studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1139A
Fig 1. Observed and predicted overall survival curves stratified
by the MESIAH score (A) with treated groups, (B) with untreated
groups before propensity score matching
seem to be a good option for the subset of patients with symptomatic
severe portal hypertension.
Disclosures:
The following authors have nothing to disclose: Vincent Soriano, Pablo Labarga,
Jose V. Fernandez-Montero, Carmen de Mendoza, Pablo Barreiro
Disclosures:
Yoon Jun Kim - Grant/Research Support: Bristol-Myers Squibb, Roche, JW Creagene,
Bukwang Pharmaceuticals, Handok Pharmaceuticals, Hanmi Pharmaceuticals,
Yuhan Pharmaceuticals; Speaking and Teaching: Bayer HealthCare
Pharmaceuticals, Gilead Science, MSD Korea, Yuhan Pharmaceuticals, Samil
Pharmaceuticals, CJ Pharmaceuticals, Bukwang Pharmaceuticals, Handok Pharmaceuticals
The following authors have nothing to disclose: Won-Mook Choi, Su Jong Yu,
Young Youn Cho, Eun Ju Cho, Jeong-Hoon Lee, Jung-Hwan Yoon, June Sung Lee
1908
Long-term Outcome of HIV+ Patients with Non-Cirrhotic
Portal Hypertension Upon Discontinuation of Didanosine
Vincent Soriano 1 , Pablo Labarga 4 , Jose V. Fernandez-Montero 2 ,
Carmen de Mendoza 3 , Pablo Barreiro 1 ; 1 La Paz University Hospital
& IdiPAZ, Madrid, Spain; 2 University Hospital Crosshouse,
Kilmarnock, United Kingdom; 3 Puerta de Hierro Research Institute,
Majadahonda, Spain; 4 La Luz Clinic, Madrid, Spain
Background: Exposure to the antiretroviral drug didanosine has
been associated to hepatic vascular damage and non-cirrhotic
portal hypertension (NCPH) in HIV+ individuals. Life-threatening
episodes of variceal bleeding and acute portal thrombosis
are the most feared complications. Herein, we describe the
long-term outcome of a series of patients that developed HIV-associated
NCPH. Methods: All HIV+ patients followed at one
single HIV reference large clinic in Madrid were examined.
Diagnosis of NCPH was made based on recognition of portal
hypertension in the absence of cirrhosis (confirmed either by
biopsy and/or elastometry), and exclusion of any known etiology
other than didanosine exposure. Following removal of
the drug, patients have been on regular follow-up using other
antiretroviral drugs. Results: From a total of 3,200 HIV+ individuals
attended during the last decade, a total of 21 (0.6%)
were diagnosed with didanosine-associated NCPH. Characteristics
features of small portal venulopathy were found in the
liver biopsy of all 12 patients with histologically available specimens.
At diagnosis, mean age was 43-years and 17 were
male. No deaths due to liver-related deaths have occurred
after an average follow-up of 8.3 years. However, two thirds
developed serious liver-related complications early on, including
portal thrombosis (7), ascites (8), variceal bleeding (6) and
encephalopathy (2). Two subjects underwent TIPPS and one
surgical porto-cava shunt due to severe portal hypertension.
Interestingly, none of these 3 patients developed encephalopathy
thereafter, most likely due to their relative well-preserved
hepatic function. No further liver-related complications occurred
beyond 2 years of didanosine removal in our series except for
one patient that suffered variceal re-bleeding 7 years later.
Conclusions: NCPH in HIV+ patients is a rare but potentially
life-threatening condition linked to didanosine exposure that
tends to ameliorate over time after stopping didanosine. TIPPS
1909
AMPK activation prevents and reverses drug-induced
mitochondrial damage in hepatocytes by regulating
mitochondrial quality control
Dong Fu 1 , Ghada Haydar 1 , Sun Woo Sophie Kang 1 , Geoffrey C.
Farrell 2 , Jennifer Lippincott-Schwartz 3 , Irwin M. Arias 3 ; 1 Faculty
of Pharmacy, The University of Sydney, Sydney, NSW, Australia;
2 Liver Research Group, National University of Australia Medical
School, Canberra, ACT, Australia; 3 NICHD, National Institutes of
Health, Bethesda, MD
Mitochondrial damage plays a central role in drug-induced
liver injury (DILI) which is responsible for many cases of acute
liver failure, and pre- or post-market withdrawal of drugs. Mitochondria
maintain function through quality control that includes
regulated fusion/fission dynamics and autophagy-mediated
degradation that eliminates damaged mitochondria. Therefore,
enhancement of mitochondrial quality control is a potential
approach for treatment of DILI. AMP activated kinase (AMPK)
is a cellular energy sensor which, when activated by phosphorylation,
promotes mitochondrial biogenesis and activates
autophagy. Using collagen sandwich cultures of rat and human
hepatocytes, we investigated the role of AMPK in mitochondrial
quality control, and prevention and reversal of drug-induced
mitochondrial and hepatocellular damage. Results: Western
blot and immunofluorescence results demonstrated that hepatotoxic
drugs, acetaminophen (for intrinsic DILI) and diclofenac
(for idiosyncratic DILI), significantly decreased expression
of mitochondrial fusion protein Mfn1; acetaminophen also
decreased expression of fusion proteins Mfn2 and Opa1. Both
drugs caused mitochondrial fragmentation, and decreased ATP
levels and mitochondrial membrane potential in human and
rat hepatocytes, revealing that both drugs cause mitochondrial
damage. Moreover, both drugs significantly decreased cell viability
and caused depolarization in human and rat hepatocytes.
Activation of AMPK, by simultaneous administration of hepatotoxic
drugs and AICAR, a specific AMPK activator, or addition
of AICAR at 5hr post exposure of both drugs when hepatocellular
damage occurred, restored mitochondrial function and
fusion, hepatocyte polarization and cell viability, revealing
that activation of AMPK prevents and reverses drug-induced
mitochondrial and hepatocellular damage. AMPK activation
prevented drug-mediated decreases in Mfn1, 2 and Opa1,
indicating AMPK induced mitochondrial fusion by regulating
fusion machinery. AMPK activation also increased autophagy
in the presence of acetaminophen but not diclofenac, suggesting
that the autophagic effect of AMPK plays a differential role
in prevention of drug-induced hepatotoxicity. Conclusion: Acetaminophen
and diclofenac fragment mitochondria through inhibition
of the fusion machinery, and cause mitochondrial and
hepatocellular damage. Through promotion of mitochondrial
fusion or together with activation of autophagy, two important
processes of mitochondrial quality control, activation of AMPK
prevents and reverses drug-induced mitochondrial and hepatocellular
damage. Activation of AMPK may provide a novel
strategy for treatment of DILI.
Disclosures:
The following authors have nothing to disclose: Dong Fu, Ghada Haydar, Sun
Woo Sophie Kang, Geoffrey C. Farrell, Jennifer Lippincott-Schwartz, Irwin M.
Arias