In this chapter, we discuss the options and consensus around the use of sedation and analgesia in the liver patient. Sedation and analgesia can be challenging in liver disease. Patient comfort, compliance, and prevention of complications during endoscopy are highly desirable and judicious use of appropriate medications ensures a safe endoscopic procedure. The pharmacokinetics and pharmacodynamics of sedatives and analgesics can be unpredictable in liver patients, thus detailed assessment of the severity of liver disease is important in decision making. Whilst midazolam, a short acting benzodiazepine, is the most commonly used sedative for conscious sedation, propofol offers deeper sedation but needs trained healthcare personnel for safe administration. Opiates are commonly used and combination with sedatives is recommended in complex and prolonged procedures. Finally, the choice of sedation with or without analgesia should involve patients through an informed decision making process.
Cardiovascular disease (CVD) remains the major cause of excess mortality in patients with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the individual contribution of NAFLD to CVD risk factors in the absence of pathogenic influences from other comorbidities often found in NAFLD patients, by using an established in-vitro model of hepatic steatosis.Histopathological events in non-alcoholic fatty liver disease were recapitulated by focused metabolic nutrient overload of hepatoblastoma C3A cells, using oleate-treated-cells and untreated controls for comparison. Microarray and proteomic data from cell culture experiments were integrated into a custom-built systems biology database and proteogenomics analysis performed. Candidate genes with significant dysregulation and concomitant changes in protein abundance were identified and STRING association and enrichment analysis performed to identify putative pathogenic pathways.The search strategy yielded 3 candidate genes that were specifically and significantly up-regulated in nutrient-overloaded cells compared to untreated controls: fibrinogen alpha chain (2.2 fold), fibrinogen beta chain (2.3 fold) and fibrinogen gamma chain (2.1 fold) (all rank products pfp <0.05). Fibrinogen alpha and gamma chain also demonstrated significant concomitant increases in protein abundance (3.8-fold and 2.0-fold, respectively, p <0.05).In-vitro modelling of NAFLD and reactive oxygen species formation in nutrient overloaded C3A cells, in the absence of pathogenic influences from other comorbidities, suggests that NAFLD is an isolated determinant of CVD. Nutrient overload-induced up-regulation of all three fibrinogen component subunits of the coagulation cascade provides a possible mechanism to explain the excess CVD mortality observed in NAFLD patients.
Oxidative stress is the central to molecular events leading to the progression of simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD). We have previously shown that an in vitro cellular steatosis model using C3A cells treated with energy substrates; lactate (L), pyruvate (P), octanoate (O) and ammonia (N), recapitulates the sequence of events in dietary-induced NAFLD; namely enhanced acute respiration and reactive oxygen species (ROS) formation leading to mitochondrial impairment. In contrast, treatment with oleate results in similar triglyceride accumulation but with relatively low ROS. Using a combined microarray, proteomic and metabolomic approach, we aimed to explore how triglyceride accumulation and enhanced ROS affect glutathione metabolism in our in vitro cell model.
Methods
C3A cells were treated with either LPON or oleate for 72 hours. Microarray RNA expression was measured using Illumina® Whole Human Genome BeadChip H12 Microarray. For proteomics, peptides were analysed by liquid chromatography (LC) coupled mass spectrometry (MS) (Agilent HPLC/OrbitrapXL). Data were quantified label-free using Progenesis LC-MS and MASCOT. For metabolomics, LC separation was performed using hydrophilic interaction chromatography with a ZIC–HILIC. MS was performed using Orbitrap Exactive with HESI 2 probe. Raw LC/MS data were processed with XCMS Centwave and mzMatch.
Results
LPON led to 2-fold downregulation of GCLC (encodes glutamate-cysteine ligase catalytic subunit, the rate limiting enzyme for glutathione synthesis) and upregulation of GPX1 and TXNDC12. Expression of GCLC and TXNDC12 was unchanged with oleate. Metabolomics confirmed that oxidised glutathione, glutathione disulfide, was higher in LPON- than oleate-treated cells. Among glutathione S-transferase genes, GSTA1 was unchanged with oleate but was upregulated by LPON (2.4-fold). Similarly, GSTT1, GSTK1 and GSTO1 were significantly increased by LPON. In contrast, MGST2 expression was higher in oleate than LPON-treated cells. Finally, proteomics showed that microsomal glutathione S-transferase 2 was downregulated by 2.5-fold by LPON.
Conclusion
Our data show that increased ROS formation rather than triglyceride accumulation alters glutathione metabolism. Such alterations may influence susceptibility to further insults, particularly those accelerating glutathione depletion, for example, paracetamol overdose.
Dysphagia is an important symptom that warrants a diagnostic evaluation for an organic etiology that is generally treatable. Esophageal motility disorders are an important cause of dysphagia that may escape detection on initial radiological and endoscopic testing. Although uncommon, achalasia is an important disease that is the best understood and most readily treatable esophageal motility disorder. It serves as a prototype for disorders of the enteric nervous system with degeneration of the myenteric neurons that innervate the esophagus. Recognition of the clinical presentation and manometric features is necessary for appropriate management. Treatment studies have demonstrated the limited efficacy of botulinum toxin as well as the less than ideal, long-term effectiveness of both pneumatic dilation and Heller's myotomy. Eosinophilic esophagitis (EoE) is another cause of esophageal dysphagia that is increasingly being recognized as one of the most common causes of dysphagia in both children and adults. Food and environmental allergy, host immunological predisposition and interactions with gastroesophageal reflux disease have emerged as important aspects of the disease. Therapeutic options include medical therapy with acid suppression, corticosteroids and biologic agents. Elimination diets and endoscopic esophageal dilation have demonstrated effectiveness.
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