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1.
JHEP Rep ; 2(5): 100137, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32775974

ABSTRACT

BACKGROUND & AIMS: Analysis of volatile organic compounds (VOCs) in exhaled breath, 'volatomics', provides opportunities for non-invasive biomarker discovery and novel mechanistic insights into a variety of diseases. The purpose of this pilot study was to compare breath VOCs in an initial cohort of patients with non-alcoholic fatty liver disease (NAFLD) and healthy controls. METHODS: Breath samples were collected from 15 participants with Child-Pugh class A NAFLD cirrhosis, 14 with non-cirrhotic NAFLD, and 14 healthy volunteers. Exhaled breath samples were collected using an established methodology and VOC profiles were analysed by gas chromatography-mass spectrometry. The levels of 19 VOCs previously associated with cirrhosis were assessed. Peaks of the VOCs were confirmed and integrated using Xcalibur® software, normalised to an internal standard. Receiver-operating characteristic (ROC) curves were used to determine the diagnostic accuracy of the candidate VOCs. RESULTS: Terpinene, dimethyl sulfide, and D-limonene provided the highest predictive accuracy to discriminate between study groups. Combining dimethyl sulfide with D-limonene led to even better discrimination of patients with NAFLD cirrhosis from healthy volunteers (AUROC 0.98; 95% CI 0.93-1.00; p <0.001) and patients with NAFLD cirrhosis from those with non-cirrhotic NAFLD (AUROC 0.91; 95% CI 0.82-1.00; p <0.001). Breath terpinene concentrations discriminated between patients with non-cirrhotic NAFLD and healthy volunteers (AUROC 0.84; 95% CI 0.68-0.99; p = 0.002). CONCLUSION: Breath terpinene, dimethyl sulfide, and D-limonene are potentially useful volatomic markers for stratifying NAFLD; in addition, a 2-stage approach enables the differentiation of patients with cirrhosis from those without. However, these observations require validation in a larger NAFLD population. (ClinicalTrials.gov Identifier: NCT02950610). LAY SUMMARY: Breath malodour has been associated with a failing liver since the ancient Greeks. Analytical chemistry has provided us an insight into ubiquitous volatile organic compounds associated with liver (and other) diseases. This has vastly improved our understanding of the mechanistic processes of liver damage. Our study aims to identify volatile organic compounds which are specific to non-alcoholic fatty liver disease and that can be exploited for rapid diagnostics.

3.
J Hepatol ; 67(1): 40-46, 2017 07.
Article in English | MEDLINE | ID: mdl-28213164

ABSTRACT

BACKGROUND & AIMS: Carvedilol, a non-selective beta-blocker (NSBB) with additional anti-alpha 1 receptor activity, is a potent portal hypotensive agent and has been used as prophylaxis against variceal bleeding. However, its safety in patients with decompensated liver cirrhosis and ascites is still disputed. In this study, we examined whether long-term use of carvedilol in patients with ascites is a risk factor for mortality. METHODS: A single-centre retrospective analysis of 325 consecutive patients with liver cirrhosis and ascites presenting to our Liver Unit between 1st of January 2009 to 31st August 2012 was carried out. The primary outcome was all-cause and liver-specific mortality in patients receiving or not receiving carvedilol as prophylaxis against variceal bleeding. RESULTS: The final cohort after propensity score matching comprised 264 patients. Baseline ascites severity and UK end-stage liver disease (UKELD) score between carvedilol (n=132) and non-carvedilol (n=132) treated patient groups were comparable. Median follow-up time was 2.3years. Survival at the end of the follow-up was 24% and 2% for the carvedilol and the non-carvedilol groups respectively (log-rank p<0.0001). The long-term survival was significantly better in carvedilol than non-carvedilol group (log-rank p<0.001). The survival difference remained significant after adjusting for age, gender, ascites severity, aetiology of cirrhosis, previous variceal bleed, spontaneous bacterial peritonitis prophylaxis, serum albumin and UKELD with hazard ratio of 0.59 (95% confidence interval [CI]: 0.44, 0.80; p=0.001), suggesting a 41% reduction in mortality risk. When stratified by the severity of ascites, carvedilol therapy resulted in hazard ratio of 0.47 (95% CI: 0.29, 0.77; p=0.003) in those with mild ascites. Even with moderate or severe ascites, carvedilol use was not associated with increased mortality risk. CONCLUSION: Long-term carvedilol therapy is not harmful in patients with decompensated cirrhosis and ascites. LAY SUMMARY: The safety of carvedilol and other non-selective beta-blocker drugs in patients with liver cirrhosis and ascites is still debated. In this study, we have shown that carvedilol therapy in these patients was associated with reduced risk of mortality, particularly in those with mild ascites. We concluded that low dose, chronic treatment with carvedilol in patients with liver cirrhosis and ascites is not detrimental.


Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Ascites/drug therapy , Carbazoles/therapeutic use , Liver Cirrhosis/drug therapy , Propanolamines/therapeutic use , Aged , Ascites/mortality , Carvedilol , Cause of Death , Female , Humans , Liver Cirrhosis/mortality , Male , Middle Aged , Retrospective Studies
4.
QJM ; 110(3): 149-153, 2017 Mar 01.
Article in English | MEDLINE | ID: mdl-27507017

ABSTRACT

BACKGROUND: Deep venous thrombosis (DVT) is increasingly being managed in the outpatient setting, particularly patients deemed low-risk at presentation. The long-term outcomes of these patients remain unclear. AIM: To determine the long-term outcomes of patients with DVT and those with raised D-dimer without DVT managed exclusively by an ambulatory care pathway. DESIGN: Retrospective cohort analysis. METHODS: 828 consecutive patients assessed at the Ambulatory Care Clinic of a tertiary care university hospital between 1 January and 31 December 2008 for potential lower limb DVT were analysed. Primary and secondary outcome was all-cause mortality and new diagnosis of cancer, respectively. Median follow-up was 6.4 years. RESULTS: The final cohort comprised 131 patients with DVT, 396 with raised D-dimer without DVT and 165 with normal D-dimer without DVT. Long-term survival was 72.5% for DVT, 75.3% for elevated D-dimer without thrombosis and 93.3% for those with normal D-dimer ( P < 0.0001). The risk of death with DVT remained significant after adjusting for age, gender, previous cancer, recent surgery and previous thromboembolism (HR 2.17, 95% CI [1.07, 4.38]). Cancer accounted for 44.4 and 37.8% of deaths within the first and second groups, respectively. 50% of cancers in the former group were diagnosed during follow-up vs. 95.1% in the latter. CONCLUSION: The 5-year survival of patients with DVT managed via ambulatory care was worse than expected. An algorithm is urgently needed to identify predictors of adverse outcomes for both these patients as well as those with raised D-dimer without thrombosis.


Subject(s)
Ambulatory Care/methods , Venous Thrombosis/mortality , Venous Thrombosis/therapy , Adult , Aged , Aged, 80 and over , Cause of Death , Female , Fibrin Fibrinogen Degradation Products/metabolism , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasms/complications , Neoplasms/mortality , Retrospective Studies , Scotland/epidemiology , Venous Thrombosis/blood , Venous Thrombosis/etiology
5.
Gastrointest Endosc ; 84(6): 900-906.e3, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27108061

ABSTRACT

BACKGROUND: Endoscopic management of nonvariceal upper GI bleed (NVUGIB) can be challenging. Hemospray is a novel endoscopic hemostatic agent for NVUGIB. Its efficacy in attaining hemostasis in NVUGIB is promising, particularly with respect to technically difficult lesions. However, most of the currently available data are focused on its application as monotherapy. The aim of this study was to evaluate its efficacy as a second agent to adrenaline, or as an addition to the combination of adrenaline with either clips or a thermal device in NVUGIB. METHODS: Consecutive patients with Forrest 1a and 1b ulcer treated with hemostatic spray as an adjunct to conventional endoscopic hemostatic measures between July 2013 and June 2015 were included in this retrospective analysis. The endpoints were initial hemostasis, 7-day rebleeding, 30-day rebleeding, all-cause, and GI-related 30-day mortality. RESULTS: A total of 20 patients (median age, 75 years, 50% men, 60% Forrest 1a ulcer) were treated with hemostatic spray as a second agent to adrenaline, or as an adjunct to the combination of adrenaline with either clips or a thermal device. Hemostatic spray was used as a second agent to adrenaline in 40% and as a third agent to combined dual therapy in 60%. Initial hemostasis was attained in 95% with an overall rebleeding rate at 7 days of 16%. There was no difference between the 7-day and 30-day rebleeding rates. The combination of hemostatic spray and adrenaline resulted in 100% initial hemostasis and 25% 7-day rebleeding. Similarly, initial hemostasis was achieved in 92% with a 9% rebleeding rate when hemostatic spray was used as the third agent to 2 of the conventional measures. All-cause mortality was 15% with 1 GI-related death (3%). CONCLUSIONS: In our single-center retrospective analysis, hemostatic spray appears promising as an adjunct to conventional methods for NVUGIB, although prospective controlled trials are needed to confirm this.


Subject(s)
Epinephrine/therapeutic use , Hemostasis, Endoscopic/methods , Hemostatics/therapeutic use , Minerals/therapeutic use , Peptic Ulcer Hemorrhage/therapy , Aged , Aged, 80 and over , Cause of Death , Drug Therapy, Combination , Electrocoagulation , Female , Hemostasis, Endoscopic/adverse effects , Hemostasis, Endoscopic/instrumentation , Humans , Male , Middle Aged , Peptic Ulcer Hemorrhage/mortality , Recurrence , Retrospective Studies , Severity of Illness Index
6.
Liver Int ; 32(7): 1079-92, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22429485

ABSTRACT

BACKGROUND/AIMS: There is still debate about the relationship between fat accumulation and mitochondrial function in nonalcoholic fatty liver disease. It is a critical question as only a small proportion of individuals with steatosis progress to steatohepatitis. In this study, we focused on defining (i) the effects of triglyceride accumulation and reactive oxygen species (ROS) on mitochondrial function (ii) the contributions of triglyceride, ROS and subsequent mitochondrial impairment on the metabolism of energy substrates. METHODS: Human hepatoblastoma C3A cells, were treated with various combinations of oleate, octanoate, lactate (L), pyruvate (P) and ammonia (N) acutely or for 72 h, before measurements of triglyceride concentration, cell respiration, ROS production, mitochondrial membrane potential, ketogenesis and gluconeogenesis, TCA cycle metabolite analysis and electron microscopy. RESULTS: Acutely, LPON treatment enhanced mitochondrial respiration and ROS formation. After 72 h, despite the similarities in triglyceride accumulation, LPON treatment, but not oleate, dramatically affected mitochondrial function as evidenced by decreased respiration, increased mitochondrial membrane potential and ROS formation with concomitant enhanced ketogenesis. By comparison, respiration and ROS formation remained unperturbed with oleate. Importantly, this was accompanied by an increased gluconeogenesis and ketogenesis. The addition of the antioxidant N-acetyl-L-cysteine prevented mitochondrial dysfunction and reversed metabolic changes seen with LPON, strongly suggesting ROS involvement in mediating mitochondrial impairment. CONCLUSIONS: Our data indicate that ROS formation, rather than cellular steatosis per se, impairs mitochondrial function. Thus, reduction in cellular steatosis may not always be the desired outcome without concomitant improvement in mitochondrial function and/or reducing of ROS formation.


Subject(s)
Fatty Liver/metabolism , Mitochondria, Liver/metabolism , Triglycerides/metabolism , Acetylcysteine/pharmacology , Antioxidants/pharmacology , Cell Line, Tumor , Cell Respiration , Gluconeogenesis/drug effects , Gluconeogenesis/physiology , Humans , Membrane Potential, Mitochondrial/drug effects , Membrane Potential, Mitochondrial/physiology , Mitochondria, Liver/ultrastructure , Oxidative Stress , Reactive Oxygen Species/metabolism , Triglycerides/analysis , Triglycerides/pharmacology
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