patterns and guide-
line recommendations have continued to evolve, and
physicians treating HIV in 2010 manage new antire-
troviral drugs and new aspects of the epidemics.9This
review focuses on the clinical consequences of liver
toxicity associated with HAART, updates information
on the subject, and includes liver safety data of most
recently approved antiretroviral drugs. This article
hysicians treating human immunodeficiency vi-
rus (HIV)-infected patients often deal with ami-
notransferase elevations which have to be inter-
aims to help health care providers prevent and handle
antiretroviral toxicity within contemporary manage-
ment of patients with HIV.
accepted definition of drug hepatotoxicity or drug-
induced liver injury, another term used to refer to the
liver disturbances caused by drugs. Although alkaline
phosphatase elevation can be also a marker of liver
toxicity (and it is very prominent in cases with a
mixed or cholestatic pattern), aminotransferase eleva-
tion reflecting hepatocellular injury is more commonly
used as definition of hepatotoxicity.10The AIDS Clini-
cal Trials Group criteria11grades it according to the
following score system: grade 1 (1.25?-2.5? upper
limit of the normal range [ULN]); grade 2 (2.6?-5?
ULN); grade 3 (5.1?-10? ULN); and grade 4
(>10? ULN). Some authors have proposed to score
HAART-related hepatotoxicity according to baseline
levels in subjects having abnormal liver enzyme values
at baseline: grade 1 (1.25?-2.5? baseline); grade 2
(2.6?-3.5? baseline); grade 3 (3.6?-5? baseline);
and grade 4 (>5? baseline).12The presence of jaun-
dice along with high aminotransferase levels is associ-
ated with a poor prognosis (?10% mortality), a phe-
nomenon known as ’’Hy’s rule’’ in honor of the
pioneer researcher Hyman Zimmerman. The validity
of Hy’s rule, first proposed in the 1970s has been con-
firmed by more recent studies.13
isnot anuniformand internationally
Abbreviations: ALT, alanine aminotransferase; d-drug, dideoxynucleoside
drug; FDA, U.S. Food and Drug Administration; HAART, highly active
antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV,
human immunodeficiency virus; HLA, human leukocyte antigen; NASH,
nonalcoholic steatohepatitis; NNRTI, non-nucleoside reverse transcriptase
inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease
inhibitor; ULN, upper limit of the normal range.
From the Wake Forest University Health Sciences, Winston Salem, NC
Address reprint requests to: Marina Nu ´n ˜ez, M.D., Ph.D., Department of
Internal Medicine, Section on Infectious Diseases, Wake Forest University
Health Sciences, Medical Center Boulevard, Winston Salem, NC 27157.
E-mail: firstname.lastname@example.org; fax: 336-716-3825.
View this article online at wileyonlinelibrary.com.
Potential conflict of interest: Nothing to report.
C 2010 by the American Association for the Study of Liver Diseases.
Challenges in Causality Assessment
There is difficulty discerning and dissecting out the
number of individual factors that may contribute collec-
tively to liver damage in patients receiving antiretroviral
therapy. Several drugs are combined in a given HAART
regimen making difficult the attribution of hepatotoxic-
ity to a particular drug. Moreover, HIV-infected
patients may be receiving concurrent medications with
potential for liver toxicity as well, such as antimycobac-
terial drugs, lipid-lowering agents, antifungals, antibiot-
ics, and anticonvulsants. It is also difficult to make com-
parisons among reported cohorts, because individuals
often differ on the factors predisposing to elevations of
liver enzymes, like the presence/absence of concurrent
viral hepatitis. Biochemical, pharmacokinetic/dynamic,
and pathological correlations of HAART hepatotoxicity
have been poorly characterized, which makes it often
difficult to determine the true incidence of drug-
induced liver injury. In many instances, the hepatotoxic
potential of a drug has been recognized only after post-
marketing experience with the drug.
Risk Factors for HAART-Related
reported to increase the risk of severe HAART hepato-
toxicity (relative risk ¼ 2.1).14There is an estimated
2.7-fold to 5-fold increased risk of severe alanine ami-
notransferase (ALT) elevation on HAART with hepati-
tis C virus (HCV) coinfection.15-17Chronic hepatitis
B virus (HBV) infection appears to also carry a higher
risk, with a 9.2 hazard risk of grade 4 liver enzyme ele-
vations reported in one study.17The same authors also
observed that discontinuing lamivudine, an antiretrovi-
ral also active against HBV, was a factor associated
with aminotransferase elevation in HIV/HBV-coin-
fected patients (hazard risk ¼ 6.8 for grade 4 liver tox-
icity).17The presence of underlying liver inflammation
as reflected by elevated ALT at baseline has been also
identified as a risk factor for HAART liver toxicity.16,17
Isolated studies have identified additional host factors
including older age, female sex, thrombocytopenia, re-
nal insufficiency, high HIV RNA levels, increased
body mass index, and non-black ethnicity.15-18
Aside from host factors, several individual antiretrovi-
rals or classes have been independently associated with
HAART hepatotoxicity, such as nevirapine, protease
inhibitors, high doses of ritonavir (?600 mg/day), and
prolonged zidovudine or stavudine exposure.14,17,18
Alcohol use and concurrent hepatotoxic medications are
additional factors identified.15,16,18Lastly, an increase in
viral hepatitishas been consistently
CD4 cell counts of >50 cells/mm3after HAART initia-
tion was associated with almost two-fold increased risk
of severe ALT elevation in one study.14Other risk fac-
tors individual to each pathogenic mechanism are cov-
ered within its corresponding section.
Mechanisms of HAART-Related
A major challenge for mechanistic classifications is
that the pathogenesis of drug hepatotoxicity is poorly
understood in many instances. It involves several
mechanisms, regulatory systems, and risk factors with
complex interactions.19Hepatotoxicity events are more
often idiosyncratic, that is, they are unpredictable and
occur with variable latency and low incidence.10Idio-
syncratic drug-induced liver injury can be further clas-
sified as allergic and nonallergic.20The pathogenesis of
drug hepatotoxicity involves exposure to the toxic
agent (the parent drug or most often a reactive metab-
olite), the amount of which depends on genetically
determined metabolism of the agent by the liver. Fol-
lowing exposure, the toxic moiety induces some type
of stress or functional disturbance, with mitochondrial
injury being one of the most important targets recog-
nized.21,22A number of adaptation mechanisms are
then initiated to counteract the inflicted damage.23,24
In addition, innate and adaptive immune responses are
other factors of interest which determine the progres-
sion and severity of liver injury.25,26Detailed reviews
focusing on pathogenesis and mechanisms of drug-
induced liver injury are available elsewhere.10,19,20,27
Liver toxicity caused by antiretroviral therapy can be
inflicted through several mechanisms. The pathogenesis
often remains enigmatic. Table 1 summarizes the mech-
anisms of HAART-related liver toxicity by antiretroviral
class. Five categories are proposed: hypersensitivity reac-
tions, direct mitochondrial inhibition, disturbances of
lipid/sugar metabolism and steatosis, direct cell stress,
and immune reconstitution in the presence of viral hep-
atitis coinfection. Despite the limitations of the classifi-
cation, which ultimately is merely descriptive, it may be
useful in clinical practice because it describes typical
clinical characteristics of hepatotoxicity for specific anti-
retrovirals or classes and might give hints on the mecha-
nism, ultimately helping the management.
As reflected in Table 1, some antiretrovirals or classes
may be toxic for the liver through different pathways, a
hepatotoxicity in general.19Immune reconstitution in
the setting of viral hepatitis is a mechanism of amino-
transferase elevation shared by all antiretrovirals, just
1144NU´N˜EZHEPATOLOGY, September 2010
70. Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomaz ˇic ˇ J,
et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl
J Med 2008;358:568-579.
71. Bannister WP, Friis-Møller N, Mocroft A, Viard JP, van Lunzen J,
Kirk O, et al. Incidence of abacavir hypersensitivity reactions in euro-
SIDA. Antivir Ther 2008;13:687-696.
72. Leung JM, O’Brien JG, Wong HK, Dean L, Winslow DL. Efavirenz-
induced hypersensitivity reaction manifesting in rash and hepatitis in
a latino male. Ann Pharmacother 2008;42:425-429.
73. Turkova A, Ball C, Gilmour-White S, Rela M, Mieli-Vergani G. A
pediatric case of acute liver failure associated with efavirenz-based
highly active antiretroviral therapy and effective use of raltegravir in
combination antiretroviral treatment after liver transplantation. J Anti-
microb Chemother 2009;63:623-625.
74. Pavel SA, Burty C, Alcaraz I, de la Tribonnie `re X, Baclet V, Ajana F,
et al. Severe liver toxicity in postexposure prophylaxis for HIV infec-
tion with a zidovudine, lamivudine and fosamprenavir/ritonavir regi-
men. AIDS 2007;21:268-269.
75. Anonymous. Liver toxicity warning for darunavir. AIDS Patient Care
76. Stern J, Robinson P, Love J, Lanes S, Imperiale M, Mayers D. A com-
prehensive hepatic safety analysis of nevirapine in different popula-
tions of HIV infected patients. J AIDS 2003;34(Suppl. 1):S21-S33.
77. Martin A, Nolan D, James I, Cameron P, Keller J, Moore C, et al. Pre-
disposition to nevirapine hypersensitivity associated with HLADRB1*
0101 and abrogated by low CD4 T-cell counts. AIDS 2005;19:97-99.
78. Littera R, Carcassi C, Masala A, Piano P, Serra P, Ortu F, et al. HLA-
dependent hypersensitivity to nevirapine in Sardinian HIV patients.
79. Gatanaga H, Yazaki H, Tanuma J, Honda M, Genka I, Teruya K,
et al. HLA-Cw8 primarily associated with hypersensitivity to nevira-
pine. AIDS 2007;21:264-265.
80. De Lazzari E, Leo ´n A, Arnaiz JA, Martinez E, Knobel H, Negredo E,
et al. Hepatotoxicity of nevirapine in virologically suppressed patients
according to gender and CD4 cell counts. HIV Med 2008;9:221-226.
81. Wit FWNM, Kesselring AM, Gras L, Richter C, van der Ende ME,
Brinkman K, et al. Discontinuation of nevirapine because of hyper-
sensitivity reactions in patients with prior treatment experience, com-
pared with treatment-naive patients: The ATHENA Cohort Study.
Clin Infect Dis 2008;46:933-940.
82. US Department of Health and Human Services. Serious adverse events
attributed to nevirapine regimens for postexposure prophylaxis after
HIVexposures–worldwide, 1997-2000. MMWR 2001;49:1153-1156.
83. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, et al.
Association between presence of HLA-B*5701, HLA-DR7, and HLA-
DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor
abacavir. Lancet 2002;359:727-732.
84. Saag M, Balu R, Phillips E, Brachman P, Martorell C, Burman W,
et al. High sensitivity of human leukocyte antigen-b*5701 as a marker
for immunologically confirmed abacavir hypersensitivity in white and
black patients. Clin Infect Dis 2008;46:1111-1118.
85. Arenas-Pinto A, Grant A, Edwards S, Weller I. Lactic acidosis in HIV
infected patients: a systematic review of published cases. Sex Transm
86. Moyle GJ, Datta D, Mandalia S, Morlese J, Asboe D, Gazzard BG. Hyper-
lactatæmia and lactic acidosis during antiretroviral therapy: relevance,
reproducibility and possible risk factors. AIDS 2002;16:1341-1349.
87. John M, Moore CB, James IR, Nolan D, Upton RP, McKinno EJ,
et al. Chronic hyperlactatemia in HIV-infected patients taking antire-
troviral therapy. AIDS 2001;15:717-723.
88. Batisse D, Van Huyen J, Duong P, Piketty C, Canali G, Gonzalez,
et al. Severe liver mitochondriopathy with normal liver histology and
normal lactate levels in patients receiving nucleoside analogues. AIDS
89. Birkus G, Hitchcock M, Cihlar T. Assessment of mitochondrial toxic-
ity in human cells treated with tenofovir: comparison with other
nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemo-
90. Coghlan M, Sommadossi J, Jhala N, Many W, Saag M, Johnson V. Symp-
tomatic lactic acidosis in hospitalized antiretroviral-treated patients with
HIV infection: a report of 12 cases. ClinInfect Dis2001;33:1914-1921.
91. Foli A, Benvenuto F, Piccinini G, Bareggi A, Cossarizza A, Lisziewicz
J, et al. Direct analysis of mitochondrial toxicity of antiretroviral
drugs. AIDS 2001;15:1687-1694.
92. Ter Hofstede HJM, de Marie S, Foudraine NA, Danner SA, Brinkman
K. Clinical features and risk factors of lactic acidosis following long-term
antiretroviral therapy: 4 fatal cases. Int J STD AIDS 2000;11:611-616.
93. Brinkman K, ter Hofstede HJ. Mitochondrial toxicity of nucleoside
analogue reverse transcriptase inhibitors: lactic acidosis, risk factors
and therapeutic options. AIDS Rev 1999;1:141-148.
94. Macı ´as J, Castellano V, Merchante N, Palacios R, Mira J, Saez C,
et al. Effect of antiretroviral drugs on liver fibrosis in HIV-infected
patients with chronic hepatitis C: harmful impact of nevirapine. AIDS
95. Fuster D, Planas R, Muga R, Ballesteros A, Santos J, Tor J, et al.
Advanced liver fibrosis in HIV/HCV-coinfected patients on antiretro-
viral therapy. AIDS Res Hum Retroviruses 2004;20:1293-1297.
96. Mehta S, Thomas DL, Toberson M, Brinkley S, Mirel L, Chaisson
RE, et al. The effect of antiretroviral therapy on liver disease among
adults with HIV and hepatitis C coinfection. HEPATOLOGY 2005;41:
97. Sterling RK, Wilson MS, Sanyal AJ, Luketic VA, Stravitz RT, Contos
MJ, et al. Impact of highly active antiretroviral therapy on the spec-
trum of liver disease in HCV-HIV coinfection. Clin Gastroenterol
98. Moodie EEM, Pant Pai N, Klein MB. Is antiretroviral therapy causing
long-term liver damage? A comparative analysis of HIV-mono-infected
and HIV/hepatitis C co-infected cohorts. PLoS ONE 2009;4:e4517.
99. Qurishi N, Kreuzberg C, Luchters G, Effenberger W, Kupfer B, Sau-
erbruch T, et al. Effect of antiretroviral therapy on liver-related mor-
tality in patients with HIV and hepatitis C virus coinfection. Lancet
100. Maida I, Nu ´n ˜ez M, Rı ´os MJ, Martı ´n-Carbonero L, Sotgiu G, Toro C,
et al. Severe liver disease associated with prolonged exposure to antiretro-
viral drugs. AIDS Res Hum Retroviruses 2006;42:177-182.
101. Maida I, Garcia-Gasco P, Sotgiu G, Rios MJ, Vispo ME, Martin-Car-
bonero L, et al. Antiretroviral-associated portal hypertension: a new
clinical condition? Prevalence, predictors and outcome. Antivir Ther
102. Mallet V, Blanchard P, Verkarre V, Vallet-Pichard A, Fontaine H, Las-
coux-Combe C, et al. Nodular regenerative hyperplasia is a new cause of
chronic liver disease in HIV-infected patients. AIDS 2007;21:187-192.
103. Garvey LJ, Thomson EC, Lloyd J, Cooke GS, Golden RD, Main J.
Response to Mallet et al., ‘Nodular regenerative hyperplasia is a new
cause of chronic liver disease in HIV-infected patients’. AIDS 2007;
104. Sandrine PF, Sylvie A, Andre E, Abdoulaye D, Bernard L, Andre C.
Nodular regenerative hyperplasia: a new serious antiretroviral drugs
side effect? AIDS 2007;21:1498-1499.
105. Arey B, Markov M, Ravi J, Prevette E, Batts K, Nadir A. Nodular re-
generative hyperplasia of liver as a consequence of ART. AIDS 2007;
106. Schiano TD, Kotler DP, Ferran E, Fiel MI. Hepatoportal sclerosis as
a cause of noncirrhotic portal hypertension in patients with HIV. Am
J Gastroenterol 2007;102:2536-2540.
107. Saifee S, Joelson D, Braude J, Shrestha R, Johnson M, Sellers M, et al.
Noncirrhotic portal hypertension in patients with human immunodefi-
ciency virus–1infection. Clin Gastroenterol Hepatol 2008;6:1167-1169.
108. Vispo E, Moreno A, Maida I, Barreiro P, Cuevas A, Albertos S, et al.
Noncirrhotic portal hypertension in HIV-infected patients: unique clini-
caland pathological findings.
AIDS 2010; doi:10.1097/
1154 NU´N˜EZ HEPATOLOGY, September 2010
109. Kovari H, Ledergerber B, Peter U, Flepp M, Jost J, Schmid P, et al.
Association of noncirrhotic portal hypertension in HIV-infected per-
sons and antiretroviral therapy with didanosine: a nested case-control
study. Clin Infect Dis 2009;49:626-635.
110. Carr A, Morey A, Mallon P, Williams D, Thorburn DR. Fatal portal
hypertension, liver failure, and mitochondrial dysfunction after HIV-1
nucleoside analogue-induced hepatitis and lactic acidaemia. Lancet
111. Rector RS, Thyfault JP, Wei Y, Ibdah JA. Non-alcoholic fatty liver
disease and the metabolic syndrome: an update. World J Gastroenterol
112. Ingiliz P, Valantin MA, Duvivier C, Medja F, Dominguez S, Charlotte F,
et al. Liver damage underlying unexplained aminotransferase elevation
in human immunodeficiency virus-1 mono-infected patients on
antiretroviral therapy. HEPATOLOGY 2009;49:436-442.
113. McGovern BH, Ditelberg JS, Taylor LE, Gandhi RT, Christopoulos
KA, Chapman S, et al., Hepatic steatosis is associated with fibrosis,
nucleoside analogue use, and hepatitis C virus genotype 3 infection in
HIV-seropositive patients. lin Infect Dis 2006;43:373-376.
114. Sulkowski MS, Mehta SH, Torbenson M, Afdhal NH, Mirel L, Moore
RD, et al. Hepatic steatosis and antiretroviral drug use among adults
coinfected with HIVand hepatitis C virus. AIDS 2005;19:585-592.
115. Rodriguez-Torres M, Govindarajan S, Sola ´ R, Clumeck N, Lissen E,
Pesso ˆa M, et al. Hepatic steatosis in HIV/HCV co-infected patients:
correlates, efficacy and outcomes of anti-HCV therapy: a paired liver
biopsy study. J Hepatol 2008;48:756-764.
116. Halfon P, Pe ´naranda G, Carrat F, Bedossa P, Bourlie `re M, Ouzan D,
et al. Influence of insulin resistance on hepatic fibrosis and steatosis in
HCV monoinfected compared with HIV-HCV co-infected patients.
Aliment Pharmacol Ther 2009;30:61-70.
117. Borghi V, Puoti M, Mussini C, Bellelli S, Angeletti C, Sabbatini F,
et al. HIV coinfection and antiretroviral therapy enhances liver steato-
sis in patients with hepatitis C, but only in those infected by HCV
genotype other than 3. Antivir Ther 2008;13:1057-1065.
118. Guaraldi G, Squillace N, Stentarelli C, Orlando G, D’Amico R, Liga-
bue G, et al. Nonalcoholic fatty liver disease in HIV-infected patients
referred to a metabolic clinic: prevalence, characteristics, and predic-
tors. Clin Infect Dis 2008;47:250-257.
119. Bani-Sadr F, Carrat F, Bedossa P, Piroth L, Cacoub P, Perronne C,
et al. Hepatic steatosis in HIV-HCV coinfected patients: analysis of
risk factors. AIDS 2006;20:525-531.
120. Neau D, Winnock M, Caste ´ra L, Bail BL, Loko MA, Ge ´raut L, et al.
Prevalence of and factors associated with hepatic steatosis in patients
coinfected with hepatitis C virus and HIV: Agence Nationale pour la
Recherche contre le SIDA et les hepatitis virales CO3 Aquitaine
Cohort. J Acquir Immune Defic Syndr 2007;45:168-173.
121. Pessayre D, Mansouri A, Haouzi D, Fromenty B. Hepatotoxicity due
to mitochondrial dysfunction. Cell Biol Toxicol 1999;15:367-373.
122. Chitturi S, Farrell GC. Etiopathogenesis of nonalcoholic steatohepati-
tis. Semin Liver Dis 2001;21:27-41.
123. Igoudjil A, Massart J, Begriche K, Descatoire V, Robin MA, Fromenty
B. High concentrations of stavudine impair fatty acid oxidation with-
out depleting mitochondrial DNA in cultured rat hepatocytes. Toxicol
In Vitro 2008;22:887-898.
124. Lemoine M, Barbu V, Girard PM, Kim M, Bastard JP, Wendum D,
et al. Altered hepatic expression of SREBP-1 and PPARgamma is
associated with liver injury in insulin-resistant lipodystrophic HIV-
infected patients. AIDS 2006;20:387-395.
125. Akhtar MA, Mathieson K, Arey B, Post J, Prevette R, Hillier A, et al.
Hepatic histopathology and clinical characteristics associated with anti-
retroviral therapy in HIV patients without viral hepatitis. Eur J Gas-
troenterol Hepatol 2008;20:1194-1204.
126. Fartoux L, Chazouille `res O, Wendum D, Poupon R, Serfaty L.
Impact of steatosis on progression of fibrosis in patients with mild
hepatitis. HEPATOLOGY 2005;41:82-87.
127. Patton HM, Patel K, Behling C, Bylund D, Blatt LM, Valle ´e M,
et al. The impact of steatosis on disease progression and early and sus-
tained treatment response in chronic hepatitis C patients. J Hepatol
128. Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Rug-
giero G. Steatosis accelerates the progression of liver damage of
chronic hepatitis C patients and correlates with specific HCV geno-
type and visceral obesity. HEPATOLOGY 2001;33:1358-1364.
129. Caste ´ra L, He ´zode C, Roudot-Thoraval F, Bastie A, Zafrani ES, Paw-
lotsky JM, et al. Worsening of steatosis is an independent factor of fi-
brosis progression in untreated patients with chronic hepatitis C and
paired liver biopsies. Gut 2003;52:288-292.
130. Biesecker G, Karimi S, Desjardins J, Meyer D, Abbott B, Bendele R,
et al. Evaluation of mitochondrial DNA content and enzyme levels in
tenofovir DF-treated rats, rhesus monkeys and woodchucks. Antiviral
131. Fouty B, Frerman F, Reves R. Riboflavin to treat nucleoside analogue-
induced lactic acidosis. Lancet 1998;352:291-292.
132. Vispo E, Mena A, Maida I, Blanco F, Cordoba M, Labarga P, et al.
Hepatic safety profile of raltegravir in HIV-infected patients with
chronic hepatitis C. J Antimicrob Chemother 2010;65:543-547.
133. Stein LL, Dong MH, Loomba R. Insulin sensitizers in nonalcoholic
fatty liver disease and steatohepatitis: current status. Adv Ther 2009;
134. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda
N. Metformin in non-alcoholic steatohepatitis. Lancet 2001;358:
135. Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, Tuzun A, et al.
Metformin in the treatment of patients with non-alcoholic steatohepa-
titis. Aliment Pharmacol Ther 2004;19:537-544.
136. De Oliveira CP, Stefano JT, de Siqueira ER, Silva LS, de Campos
Mazo DF, Lima VM, et al. Combination of N-acetylcysteine and met-
formin improves histological steatosis and fibrosis in patients with
non-alcoholic steatohepatitis. Hepatol Res 2008;38:159-165.
137. Idilman R, Mizrak D, Corapcioglu D, Bektas M, Doganay B, Sayki
M, et al. Clinical trial: insulin-sensitizing agents may reduce conse-
quences of insulin resistance in individuals with non-alcoholic steato-
hepatitis. Aliment Pharmacol Ther 2008;28:200-208.
138. Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, Borg BB,
et al. Clinical trial: pilot study of metformin for the treatment of non-
alcoholic steatohepatitis. Aliment Pharmacol Ther 2008;29:172-182.
139. Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH,
Sheppard BL. A pilot study of a thiazolidinedione, troglitazone, in
nonalcoholic steatohepatitis. Am J Gastroenterol 2001;96:519-525.
140. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J,
et al. A placebo-controlled trial of pioglitazone in subjects with nonal-
coholic steatohepatitis. N Engl J Med 2006;355:2297-2307.
141. Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I,
et al. Randomized, placebo-controlled trial of pioglitazone in nondia-
betic subjects with nonalcoholic steatohepatitis. Gastroenterology
142. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A,
Serfaty L, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-
year results of the randomized placebo-controlled Fatty Liver Improve-
ment with Rosiglitazone Therapy (FLIRT) trial. Gastroenterology
143. Ding A, Lee A, Callender M, Loughrey M, Quah SP, Dinsmore WW.
Hepatic encephalopathy as an unusual late complication of transjugu-
lar intrahepatic portosystemic shunt insertion for noncirrhotic portal
hypertension caused by nodular regenerative hyperplasia in an HIV-
positive patient on highly active antiretroviral therapy. Int J STD
144. Tateo M, Sebagh M, Bralet MP, Teicher E, Azoulay D, Mallet V,
et al. A new indication for liver transplantation: nodular regenerative
hyperplasia in human immunodeficiency virus-infected patients. Liver
145. Bihl F, Janssens F, Boehlen F, Rubbia-Brandt L, Hadengue A, Spahr
L. Anticoagulant therapy for nodular regenerative hyperplasia in a
HIV-infected patient. BMC Gastroenterol 2010;10:6.
HEPATOLOGY, Vol. 52, No. 3, 2010NU´N˜EZ1155