Liver transplantation: a life-saving procedure following amatoxin mushroom poisoning

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Studies in acute liver failure

Acute liver failure (ALF) is a devastating condition with a high associated mortality rate. Paracetamol hepatotoxicity remains the leading cause of ALF in the developed world. The studies outlined in this thesis explore the current management of ALF, and systematically review the prognostic tests currently used in paracetamol-induced ALF. Using a database of over 900 acute liver injury patients, the impact of unintentional paracetamol overdose is retrospectively analysed, demonstrating a strong association between this mode of paracetamol overdose and adverse clinical outcomes, including the requirement for emergency orthotopic liver transplantation.Current prognostic tests for severe paracetamol-induced hepatotoxicity have been criticised for their relatively low sensitivity, with the result that not all patients who might benefit from tertiary level care are identified. This thesis demonstrates that the development of the Systemic Inflammatory Response Syndrome (SIRS) or extrahepatic organ failure is strongly associated with death following paracetamol overdose. Due to their very high sensitivity in this condition, both the SIRS and Sequential Organ Failure Assessment scores have potential as future gatekeepers to improve the triage of paracetamol overdose patients, thereby delivering tertiary level care to those most likely to require emergency transplantation.A greater understanding of the pathophysiological links between the initial hepatic injury and development of the SIRS could help to identify novel biomarkers for ALF, and help guide future therapeutic avenues. Using serum samples from a prospectively collected cohort of acute liver injury patients, this thesis identifies two novel biomarkers, serum ferritin and the long pentraxin PTX3, which show a strong association with outcome following paracetamol hepatotoxicity. These biomarkers illustrate the importance that the innate immune system plays in the pathogenesis of paracetamol-induced ALF, and identifies several exciting areas for future cellular and animal-based studies

Clinical profile, etiology of acute liver failure in children between 1 month - 12 yrs

OBJECTIVE / AIM: The aim of my study is to study and determine the clinical profile, etiology of acute liver failure in children between 1mon-12yrs of age in tertiary centre in South India. INTRODUCTION: Acute liver failure in children is a rare but potentially fatal disease In children the definition of acue liver failure is 1. children with no evidence of preexisting liver disease 2. biochemical evidence of acute liver injury 3. hepatic based coagulopathy defined as prothrombin time >15sec or INR>2.0 regardless of the presence or absence of clinical hepatic encephalopathy STUDY JUSTIFICATION: Acute liver failure in children had variety of etiologies , a specific diagnosis could be estabilised in 40% of cases,by various diagnostic tests,so that appropriate therapy can be instituted to reduce morbidity and mortality. METHODOLOGY (MATERIALS & METHODS) 1)STUDY DESIGN: Prospective study 2)STUDY POPULATION: Children in study age group attending gastroenterology department and admitted in medical ward , satisfying the inclusion criteria. 3)Place of study: Department of gastroenterology and paediatric medical ward in ICH 4)STUDY PERIOD: october2016 to june 2017 5)SAMPLE SIZE:50 6)INCLUSION CRITERIA: All children aged 1 month to 12years presenting with acute liver failure attending the hospital 7)EXCLUSION CRITERIA: children with pre-existing liver disease PROCEDURE :- After obtaining informed consent from parent/guardian, various patient demographic characteristics, history ,clinical details,anthropometry,will be entered in a pre structured profoma. All these children will have basic investigations like LFT Serum albumin total proteins liver enzymes viral markers,coagulation profile STATISTICAL ANALYSIS: Data will be entered in excel sheet. Statistical analysis of data will be performed by statistical software SPSS. Outcome variables will be categorized as normal or abnormal and their prevalence will be expressed as percentage and p value of <0.05 will be considered significant. RESULTS: In this study among the 50 children studied the age distribution was found to be 42% of the children belong to 6-12 years, 36% belong to 1-5 years and 22% belong to <1 year group. In this study, out of the 50 children studied, 16(32%) improved and 34(68%) died. In this study, the etiology of liver failiure was found to be infection(34%), drug induced(30%), inconclusive(16%), congestivecauses(8%)and inconclusive in 16% CONCLUSION: 1. In this study infection(34%) was the most common cause of acute liver failure followed by drug (30%) 2. In this study out of the 50 cases studied 68% died and 32% improved 3. Highest mortality was in the drug (80%) and congestive etiology(75%) 4. There was no correlation between demographic factors such as age sex and outcome 5. Our study failed to establish any association between clinical laboratory values and outcome Since ALF is a potentially fatal condition, estimating the likelihood of spontaneous recovery and identifying patients who cannot be salvaged without liver transplantation is necessary. Prognostic factors that predict mortality and need for early liver transplantation are required. Our study results highlight the fact that viral hepatitis remains the most common cause of acute liver failiur

Investigations into the pathophysiology, prognosis and clinical management of acute liver failure

In this thesis I will describe how my work has contributed to the understanding and management of acute liver failure (ALF). There are three main themes of my work: 1. Understanding the pathophysiological mechanisms in ALF 2. Defining prognosis in ALF. 3. Management of ALF, in particular focusing on the prevention of intracranial hypertension (ICH). Acute liver failure (ALF) is a rare syndrome, estimated to result in less than 10 cases per million in the West (1). In severe form it results in critical illness with multiple organ failure. It occurs in all age groups and usually presents in young adults without any previous liver disease. It has a high mortality and for those with a severe presentation the only treatment option is liver transplantation, however, the shortage of donor organs means that is only an option for selected cases (2). The ability to predict outcome early in the course of the illness is of critical importance when considering transplantation; there is only a short window of clinical opportunity during which liver transplantation is a viable option before the condition of the patient deteriorates to the point where transplantation becomes futile (3). Like other forms of critical illness, the progression to multiple organ failure dictates outcome. Additionally, patients with ALF can develop intracranial hypertension (ICH) due to cerebral oedema which has a further, significant, impact on morbidity and mortality. Management strategies to reduce the incidence and impact of ICH are, alongside accurate prognostication, an essential part of intensive care unit management of patients with ALF (4). Furthermore, performing clinical research in patients with ALF is very difficult for a number of reasons. It is a rare condition thus studies take a long time to recruit sufficient numbers. Patients are also extremely sick with the illness following a fulminating course and so often die early or are transplanted, confounding trial outcomes. Consequently, the number of randomised clinical trials in ALF is very small internationally and collaborations of liver centres have been developed with only varying degrees of success. The US ALF study group has produced 68 papers over its 22-year history. To this end, I was a founding member of the European ALF initiative in 2010, which initiated a number of surveys in clinical practice across Europe (5,6). The work that I authored with colleagues has had a significant impact on the understanding and management of ALF. It has directly influenced international management guidelines (7,8) in both Europe and the USA through the national hepatology associations (EASL & AASLD). My works covers the following principal themes: $\underline{\textbf{1. Pathophysiology}}$ Lactic acidosis was recognised as a prominent feature of ALF during the 1960s and the importance of it as a prognostic marker was elucidated during the late 1980s (9,10). The metabolic acidosis seen in ALF is due to a combination of lactic acidosis and acute kidney injury, both of which contribute to prognostic indices. I have directly contributed to the understanding of lactate metabolism in ALF through innovative work revealing the changes in lactate metabolism that occur during and following liver transplantation. The liver becomes a net producer of lactate in ALF instead of a consumer and I demonstrated that splanchnic lactate production comes from both the gut and the liver in ALF. The accompanying editorial noted that due to the design of the study which enabled sampling of portal vein lactate we were uniquely placed to distinguish between splanchnic and liver metabolism (11). The net production of lactate from the liver reverses following emergency liver transplantation, contributing to the rapid fall in serum lactate seen (12,13). This is significant as it helps to explain why a high lactate has prognostic value. The lactate produced within the liver represents the activation of inflammatory cells which use glycolysis aerobically and is a marker for the inflammatory burden. This inflammatory burden contributes to liver damage and to the systemic inflammatory response and organ failure seen (11). As well as work into lactate metabolism in ALF I have worked with colleagues in the Centre for Liver and GI Research in Birmingham to delineate the immunological mechanisms perpetuating liver damage. In particular, we demonstrated T-cell recruitment and activation within the liver during ALF (14). This work adds to the understanding of how the migration to and activation of inflammatory cells, stimulates the lactate production within the liver and result in systemic inflammation and organ failure. $\underline{\textbf{2. Prognosis in ALF}}$ Bernal and colleagues showed that serum lactate, which contributes to the metabolic acidosis in ALF, was also a prognostic marker in ALF due to paracetamol toxicity. I led work with colleagues in Birmingham, extending this work and demonstrated that it held true for non-paracetamol causes of ALF as well (15,16). This study confirmed and supports the use of lactate as a prognostic marker in a different cohort of patients with ALF, strengthening the evidence for its use. In our centre lactate levels at 12 hours following admission was shown, on multivariate analysis, to be a significant differentiator for survival. The 12 hour interval is important as it differentiates those patients in whom arterial lactate falls following initial resuscitation from those with persistent hyperlactataemia. I have continued to maintain an interest in prognostic models in ALF and contributed data and was an author on a recent publication examining dynamic models of predicting outcome in paracetamol induced ALF (17). The dynamic models look at both day one and day 2 markers. The lead time effect of early critical care intervention on organ failure increases the fidelity of the model and increases confidence in predication. $\underline{\textbf{3. Management of ALF}}$ Cerebral ischaemia and herniation related to cerebral swelling remains a significant cause of death in ALF (18). The recognition that cerebral oedema was a significant cause of death in ALF led to the introduction of intracranial pressure (ICP) monitoring and strategies to reduce it in patients with established intracranial hypertension (19,20). The use of osmotherapy with mannitol became the main therapy for cerebral oedema complicating ALF. Once established ICH is difficult to treat and tends to recure despite therapy. In novel work I initiated and studied, I looked at alternative types of osmotherapy in ALF by considering the use of hypertonic saline. It can increase blood osmolality and as sodium does not cross the blood brain barrier it serves to reduce brain water. In fact, because of the active nature of the barrier, sodium is actively pumped out, making its reflection coefficient (the tendency to not cross the blood brain barrier) higher than that of mannitol (21). ICH has a very poor prognosis and so prevention is a logical approach. In a landmark study I, together with colleagues investigated the prophylactic use of hypertonic saline infusions in patients with ALF in a randomised controlled trial. We demonstrated that maintaining serum sodium at approximately 150 mmol/l, prevented the increase in intracranial pressure seen in the control group. This study has now been cited over 340 times and has been adopted as standard therapy internationally (22). I have had a long-standing interest in the use of extracorporeal liver support in ALF, with the concept of liver dialysis being particularly appealing. Many systems have been investigated including the use of albumin dialysis via the molecular absorbent recirculating system (MARS). Together with colleagues I investigated the effects of the MARS extracorporeal liver support on physiological parameters in a series of patients with ALF (23). The study demonstrated that MARS therapy improved haemodynamic stability and decreased jugular bulb oxygen saturation reflecting an increase in cerebrovascular tone during the sessions. Notably, intracranial pressure did not change significantly over the treatment period suggesting that factors, not cleared via MARS, are important in the pathology. More recently, I helped develop the concept and design of an international collaboration, with colleagues in King’s College London and the Rigshospitalet (Copenhagen), to investigate the effects of prophylactic hypothermia on intracranial pressure in ALF (24). This international, multicentre, randomised controlled clinical trial compared moderate hypothermia with standard of care in patients with ALF at risk of cerebral oedema. Whilst the study was unable to show any difference in the rates of ICH the accompanying editorial noted that this “landmark study” highlighted the need to determine the correct target temperature to manage patients with ALF and how further experimental research is needed (25). 1. Bernal W, Wendon J. Acute Liver Failure. N Engl J Med. 2013 Dec 26;369(26):2525–34. 2. Reuben A, Tillman H, Fontana RJ, Davern T, McGuire B, Stravitz RT, et al. Outcomes in Adults With Acute Liver Failure Between 1998 and 2013. Ann Intern Med. 2016 Jun 7;164(11):724–32. 3. O’Grady J. Timing and benefit of liver transplantation in acute liver failure. J Hepatol. 2014 Mar;60(3):663–70. 4. Murphy ND. The pathology and management of intracranial hypertension in acute liver failure. 2007;678–90. 5. Bernal W, Han Y, Laterre PF, Lee A, Mas A, Murphy N, et al. 912 CLINICAL MANAGEMENT OF ACUTE LIVER FAILURE 2010: RESULTS OF A PAN-EUROPEAN SURVEY. J Hepatol. 2011 Mar;54:S364. 6. Wendon J, Bernal W, Laterre P, Nevens F, Hudson M, Aldersly M, et al. Acute liver failure: a European perspective. Crit Care. 2010;14(Suppl 1):P541. 7. Lee WM, Stravitz RT, Larson AM. Introduction to the Revised American Association for the Study of Liver Diseases Position Paper on Acute Liver Failure 2011. Hepatol Baltim Md. 2012 Mar;55(3):965–7. 8. Wendon J, Cordoba J, Dhawan A, Larsen FS, Manns M, Nevens F, et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66(5):1047–81. 9. Colombi A, Tholen H. Haemodialysis in the treatment of lactic acidosis associated with acute hepatic and renal failure. Postgrad Med J. 1971 Sep 1;47(551):628–31. 10. O’Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug;97(2):439–45. 11. Chang D-M. Hyperlactatemia in acute liver failure: Decreased clearance versus increased production: Crit Care Med. 2001 Nov;29(11):2225–6. 12. Murphy ND, Kodakat SK, Wendon JA, Jooste CA, Muiesan P, Rela M, et al. Liver and intestinal lactate metabolism in patients with acute hepatic failure undergoing liver transplantation. Crit Care Med. 2001 Nov;29(11):2111–8. 13. Walsh TS, McLellan S, Mackenzie SJ, Lee A. Hyperlactatemia and pulmonary lactate production in patients with fulminant hepatic failure. Chest. 1999 Aug;116(2):471–6. 14. Tuncer C, Oo YH, Murphy N, Adams DH, Lalor PF. The regulation of T-cell recruitment to the human liver during acute liver failure. Liver Int. 2013 Jul;33(6):852–63. 15. Bernal W, Donaldson N, Wyncoll D, Wendon JA. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet. 2002 Feb;359(9306):558–63. 16. Macquillan GC, Seyam MS, Nightingale P, Neuberger JM, Murphy ND. Blood lactate but not serum phosphate levels can predict patient outcome in fulminant hepatic failure. Liver Transplant Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc. 2005 Sep;11(9):1073–9. 17. Bernal W, Wang Y, Maggs J, Willars C, Sizer E, Auzinger G, et al. Development and validation of a dynamic outcome prediction model for paracetamol-induced acute liver failure: a cohort study. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):217–25. 18. Boeckx NK, Haydon G, Rusli F, Murphy N. Multiorgan failure is the commonest cause of death in fulminant hepatic failure: a single centre experience. Liver Int. 2004;24(6):702–3. 19. Braude S, Gimson AES, Williams R. Progress in the management of fulminant hepatic failure. Intensive Care Med. 1981 May;7(3):101–3. 20. Hanid MA, Mackenzie RL, Jenner RE, Chase RA, Mellon PJ, Trewby PN, et al. Intracranial pressure in pigs with surgically induced acute liver failure. Gastroenterology. 1979 Jan;76(1):123–31. 21. Qureshi AI, Suarez JI. Use of hypertonic saline solutions in treatment of cerebral edema and intracranial hypertension: Crit Care Med. 2000 Sep;28(9):3301–13. 22. Murphy ND, Auzinger G, Bernel W, Wendon JA. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatol Baltim Md. 2004 Feb;39(2):464–70. 23. Lai WK, Haydon G, Mutimer D, Murphy ND. The effect of molecular adsorbent recirculating system on pathophysiological parameters in patients with acute liver failure. Intensive Care Med. 2005 Nov;31(11):1544–9. 24. Bernal W, Murphy ND, Brown S, Whitehouse T, Bjerring PN, Hauerberg J, et al. A multicentre randomized controlled trial of moderate hypothermia to prevent intracranial hypertension in acute liver failure. J Hepatol. 2016 Aug;65(2):273–9. 25. Porcher R, Vaquero J. Hypothermia in acute liver failure: What got lost in translation? J Hepatol. 2016 Aug;65(2):240–2

34th Malaysian Association of Clinical Biochemists Annual Conference in collaboration with 2nd Malaysian Biomedical Science Association Symposium 2024

The Malaysian Association of Clinical Biochemists (MACB) and the Malaysian Biomedical Science Association (MyBiomed) successfully organized the 34th MACB Conference in conjunction with the 2nd MyBiomed Symposium 2024. Under the theme 'Towards Holistic Integration and Sustainability in Medical Laboratories, the event brought together experts from various disciplines to explore advancements and sustainability in laboratory medicine and biomedical science. The conference featured a comprehensive program including plenary lectures, industrial talks, oral and poster presentations, and trade exhibitions. It provided a platform for the exchange of scientific knowledge and insights into emerging technologies and practices. A diverse range of professionals participated, including local and international chemical pathologists, clinical biochemists, medical laboratory scientists, researchers, and postgraduate students. Key topics covered included natural product research, herbs and metabolic disease, molecular diagnostics, pharmacology and toxicology, endocrinology, reference intervals, value-based laboratory medicine, newborn screening, the role of digital technologies in medical labs, and strategies for developing green & sustainable medical laboratories. The discussions were aligned with the conference’s goal of fostering integration and sustainable practices in the medical laboratory sector, reflecting the latest trends and future directions of the field. The event achieved its aim of providing participants with valuable updates on scientific and technological innovations while fostering collaboration and dialogue among laboratory professionals at a global scale

Frequency of significant steatosis in various chronic liver diseases: an evaluation with Transient Elastography (TE)

INTRODUCTION: TE was developed as a non-invasive method to assess liver fibrosis and steatosis using shear wave velocity. Many studies have proven its’ effectiveness as a method for evaluating liver fibrosis and steatosis.1-2 OBJECTIVE: To determine the prevalence and aetiology of steatosis in our local population. METHOD: This study was conducted as a retrospective review on all patients who had TE performed at UMMC from 1 January 2013 to 31 December 2021. Their demographics, clinical characteristics and TE findings were charted. RESULTS: A total of 3066 patients were included. 51.7% were males and 48.3% were females. The median CAP value was 271 dB/m. The median E value was 6.5kPa. 61.2% of patients had steatosis, with a staggering number of of these patients having significant steatosis (51.8%). 6.3% of patients had S2 steatosis whereas 45.5% of patients had severe (S3) steatosis. Interestingly, in those with S2 steatosis, 34.7% had chronic hepatitis B (CHB), 31.5% had non-alcoholic fatty liver disease (NAFLD), 5.2% with chronic hepatitis C (CHC) and 1% had alcoholic liver disease (ALD). In the S3 steatosis group, 66.7% had NAFLD, followed by ALD (36.6%), CHB (30.1%) and CHC (27.7%). 221 DISCUSSION: It is important to highlight that a large proportion of our patients has significant steatosis. This is likely in keeping with the global rise of obesity and sedentary lifestyle.3 NAFLD is a 4-decades old nomenclature that does not appropriately address the heterogenous pathogenicity of fatty liver disease. Our study reflects this heterogeneity, as it shows that steatosis often co-exists with other diverse aetiologies. CONCLUSION: Whilst NAFLD clearly has the greatest frequency of severe steatosis, it is also present in other aetiologies. These findings support the new terminology of metabolic associated fatty liver disease (MAFLD), which reflects the fact that NAFLD commonly co-exists with other aetiologies

Case Reports

Abstracts of the&nbsp;29th Annual Scientific Meeting of the Indonesian Heart Association (ASMIHA) 1st ASMIHA Digital Conference, 23-25 October 202

Antioxidant and DPPH-Scavenging Activities of Compounds and Ethanolic Extract of the Leaf and Twigs of Caesalpinia bonduc L. Roxb.

Antioxidant effects of ethanolic extract of Caesalpinia bonduc and its isolated bioactive compounds were evaluated in vitro. The compounds included two new cassanediterpenes, 1α,7α-diacetoxy-5α,6β-dihydroxyl-cass-14(15)-epoxy-16,12-olide (1)and 12α-ethoxyl-1α,14β-diacetoxy-2α,5α-dihydroxyl cass-13(15)-en-16,12-olide(2); and others, bonducellin (3), 7,4’-dihydroxy-3,11-dehydrohomoisoflavanone (4), daucosterol (5), luteolin (6), quercetin-3-methyl ether (7) and kaempferol-3-O-α-L-rhamnopyranosyl-(1Ç2)-β-D-xylopyranoside (8). The antioxidant properties of the extract and compounds were assessed by the measurement of the total phenolic content, ascorbic acid content, total antioxidant capacity and 1-1-diphenyl-2-picryl hydrazyl (DPPH) and hydrogen peroxide radicals scavenging activities.Compounds 3, 6, 7 and ethanolic extract had DPPH scavenging activities with IC50 values of 186, 75, 17 and 102 μg/ml respectively when compared to vitamin C with 15 μg/ml. On the other hand, no significant results were obtained for hydrogen peroxide radical. In addition, compound 7 has the highest phenolic content of 0.81±0.01 mg/ml of gallic acid equivalent while compound 8 showed the highest total antioxidant capacity with 254.31±3.54 and 199.82±2.78 μg/ml gallic and ascorbic acid equivalent respectively. Compound 4 and ethanolic extract showed a high ascorbic acid content of 2.26±0.01 and 6.78±0.03 mg/ml respectively.The results obtained showed the antioxidant activity of the ethanolic extract of C. bonduc and deduced that this activity was mediated by its isolated bioactive compounds