Baseline urine metabolic phenotype in patients with severe alcoholic hepatitis and its association with outcome

Abstract

Severe alcoholic hepatitis (SAH) has a high mortality rate, and corticosteroid therapy is effective in 60% patients. This study aimed to investigate a baseline metabolic phenotype that could help stratify patients not likely to respond to steroid therapy and to have an unfavorable outcome. Baseline urine metabolome was studied in patients with SAH using ultra‐high performance liquid chromatography and high‐resolution mass spectrometry. Patients were categorized as responders (Rs, n = 52) and nonresponders (NRs, n = 8) at day 7 according to the Lille score. Multivariate projection analysis identified metabolites in the discovery cohort (n = 60) and assessed these in a validation cohort of 80 patients (60 Rs, 20 NRs). A total of 212 features were annotated by using metabolomic/biochemical/spectral databases for metabolite identification. After a stringent selection procedure, a total of nine urinary metabolites linked to mitochondrial functions significantly discriminated nonresponders, most importantly by increased acetyl‐L‐carnitine (12‐fold), octanoylcarnitine (4‐fold), decanoylcarnitine (4‐fold), and alpha‐ketoglutaric acid (2‐fold) levels. Additionally, urinary acetyl‐L‐carnitine and 3‐hydroxysebasic acid discriminated nonsurvivors (P < 0.01). These urinary metabolites significantly correlated to severity indices and mortality (r > 0.3; P < 0.01) and were associated with nonresponse (odds ratio >3.0; P < 0.001). In the validation cohort, baseline urinary acetyl‐L‐carnitine documented an area under the receiver operating curve of 0.96 (0.85‐0.99) for nonresponse prediction and a hazard ratio of 3.5 (1.5‐8.3) for the prediction of mortality in patients with SAH. Acetyl‐L‐carnitine at a level of >2,500 ng/mL reliably segregated survivors from nonsurvivors (P < 0.01, log‐rank test) in our study cohort. Conclusion: Urinary metabolome signatures related to mitochondrial functions can predict pretherapy steroid response and disease outcome in patients with SAH. (Hepatology Communications 2018;2:628‐643)

Efficacy of Granulocyte Colony‐stimulating Factor in the Management of Steroid‐Nonresponsive Severe Alcoholic Hepatitis: A Double‐Blind Randomized Controlled Trial

“…In addition, we have previously shown that steroid nonresponse could be due to failure of cellular energy metabolism. High levels of acetyl carnitine in SAH are associated with high mortality . It is possible that G‐CSF therapy could help in restoring cellular energy and hepatic regeneration.…”

“…High levels of acetyl carnitine in SAH are associated with high mortality. (21) It is possible that G-CSF therapy could help in restoring cellular energy and hepatic regeneration.…”

Predictors of steroid non-response and new approaches in severe alcoholic hepatitis

“…Acetyl-Lcarnitine levels of >2,500 ng/mL reliably segregated survivors from non-survivors (P< 0.01, log-rank test) in the study cohort. 3 This low cost test, if validated in other studies, could be of help in selection of patients for steroid therapy.…”

“…Whether baseline metabolic phenotype could identify non-re-sponders and those with unfavorable outcome was investigated. 3 Baseline urine metabolome of SAH patients was subjected to ultra-high performance liquid chromatography and high-resolution mass spectrometry. Nine urinary metabolites linked to mitochondrial functions significantly discriminated non-responders, most importantly the increased acetyl-L-carnitine (12-fold) levels.…”

“…ALD now contribute to 47.9% of all liver cirrhosis-related deaths globally. 3,4 AH is the most florid manifestation of ALD with substantial morbidity, mortality, and financial burden.…”