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AimPaediatric acute liver failure (P-ALF) is a rare and devastating condition that leads to death or liver transplantation (LTx) in 40%–60% of cases. Determining the aetiology can enable disease-specific treatment, aid in prognostication for hepatic recovery and guide the decision-making for liver transplantation. This study aimed to retrospectively evaluate a systematic diagnostic approach to P-ALF in Denmark and to collect epidemiological nationwide data.MethodsAll Danish children aged 0–16 years with P-ALF diagnosed between 2005 and 2018, and who were evaluated using a standardised diagnostic assessment programme, were eligible for retrospective analysis of clinical data.ResultsA total of 102 children with P-ALF were included (presentation at 0 days to 16.6 years of age, 57 females). Aetiological diagnosis was established in 82% of cases, the remainder were indeterminate. Fifty percent of children with P-ALF of indeterminate aetiology died or underwent LTx within 6 months after their P-ALF diagnosis, compared to 24% of children with an aetiological diagnosis, p = 0.04.ConclusionFollowing a systematic diagnostic evaluation programme, made it possible to identify the aetiology of P-ALF in 82% of cases which is associated with improved outcomes. The diagnostic workup should never be considered complete but rather adapt to ongoing diagnostic advances. Aim: Paediatric acute liver failure (P-ALF) is a rare and devastating condition that leads to death or liver transplantation (LTx) in 40%–60% of cases. Determining the aetiology can enable disease-specific treatment, aid in prognostication for hepatic recovery and guide the decision-making for liver transplantation. This study aimed to retrospectively evaluate a systematic diagnostic approach to P-ALF in Denmark and to collect epidemiological nationwide data. Methods: All Danish children aged 0–16 years with P-ALF diagnosed between 2005 and 2018, and who were evaluated using a standardised diagnostic assessment programme, were eligible for retrospective analysis of clinical data. Results: A total of 102 children with P-ALF were included (presentation at 0 days to 16.6 years of age, 57 females). Aetiological diagnosis was established in 82% of cases, the remainder were indeterminate. Fifty percent of children with P-ALF of indeterminate aetiology died or underwent LTx within 6 months after their P-ALF diagnosis, compared to 24% of children with an aetiological diagnosis, p = 0.04. Conclusion: Following a systematic diagnostic evaluation programme, made it possible to identify the aetiology of P-ALF in 82% of cases which is associated with improved outcomes. The diagnostic workup should never be considered complete but rather adapt to ongoing diagnostic advances.

International audience; Cyclopeptide mushroom poisoning is responsible for 90%-95% of deaths from macrofungi ingestion. The main objectives of this study are to describe cases of cyclopeptide mushroom poisoning and to determine risk factors that may influence the severity/mortality of poisoned patients. We included all cases of amatoxin toxicity reported to two French Poison Centers from 2013 through 2019. We compared the severity with the Poison Severity Score (PSS) and the outcomes of patients using simple logistic regression and multinomial logistic regression. We included 204 cases of amatoxin toxicity. More than three-quarters developed an increase in AST and/or ALT (78.1%), and over half developed a decrease in prothrombin ratio (

Background: Acetaminophen (N-acetyl-para-aminophenol, or APAP) poisoning, whether intentional or accidental, is a major general health problem, with its toxicity prevalence significantly increasing in many countries. Currently, acetaminophen is considered one of the main causes of acute liver failure globally. Aim: The aim of this study was to evaluate the possible hepatoprotective effect of Omega-3,6,9 against acetaminophen-induced hepatotoxicity in albino male mice. Methods: Thirty-five albino male mice were randomly divided into five groups: Group 1 (the negative control) received liquid paraffin orally at a dose of 10 ml/kg for ten days, followed by a single intraperitoneal injection (IP) of 10 ml/kg normal saline on the eleventh day of the test. Group 2 (positive control) received liquid paraffin. Group 3 was treated with Omega-3,6,9 (50 mg/kg/80 mL). Group 4 was treated with Omega-3,6,9 (100 mg/kg/35 mL). Group 5 was treated with N-acetylcysteine (100 mg/kg/10 ml). The mice were treated with Omega-3,6,9, N-acetylcysteine, and liquid paraffin once daily by oral gavage for ten days. Result: TNF-α, IL-10, ALT, and AST levels in the positive control group were significantly higher than those in the negative control group. TNF-α, IL-10, ALT, and AST levels in mice given Omega-3,6,9 (50 mg/kg), Omega-3,6,9 (100 mg/kg), and N-acetylcysteine (100 mg/kg) orally prior to acetaminophen injection were significantly decreased compared to those in the positive control group. Conclusion: Oral intake of Omega-3,6,9 may reduce the risk of acetaminophen-induced liver damage.

BACKGROUND The liver has traditionally been regarded as resistant to antibody-mediated rejection (AMR). AMR in liver transplants is a field in its infancy compared to kidney and lung transplants. In our case we present a patient with alpha-1-antitrypsin disease who underwent ABO compatible liver transplant complicated by acute liver failure (ALF) with evidence of antibody mediated rejection on allograft biopsy and elevated serum donor-specific antibodies (DSA). This case highlights the need for further investigations and heightened awareness for timely diagnosis. CASE SUMMARY A 56 year-old woman with alpha-1-antitrypsin disease underwent ABO compatible liver transplant from a deceased donor. The recipient MELD at the time of transplant was 28. The flow cytometric crossmatches were noted to be positive for T and B lymphocytes. The patient had an uneventful recovery postoperatively. Starting on postoperative day 5 the patient developed fevers, elevated liver function tests, distributive shock, renal failure, and hepatic encephalopathy. She went into ALF with evidence of antibody mediated rejection with portal inflammation, bile duct injury, endothelitis, and extensive centrizonal necrosis, and C4d staining on allograft biopsy and elevated DSA. Despite various interventions including plasmapheresis and immunomodulating therapy, she continued to deteriorate. She was relisted and successfully underwent liver retransplantation. CONCLUSION This very rare case highlights AMR as the cause of ALF following liver transplant requiring retransplantation.

The liver has been thought to protect against oxidative stress through mechanisms involving reduced glutathione (GSH) that consumes high-energy phosphor-nucleotides on its synthesis. However, hepatoprotective mechanisms in acute liver failure (ALF) where the phosphor-nucleotides are decreased in remain to be solved. Liver tissues were collected from patients with ALF and liver cirrhosis (LC) and living donors (HD) who had undergone liver transplantation. Tissues were used for metabolomic analyses to determine metabolites belonging to the central carbon metabolism, and to determine sulfur-containing metabolites. ALF and LC exhibited a significant decline in metabolites of glycolysis and pentose phosphate pathways and high-energy phosphor-nucleotides such as adenosine triphosphate as compared with HD. Conversely, methionine, S-adenosyl-l-methionine, and the ratio of serine to 3-phosphoglycerate were elevated significantly in ALF as compared with LC and HD, suggesting a metabolic boost from glycolysis towards trans-sulfuration. Notably in ALF, the increases in hypotaurine (HTU) + taurine (TU) coincided with decreases in the total amounts of reduced and oxidized glutathione (GSH + 2GSSG). Plasma NH3 levels correlated with the ratio of HTU + TU to GSH + 2GSSG. Increased tissue levels of HTU + TU vs total glutathione appear to serve as a biomarker correlating with hyperammonemia, suggesting putative roles of the HTU-TU pathway in anti-oxidative protective mechanisms.

Acute hepatitis B virus (HBV) infection occasionally progresses to acute liver failure, often with poor prognosis. The appropriate pharmacological approach is yet to be established. Although nucleotide analogs (NA) and corticosteroids are candidates for the treatment of acute HBV infection, their therapeutic effects, especially their effect on HBV clearance, remain unclear. To clarify effects on the HBV clearance of combination therapy of NA and steroid pulse therapy (SPT) for acute HBV infection, we first analyze the effectiveness of this therapy in patients with HBV infection compared with NA monotherapy (NAM). Of the 57 consecutive patients with acute hepatitis B infection from May 2007 to December 2018, we have included 25 patients for this study, whom we followed up until HBV clearance. According to the administration of NA and SPT, we divided patients into two groups (NAM group and NA + SPT group) and compared their results. Of the 25 patients, 10 received NAM, whereas 15 received NA + SPT. There were no appreciable adverse effects related to SPT. The time required for the clearance of HBsAg (76 (43–116) days vs. 26 (14–51) days, p = 0.0418) and HBV-DNA (NAM group vs. NA + SPT group: 180 (83.5–220) vs. 69 (43–136) days, p = 0.0420) was significantly shorter in the NA + SPT group than in the NAM group. The hazard ratio of NA + SPT for the clearance of HBsAg and HBV-DNA were 0.45 (0.19–1.09) and 0.35 (0.14–0.89), respectively. In conclusion, we showed that NA + SPT promoted HBV elimination. These findings support the use of the NA + SPT combination for acute HBV infection without the concern of persistent HBV infection.

Dengue hemorrhagic fever (DHF) is one of the most rapidly emerging infections of tropical and subtropical regions worldwide. It affects more rural and urban areas due to many factors, including climate change. Although most people with dengue viral infection are asymptomatic, approximately 25% experience a self-limited febrile illness with mild to moderate biochemical abnormalities. Severe dengue diseases develop in a small proportion of these patients, and the common organ involvement is the liver. The hepatocellular injury was found in 60%-90% of DHF patients manifested as hepatomegaly, jaundice, elevated aminotransferase enzymes, and critical condition as an acute liver failure (ALF). Even the incidence of ALF in DHF is very low (0.31%-1.1%), but it is associated with a relatively high mortality rate (20%-68.3%). The pathophysiology of liver injury in DHF included the direct cytopathic effect of the DENV causing hepatocytes apoptosis, immune-mediated hepatocyte injury induced hepatitis, and cytokine storm. Hepatic hypoperfusion is another contributing factor in dengue shock syndrome. The reduction of morbidity and mortality in DHF with liver involvement is dependent on the early detection of warning signs before the development of ALF.

Liver disease, occurring during pediatric or adult age, is often of undetermined cause. Some cases are probably related to undiagnosed inherited metabolic disorders. Hepatic disorders associated with fructose-1,6-bisphosphatase deficiency, a gluconeogenesis defect, are not reported in the literature. These symptoms are mainly described during acute crises, and many reports do not mention them because hypoglycemia and hyperlactatemia are more frequently in the forefront. Herein, the liver manifestations of 18 patients affected with fructose-1,6-bisphosphatase deficiency are described and the corresponding literature is reviewed. Interestingly, all 18 patients had liver abnormalities either during follow-up (hepatomegaly [n = 8/18], elevation of transaminases [n = 6/15], bright liver [n = 7/11]) or during acute crises (hepatomegaly [n = 10/17], elevation of transaminases [n = 13/16], acute liver failure [n = 6/14], bright liver [n = 4/14]). Initial reports described cases of liver steatosis, when liver biopsy was necessary to confirm the diagnosis by an enzymatic study. There is no clear pathophysiological basis for this fatty liver disease but we postulate that endoplasmic reticulum stress and de novo lipogenesis activation could be key factors, as observed in FBP1 knockout mice. Liver steatosis may expose patients to severe long-term liver complications. As hypoglycemia becomes less frequent with age, most adult patients are no longer monitored by hepatologist. Signs of fructose-1,6-bisphosphatase deficiency may be subtle and can be missed in childhood. We suggest that fructose-1,6-bisphosphatase deficiency should be considered as an etiology of hepatic steatosis, and a liver monitoring protocol should be set up for these patients, during lifelong follow-up.

BACKGROUND Wilson’s disease (WD) is a rare autosomal recessive inherited disorder of copper metabolism. Acute liver failure (ALF) and hemolytic anemia represent the most severe presentation of WD in children. No clear genotype-phenotype correlations exist in WD. Protein-truncating nonsense, frame-shift, or splice-site variants may be associated with more severe disease. In contrast, missense variants may be associated with late-onset, less severe disease, and more neurological manifestations. Recently, a gene variant (HSD17B13:TA, rs72613567) with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD. AIM To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia. METHODS The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed. The clinical manifestations (ALF with non-immune hemolytic anemia or other less severe forms), laboratory parameters, copper metabolism, ATP7B variants, and the HSD17B13:TA (rs72613567) variant were reviewed to analyze the possible genotype-phenotype correlations. RESULTS We analyzed the data of 51 patients with WD, 26 females (50.98%), with the mean age at the diagnosis of 12.36 ± 3.74 years. ALF and Coombs-negative hemolytic anemia was present in 8 children (15.67%), all adolescent girls. The Kayser-Fleisher ring was present in 9 children (17.65%). The most frequent variants of the ATP7B gene were p.His1069Gln (c.3207A>G) in 38.24% of all alleles, p.Gly1341Asp (c.4021G>A) in 26.47%, p.Trp939Cys (c.2817G>T) in 9.80%, and p.Lys844Ter (c.2530A>T) in 4.90%. In ALF with hemolytic anemia, p.Trp939Cys (c.2817G>T) and p.Lys844Ter (c.2530A>T) variants were more frequent than in other less severe forms, in which p.His1069Gln (c.3207A>G) was more frequent. p.Gly1341Asp (c.4021G>A) has a similar frequency in all hepatic forms. For 33 of the patients, the HSD17B13 genotype was evaluated. The overall HSD17B13:TA allele frequency was 24.24%. Its frequency was higher in patients with less severe liver disease (26.92%) than those with ALF and hemolytic anemia (14.28%). CONCLUSION It remains challenging to prove a genotype-phenotype correlation in WD patients. In children with ALF and hemolytic anemia, the missense variants other than p.His1069Gln (c.3207A>G) and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants. As genetic analysis is usually time-consuming and the results are late, the importance at the onset of the ALF is questionable. If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease, this could be essential to predict a possible severe evolution.

Introduction and aim: Drug-induced liver injury (DILI) manifests as a spectrum of clinical presentations that carries morbidity and mortality. Patients with chronic liver disease (CLD), particularly hospitalized, are at high risk for developing DILI. We aimed to investigate the use of potentially hepatotoxic drugs (PHD) in patients with CLD in a tertiary university hospital. Materials and methods: Adult (≥ 18 years-old) with CLD admitted to the hospital from January 2016 to December 2018 were evaluated regarding PHD, assessing the risk of DILI and liver enzymes behavior after exposure. Results: From 931 hospitalized patients with CLD, 291 (31.3%) were exposed to hepatotoxic drugs during their hospitalization. Of those, 244 (83.8%) were cirrhotic. The most frequent causes of liver disease were hepatitis C (41.2%), followed by alcohol (13.2%), hepatitis C/alcohol (11.7%) and non-alcoholic fatty liver disease (5.8%). Decompensated cirrhosis (46.7%) was the main reason for hospital admission. The most often prescribed PHD were antibiotics (67.7%), cardiovascular drugs (34.4%), neuromodulators (26.1%) and anesthetics (19.9%). After exposure, 113 patients (38.8%) presented significant elevated liver enzymes. Surprisingly, PHD were more often prescribed in GI/Liver unit (48.8%) followed by emergency/intensive care unit (28.5%). A total of 65 patients (22%) died, however in neither case was it possible to safely infer causal relationship among PHD, liver enzymes and death. Conclusion: PHD prescription is frequent in patients with CLD even in a tertiary university hospital and in the gastroenterology and hepatology department, exposing these patients to an additional risk.

Background. Today paracetamol poisoning is one of the most common and most dangerous types of drug poisoning. In Ukraine, the number of suicide attempts involving paracetamol in 2018 has doubled compared to 2017. The purpose was to investigate the dynamics of clinical and laboratory indicators for severe paracetamol poisoning, complicated by the development of acute liver failure, and evaluate the effectiveness of the use of antidotes and pharmacological remedies. Material and methods. The article presents a case of severe paracetamol tablets poisoning in a 22-year old woman. The treatment was conducted in the toxic-therapeutic department of the hospital of emergency medical aid of the city of Mykolaiv in 2018. Data of clinical, laboratory, functional research methods was analyzed. Results. In June 2018, a 22-year woman, a student, admitted to the toxic-therapeutic department of the emergency hospital in Mykolaiv. Relatives informed that on the eve of the evening the woman had swallowed a large number of various pills, mainly paracetamol, for suicidal purposes. She also tried to cut the veins in her forearm. The patient bought paracetamol tablets the same day at various drugstores in the city; 110 tablets (200, 350, and 500 mg) of paracetamol and 10 sleeping pills were purchased. According to approximate estimates, the total dose of paracetamol taken exceeded 250 mg/kg body weight. Diagnosis: acute household drugs poisoning (paracetamol, hypnotics). Suicidal attempt. Cut wounds of forearms of both hands. The gastric lavage and bo­wel cleansing were carried out. There were prescribed the antidote — ACC (acetylcysteine, NAC — 140 mg/kg/day); hepatoprotective remedies: thioctic acid (20 mg/kg/day), silibinin (20 mg/kg/day), ademetionine (400 mg/day), arginine glutamate (40%, 5.0 ml/day), dexamethasone (8 mg/day). After 24 hours, there developed a sharp increase in the level of ASAT — 1073 U/l (normal — up to 32 U/l), ALAT — 1116 U/l (normal — up to 33 U/l), GGTP — 57 (normal — up to 32 U/l) and decrease in prothrombin index (PTI) — 38.0 % (normal — 97–100 %), INR — 2 (normal — 0.85–1.35), APTCH — 34 (normal — 24.0–34.0 sec.). After 48 hours, the indicators reached maximum values: ASAT — 19,740 U/l, ALAT — 14,800 U/l, GGTP — 157 U/l. However, the indicator of PTI critically decreased to 13.0 %, indicators of INR increased — 4, APTCH — 48. At the same time, yellowing of the sclera of the eyes and skin developed; the enlargement of the abdomen, liver, ascites were observed; bloody vaginal discharge and decreased urine output appeared. The neurological status of the patient worsened; drowsiness and negativism were noted. During the ultrasound examination of abdominal organs, enlargement of the liver and the presence of free fluid were noted. After a consultation, it was decided to continue the treatment with antidotes, sorbents, glucose solutions, crystalloids, fresh frozen blood plasma. Besides, there were prescribed vitamin K, etamsylate, furosemide, spironolactone, dexamethasone, and pentoxifylline. On the fifth day of treatment, the positive dynamics of blood biochemical parameters was noted. ASAT — 240 U/l, ALAT — 3,495 U/l, PTI — 61 % stabilized, daily diuresis increased. On the 14th day of treatment, the second examination of abdominal organs showed positive dynamics, the normal size of the liver, pancreas, and kidney had no pathology; free fluid in the abdomen was not detected. A psychiatrist examined the patient. On the 16th day of treatment, the patient was discharged in satisfactory condition. At the time of discharge, the patient did not have any complaints. Consultation of a fami­ly physician, diet, and hepatoprotectors (silibinin) were recommended for one month. Abdominal ultrasound control and laboratory control of blood biochemical parameters were recommended to be performed one month later. The specialist’s focus should be on the clinical signs of poisoning. The basic treatment for acute paracetamol poisoning is a specific antidote therapy, which is most effective in the first twelve hours after taking acetaminophen. In the world and domestic practice, ACC — N-acetylcysteine (N-acetyl-1-cysteine, NAC, acetylcysteine, LNAC) is used as an antidote. The mechanism of the antidote action of acetylcysteine is based on the ability of its SH reactive group to bind chemical radicals. Besides, acetylcysteine enhances the synthesis of glutathione, which is particularly valuable for paracetamol poisoning. Therefore, the use of ACCs is indicated in all cases of taking paracetamol at a dose of 5 g in adults and 100 mg/kg in children. ACC tablets or a solution are given in the first 12–72 hours at a dose of 140 mg/kg every 12 hours, for more than 72 hours after poisoning it is administered at a dose of 70 mg/kg every 12 hours. The estimated daily dose is 3,000–6,000 mg of ACC. Despite the decrease in the effectiveness of specific therapy at a later date, we consider it advisable to conduct even after 24–48 hours from the moment of poisoning for at least 1–3 days under the control of blood biochemical parameters (ASAT, ALAT, PTI). The duration of specific therapy is still a matter of debate. With the oral administration, it is recommended to continue for 72 hours, with intravenous administration within 24–48 hours. Current studies suggest the administration of antidotes throughout the paracetamol presence in a patient’s body. The use of extracorporeal treatment, in our opinion, does not solve the problem of detoxication after paracetamol poisoning. Howe­ver, some of the methods (hemodiafiltration, hemodialysis, and ultrafiltration) can help to correct the water-electrolyte balance, compensate for acidosis, reduce swelling and the effects of intoxication. Conclusions. The problem of acute paracetamol poisoning remains urgent in toxicology practice due to a significant increase in the number of such poisonings among patients of different age groups. Using an antidote, ACC (acetylcysteine, NAC) is effective in case of timely treatment of patients. The development of toxic hepatitis, pancreatitis and renal failure are typical complications of acute paracetamol poisonings and require complex treatment. The biomarkers of the toxic process are ASAT, ALAT, GGTP in blood, PTI, and INR., Актуальность. На сегодняшний день отравление парацетамолом является одним из наиболее распространенных и опасных видов лекарственных отравлений. В Украине количество суицидальных попыток с участием парацетамола в 2018 году выросло вдвое по сравнению с 2017 годом. Цель: исследовать динамику клинических и лабораторных показателей при отравлении парацетамолом тяжелой степени, осло­жненном развитием острой печеночной недостаточности, и оценить эффективность применения антидотов и средств фармакологической коррекции. Материалы и методы. Случай отравления таблетками парацетамола тяжелой степени у женщины 22 лет. Результаты. Гражданка Я., 22 лет, с суицидальной целью приняла 110 таблеток парацетамола и 10 таблеток снотворного средства. Общая доза принятого парацетамола превысила 250 мг/кг массы тела. Проведено промывание желудка и кишечника. Начата инфузионная терапия растворами кристаллоидов, глюкозы, сорбитола, натрия гидрокарбоната 4%. Назначено лечение: ацетилцистеин (АЦЦ) (140 мг/кг/день), тиоктовая кислота (20 мг/кг/день), силибинин (20 мг/кг/день), адеметионин (400 мг/день), аргинина глутамат (40%, 5,0 мл/день), дексаметазон (8 мг/день). Через 24 часа зарегистрированы высокие уровни ферментов АсАт, АлАт, гамма-глутамилтранспептидазы (ГГТП), явления коагулопатии. Изменения достигли максимальных значений через 48 часов после поступления: АсАт — 19 740 Ед/л (норма — до 32 Ед/л), АлАт — 14 800 Ед/л (норма — до 33 Ед/л), ГГТП — 157 Ед/л (норма — до 32 Ед/л); протромбиновый индекс (ПТИ) — 13,0 %, международное нормализованное отношение — 4, активированное частичное тромбопластиновое время — 48. Отмечены пожелтение склер и кожи, увеличение живота, печени, асцит, появились кровянистые выделения из влагалища, уменьшение диуреза. Назначены свежезамороженная плазма, витамин К, этамзилат, фуросемид, спиронолактон, дексаметазон, пентоксифиллин. На 5-е сутки лечения началась нормализация биохимических показателей крови, а на 16-е сутки лечения пациентка была выписана в удовлетворительном состоянии. Выводы. Проблема острых отравлений парацетамолом остается актуальной в практике врача-токсиколога. Использование антидота — АЦЦ дает положительный результат при своевременном обращении пациента за медицинской помощью. Токсический гепатит, панкреатит и почечная недостаточность — типичные осложнения тяжелого отравления парацетамолом и требуют сложного комплексного лечения. Биологическими маркерами токсического процесса являются уровни в крови АсАт, АлАт, ГГТП и ПТИ., Актуальність. На сьогодні отруєння парацетамолом є одним з найбільш поширених і небезпечних видів отруєння лікарськими засобами. В Україні кількість суїцидальних спроб за участю парацетамолу в 2018 році зросла вдвічі порівняно з 2017 роком. Мета: дослідити динаміку клінічних і лабораторних показників при отруєнні парацетамолом тяжкого ступеня, що ускладнилося розвитком гострої печінкової недостатності, та оцінити ефективність застосування антидотів і засобів фармакологічної корекції. Матеріали та методи. Випадок отруєння таблетками парацетамолу тяжкого ступеня у жінки 22 років. Результати. Громадянка Я., 22 років, з суїцидальної метою прийняла 110 таблеток парацетамолу і 10 таблеток снодійного засобу. Загальна доза парацетамолу перевищила 250 мг/кг маси тіла. Проведене промивання шлунка й очищення кишечника. Розпочата інфузійна терапія розчинами кристалоїдів, глюкози, сорбітолу, натрію гідрокарбонату 4%. Призначене лікування: ацетилцистеїн (АЦЦ) (140 мг/кг/добу); тіоктова кислота (20 мг/кг/добу); силібінін (20 мг/кг/добу); адеметіонін (400 мг/добу); аргініну глутамат (40%, 5,0 мл/добу), дексаметазон (8 мг/добу). Через 24 години зареєстровано різке підвищення рівня ферментів АсАт, АлАт, гамма-глутамілтранспептидази (ГГТП), явища коагулопатії. Зміни набули максимальних значень через 48 годин після надходження: АсАт — 19 740 Од/л (норма — до 32 Од/л), АлАт — 14 800 Од/л (норма — до 33 Од/л), ГГТП — 157 Од/л (норма — до 32 Од/л); протромбіновий індекс (ПТІ) — 13,0 %, міжнародне нормалізоване відношення — 4, активований частковий тромбопластиновий час — 48. Відмічені пожовтіння склери очей і шкіри, збільшення живота, печінки, асцит, з’явилися кров’янисті виділення з піхви, зниження діурезу. Призначено свіжозаморожену плазму, вітамін К, етамзилат, фуросемід, спіронолактон, дексаметазон, пентоксифілін. На 5-ту добу лікування була відмічена позитивна динаміка біохімічних показників крові, а на 16-ту добу лікування пацієнтка була виписана в задовільному стані. Висновки. Проблема гострих отруєнь парацетамолом залишається актуальною в практиці лікаря-токсиколога. Використання антидоту — АЦЦ дає позитивний результат при своєчасному зверненні пацієнта за медичною допомогою. Токсичний гепатит, панкреатит і ниркова недостатність — типові ускладнення тяжкого отруєння парацетамолом і потребують складного комплексного лікування. Біологічними маркерами токсичного процесу є рівні в крові АсАт, АлАт, ГГТП і ПТІ.

Introduction The prevalence and significance of acute liver injury in patients with COVID-19 are poorly characterized. Methods Patients with confirmed COVID-19 who were hospitalized in geographically diverse medical centers in North America were included. Demographics, symptoms, laboratory data results, and outcomes were recorded. Linear and logistic regression identified factors associated with liver injury, in-hospital mortality, and length of stay (LOS). Results Among 1555 patients in the cohort, most (74%) had an elevated alanine aminotransferase (ALT) during hospitalization, which was very severe (> 20 × upper limit of normal [ULN]) in 3%. Severe acute liver injury (ALI) was uncommon, occurring in 0.1% on admission and 2% during hospitalization. No patient developed acute liver failure (ALF). Higher ALT was associated with leukocytosis (per mL3) (β 10.0, 95% confidence interval (CI) 6.7–12.6, p 20 × ULN (unadjusted OR 6.0, 95%CI 3.1–11.5, p 3 × ULN (unadjusted OR 4.4, 95%CI 2.5–7.7, p

This study aimed to investigate the therapeutic potential of human umbilical cord mesenchymal stem cells derived exosomes (hUCMSC-Exo) in acute liver failure (ALF) in mice as well as its underlying mechanism. We found that a single tail vein administration of hucMSC-Exo effectively enhanced the survival rate, inhibited apoptosis in hepatocytes, and improved liver function in APAP-induced mouse model of ALF. Furthermore, the deletion of glutathione (GSH) and superoxide dismutase (SOD), generation of malondialdehyde (MDA), and the over production of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) caused by APAP were also inhibited by hucMSC-Exo, indicating that hucMSC-Exo inhibited APAP-induced apoptosis of hepatocytes by reducing oxidative stress. Moreover, hucMSC-Exo significantly down-regulated the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α in APAP-treated livers. Western blot showed that hucMSC-Exo significantly promoted the activation of ERK1/2 and IGF-1R/PI3K/AKT signaling pathways in APAP-injured LO2 cells, resulting in the inhibition of apoptosis of LO2 cells. Importantly, PI3K inhibitor LY294002 and ERK1/2 inhibitor PD98059 could reverse the function of hucMSC-Exo on APAP-injured LO2 cells in some extent. Our results suggest that hucMSC-Exo offer antioxidant hepatoprotection against APAP in vitro and in vivo by inhibitiing oxidative stress-induced apoptosis via upregulation of ERK1/2 and PI3K/AKT signaling pathways.

Pediatric acute liver failure (PALF) is a common cause of liver transplantation (LT) but showed poor post-LT outcomes. We reviewed 36 PALF patients and 120 BA patients who underwent LT in our institution. The cause of PALF was unknown in 66.7%. PALF patients were older (6.2 vs. 2.9 years) with higher PELD scores (31.5 vs. 24.4) and shorter waitlist time (15.7 vs. 256.1 days) (p < 0.01). PALF patients showed higher rates of post-transplant renal replacement therapy (RRT) (13.9% vs. 4.2%) and hepatic artery complications (13.9% vs. 0.8%), while portal vein complications rates were lower (0% vs. 10.8%), (p < 0.05). Although PALF patients showed lower 5-year survival rates (77.8% vs. 95.0 %, p < 0.01), the 5-year survival rates of patients who lived beyond the first year were comparable (96.6% vs. 98.3%, p = 0.516). The most common cause of deaths within one year was graft failure (75.0%) in PALF patients, but infection (67.7%) in BA patients. In multivariate analysis, lower body weight, hepatic artery complications and post-transplant RRT were associated with worse survival outcomes (p < 0.05). In conclusion, physicians should be alert to monitor the immediate postoperative graft dysfunction and hepatic artery complications and patients on post-transplant RRT in order to improve survival outcomes in PALF patients.

The multi-organ failure syndrome associated with acute and acute-on-chronic liver failure (ACLF) is thought to be mediated by overwhelming systemic inflammation triggered by both microbial and non-microbial factors. Therapeutic plasma exchange (TPE) has been proven to be an efficacious therapy in autoimmune conditions and altered immunity, with more recent data supporting its use in the management of liver failure. Few therapies have been shown to improve survival in critically ill patients with liver failure who are not expected to survive until liver transplantation (LT), who are ineligible for LT or who have no access to LT. TPE has been shown to reduce the levels of inflammatory cytokines, modulate adaptive immunity with the potential to lessen the susceptibility to infections, and reduce the levels of albumin-bound and water-bound toxins in liver failure. In patients with acute liver failure, high volume TPE has been shown to reduce the vasopressor requirement and improve survival, particularly in patients not eligible for LT. Standard volume TPE has also been shown to reduce mortality in certain sub-populations of patients with ACLF. TPE may be most favorably employed as a bridge to LT in patients with ACLF. In this review, we discuss the efficacy and technical considerations of TPE in both acute and acute-on-chronic liver failure.

Autochthonous hepatitis E virus (HEV) infection is an increasingly recognized zoonosis in western countries. It is often asymptomatic but may cause severe illness, particularly in immunocompromised patients or those with underlying chronic liver diseases. Even less frequently, cases of acute failure have been reported. In this article, we describe a case of an immunocompetent patient who presented with symptomatic acute HEV hepatitis and progressed to acute liver failure. The patient was transferred to another hospital for further management and transplant consideration. Unfortunately, he developed multi-organ failure thereafter and died before the transplantation became feasible. Subsequently, HEV was confirmed in archived serum by detection of HEV RNA using commercial RT-PCR. The results of this study have confirmed that HEV testing should be included in the initial evaluation of every acute liver failure regardless of travel history, risk factors or underlying chronic liver diseases. This approach might support clinical decisions and enable to use of potential antiviral therapy.

Background DJ-1 (also known as PARK7), a noted protein implicated in modulating ROS production and immune response, has been observed to play critical roles in the pathogenesis of many forms of liver disease through multiple mechanisms. However, its role and specific mechanism in acetaminophen (APAP) -induced liver injury have not been explored. Results In this present study, by employing an acute liver injury induced by APAP overdose mouse model, we demonstrated that DJ-1 knockout (DJ-1-/-) mice showed reduced liver injury and lower mortality. In accordance with these changes, there were also alleviating inflammatory responses in both the serum and the liver of the DJ-1-/- mice compared to those of the wild-type (WT) mice. Functional experiments showed that APAP metabolism did not affected by DJ-1 deficiency. In addition, to investigate DJ-1 modulates which kind of cell types during APAP-overdose-induced acute liver injury, hepatocyte-specific DJ-1-knockout (Alb-DJ-1-/-) and myeloid-specific DJ-1-knockout (Lysm-DJ-1-/-) mice were generated. Interestingly, hepatic deletion of DJ-1 did not protect APAP-overdose induced hepatotoxicity and inflammation, whereas Lysm-DJ-1-/- mice showed similar protective effects as DJ-1-/- mice which suggest that the protective effects of deletion of DJ-1 was through modulating myeloid cell function. Consistently, there were alleviated pro-inflammatory cells infiltration and reduced reactive oxygen species (ROS) production in the liver of Lysm-DJ-1-/- mice relative to control mice. Conclusion our findings clearly defined that deletion of DJ-1 protects APAP-induced acute liver injury through decreasing inflammatory response, and suggest DJ-1 as a potential therapeutic and/or prophylactic target of APAP-induced acute liver injury.

Background and Aim Wilson's disease (WD) is a rare inherited disease that causes systemic copper accumulation. This study examined the long‐term course of WD patients with liver disease. Methods The 12 patients (9 female patients) enrolled in the study had a median age of 28 years (range: 19–57 years) at their first visit to our hospital. Clinical course and fibrosis markers were assessed in all patients. Results The median age at diagnosis was 24 years (range: 5–42 years). One patient had acute liver failure (ALF) and 11 patients had chronic liver disease (CLD, 5 with cirrhosis). The patients were followed‐up for >20 years. The patient with ALF underwent liver transplantation; the postoperative course during the subsequent 20 years was good. Of the six patients with CLD, liver cirrhosis developed in four patients with interrupted chelating therapy. Two of the patients with cirrhosis died; one of these two patients died at 21 years after liver transplantation. However, the remaining patients with continued treatment exhibited a favorable clinical course for 30 years and none developed hepatocellular carcinoma (HCC). The duration of chelation therapy was significantly negatively correlated (P, The duration of chelation therapy for Wilson's disease complicated by liver disease was significantly negatively correlated with the fibrosis‐4 index and aspartate aminotransferase to platelet ratio index (APRI) score at the last visit.

Revisão de escopo sobre Hepatite Aguda Grave de etiologia desconhecida potencialmente causada por Adenovírus

This working group of the International Society of Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) was commissioned to summarize and update current efforts in the development and characterization of animal models of hepatic encephalopathy (HE). As defined in humans, HE in animal models is based on the underlying degree and severity of liver pathology. Although hyperammonemia remains the key focus in the pathogenesis of HE, other factors associated with HE have been identified, together with recommended animal models, to help explore the pathogenesis and pathophysiological mechanisms of HE. While numerous methods to induce liver failure and disease exist, less have been characterized with neurological and neurobehavioural impairments. Moreover, there still remains a paucity of adequate animal models of Type C HE induced by alcohol, viruses and non-alcoholic fatty liver disease; the most common etiologies of chronic liver disease.

Background and Aim Acute liver failure (ALF) poses a serious public health issue. The menstrual blood‐derived mesenchymal stem cells (MenSCs) have been applied to cure various liver‐related diseases. However, the efficacy and mechanism are far from clear. This study aims to explore the efficacy and potential mechanism of MenSCs to cure ALF. Methods We investigate the potential mechanism of MenSCs on the ALF in vitro and in vivo. A2A adenosine receptor (A2AR) activation was investigated as the potential reinforcer for MenSCs treatment. Lipid polysaccharide/d‐galactosamine (d‐GalN) was employed to induce ALF. Diverse techniques were used to measure the inflammatory cytokines and key signaling molecules. Hematoxylin–eosin stain and aminotransaminases were applied to evaluate the liver injury. Flow cytometry was employed to assess the T cells. Results The MenSCs can decrease the lipid polysaccharide‐induced inflammatory cytokine elevation and related signaling molecules in ALF, including TLR4, phosphorylated‐NF‐kBp65 (p‐NF‐kBp65), PI3K, and p‐AKT, p‐mTOR and p‐IKK in vitro. Moreover, MenSCs also can significantly reverse the liver injury, inflammatory cytokines elevation and related signaling molecules increase, and Treg/Th17 ratio decrease in vivo. In addition, MenSCs plus A2AR agonist can enhance the above changes. Conclusions The MenSCs can attenuate the ALF‐induced liver injury via inhibition of TLR4‐mediated PI3K/Akt/mTOR/IKK signaling. Then, this inhibits the p‐NF‐κBp65 translocate into nuclear, which causes a decrease of inflammatory cytokines release. Moreover, A2AR agonist can play a synergic role with MenSCs and enhance the above‐mentioned effects.

Background and Aim Quinolones are globally popular antibiotics with proven potency, broad coverage, and reasonable safety. However, some concerns were raised as to their possible association with acute liver failure (ALF). The aim of this study is to assess ALF risk within 30 days of receiving a systemically administered quinolone antibiotic, in individuals with no history of liver/diseases. Methods We conducted a nested case–control study using electronic health records from the Cerner Health Facts. The initial cohort (n = 35 349 943) included all patients who were admitted between 2000 and 2016, with no history of liver diseases, and had a minimum medical history of one year. Eligible cases were inpatients who were first diagnosed with ALF between 2010 and 2015. Using incidence density sampling, each case was matched with up to five unique controls by sex, race, age at index encounter, and period‐at‐risk. We used conditional logistic regression to calculate the odds ratio and 95% confidence interval for ALF risk, upon adjusting for exposure to other medications, and major confounders (diabetes mellitus and alcohol abuse). We used the STROBE Statement for reporting on our study. Results We identified 3151 cases and 15 657 controls. Our primary analysis did not reveal an association between quinolones and ALF risk. However, some risk was identified among those with no or few comorbidities, those ≤ 60 years of age, women, men, African Americans, and Caucasians. Conclusion Although our study does not suggest an overall association between quinolones and ALF, elevated risks seen in some subgroups warrant further investigation.

Drug-induced liver injury (DILI), which refers to liver damage caused by a drug or its metabolites, has emerged as an important cause of acute liver failure (ALF) in recent years. Chemically-induced ALF in animal models mimics the pathology of DILI in humans; thus, these models are used to study the mechanism of potentially effective treatment strategies. Mesenchymal stromal cells (MSCs) possess immunomodulatory properties, and they alleviate acute liver injury and decrease the mortality of animals with chemically-induced ALF. Here, we summarize some of the existing research on the interaction between MSCs and immune cells, and discuss the possible mechanisms underlying the immuno-modulatory activity of MSCs in chemically-induced ALF. We conclude that MSCs can impact the phenotype and function of macrophages, as well as the differentiation and maturation of dendritic cells, and inhibit the proliferation and activation of T lymphocytes or B lymphocytes. MSCs also have immuno-modulatory effects on the production of cytokines, such as prostaglandin E2 and tumor necrosis factor-alpha-stimulated gene 6, in animal models. Thus, MSCs have significant benefits in the treatment of chemically-induced ALF by interacting with immune cells and they may be applied to DILI in humans in the near future.

Management of children with acute liver failure is challenging. In this retrospective study, paediatric patients diagnosed with ALF at our centre, in the last 26 years, were divided into two groups (G1 = diagnosed from 1997 to 2009; G2 = from 2010 to 2022) and compared to see whether they differed with regard to aetiologies, need for liver transplantation (LT), and outcome. A total of 90 children (median age 4.6 years, range 1.2–10.4; M/F = 43/47) were diagnosed with ALF, by autoimmune hepatitis (AIH) in 16 (18%), paracetamol overdose in 10 (11%), Wilson disease in 8 (9%), and other causes in 19 (21%); 37 (41%) had indeterminate ALF (ID-ALF). Comparing the two periods, the clinical features, aetiologies, and median peak values of INR [3.8 (2.9–4.8) in G1 vs. 3.2 (2.4–4.8) in G2] were similar (p > 0.05). The percentage of ID-ALF tended to be higher in G1 compared to G2 (50% vs. 32% in G2, p = 0.09). The overall percentage of patients diagnosed with Wilson disease, inborn errors of metabolism, neonatal hemochromatosis or viral infection was higher in G2 (34% vs. 13% in G1, p = 0.02). A total of 21/90 patients (23%; 5 with indeterminate ALF) were treated with steroids; 12 (14%) required extracorporeal liver support treatment. The need for LT was significantly higher in G1 compared to G2 (56% vs. 34%; p = 0.032). Among 37 children with ID-ALF, 6 (16%) developed aplastic anaemia (all in G2, p < 0.001). The survival rate at last follow up was of 94%. On a KM curve, the transplant-free survival was lower in G1 compared to G2. In conclusion, we report a lower need for LT in children diagnosed with PALF during the most recent period compared to the first era. This suggests improvements over time in the diagnosis and management of children with PALF.

OBJECTIVE: Increased mortality risk because of severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) infection in adults with native liver disease (LD) and liver transplant (LT) is associated with advanced age and comorbid conditions. We aim to report outcomes for children with LD and LT enrolled in the NASPGHAN/SPLIT SARS-CoV2 registry. METHODS: In this multicenter observational cohort study, we collected data from 91 patients

Invasive infections are a major complication before liver transplantation (LT) and in the early phase after surgery. There has been an increasing prevalence of invasive fungal disease (IFD), especially among the sickest patients with decompensated cirrhosis and acute-on-chronic liver failure, who suffer from a profound state of immune dysfunction and receive intensive care management. In such patients, who are listed for LT, development of an IFD often worsens hepatic and extra-hepatic organ dysfunction, requiring a careful evaluation before surgery. In the post-transplant setting, the burden of IFD has been reduced after the clinical advent of antifungal prophylaxis, even if several major issues still remain, such as duration, target population and drug type(s). Nevertheless, the development of IFD in the early phase after surgery significantly impairs graft and patient survival. This review outlines presentation, prophylactic and therapeutic strategies, and outcomes of IFD in LT candidates and recipients, providing specific considerations for clinical practice.

Hamidreza Mohammadi,1,2 Reza Heidari,1 Seyyed Vahid Niknezhad,1 Akram Jamshidzadeh,1,2 Fatemeh Farjadian1 1Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, IranCorrespondence: Fatemeh FarjadianPharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P. O. Box 158371345, Karafarin Ave., Shiraz, Fars, IranTel + 987132424127 302Fax + 987132424126Email farjadian_f@sums.ac.irAkram JamshidzadehDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Shiraz University of Medical Sciences, P. O. Box 158371345, Karafarin Ave., Shiraz, Fars, IranEmail ajamshid@sums.ac.irPurpose: Hepatic encephalopathy (HE) is a critical situation in which liver failure affects brain function. HE could result in a state of coma and death. The liver is the main organ for ammonium ion (NH4+) metabolism. Hence, acute and/or chronic liver failure could lead to hyperammonemia. NH4+ is the most suspected neurotoxic agent in HE. Thus, finding new therapeutic options to decrease plasma and brain NH4+ levels has a significant clinical value. Mesoporous silica (MS) particles have revolutionized many aspects of pharmaceutical sciences, including drug delivery systems. Moreover, recently, MS has been applied as agents for the detoxification of chemicals (eg, drugs and poisons).Methods: First, MS particles containing amine groups (MS-NH2) were synthesized in co-condensation processes. Then, the structure was modified by succinic anhydride to have MS-SA. The MS-SA was characterized (FT-IR, XRD, X-ray photoelectron spectroscopy (XPS), DLS-Zeta FESEM-EDX, and HRTEM). Then, the potential of MS-NH2 and MS-SA particles in adsorption of NH4+ was investigated in vitro and in vivo. MS-NH2 and MS-SA were incubated with increasing concentrations (0.1– 10 mM) of NH4+, and the scavenging capacity of the investigated particles was evaluated. On the other hand, different doses (1 and 5 mg/kg per day) of nanoparticles were administered to a hyperammonemia animal model.Results: It was figured out that both MS-NH2 and MS-SA significantly scavenged NH4+ in the in vitro model. However, the NH4+ scavenging capability of MS-SA was more significant. Administration of MS-NH2 and MS-SA also considerably decreased the level of ammonium in plasma and brain and improved cognitive and locomotor activity in hyperammonemic animals. The effects of MS-SA were more significant than MS-NH2 in the HE animal model.Conclusion: Collectively, our data suggest that MS particles, especially succinic acid-functionalized MS, could act as special ancillary treatment in HE as a critical clinical complication.Keywords: acute liver failure, ammonia, hyperammonemia, nanomedicine

© 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved., Backround: In acute severe autoimmune hepatitis (AS-AIH), the early identification of predictors of non-response to corticosteroids and the optimal timing for liver transplantation (LT) remains controversial. Aims: To determine early predictors of non-response to corticosteroids and to assess the usefulness of severity scores, namely the recently developed SURFASA. Methods: Retrospective multicentre cohort study including consecutive patients admitted for AS-AIH between 2016 and 2020. Definitions- response to corticosteroids: LT-free survival at 90 days (D90); SURFASA score: -6.8 + 1.92x(D0-INR)+1.94xINR[(D3-D0)/D0]+1.64xbilirubin[(D3-D0)/D0]. Results: We included 26 patients [median age 56 (45-69) years; 22 (84.6%) women]. All patients underwent corticosteroid therapy. Overall survival reached 73%. amongst the non-responders, 2 (7.8%) underwent LT and 5 (19.2%) died. The interval between admission and initiation of corticosteroids was not different between responders and non- responders [13 (7-23) vs. 8 (3-10), P:0.06], respectively. SURFASA and MELD-Na+ (D3) scores showed an AUROC of 0.96 (0.87-1) and 0.92 (0.82-0.99), respectively, for prediction of non-response. SURFASA >-2.5 had a sensitivity of 85.7% and a specificity of 100% and MELD-Na+ (D3) >26 had sensitivity of 85.7% and a specificity of 78% for the prediction of non-response. Conclusions: SURFASA and MELD-Na+ at D3 scores are useful in early identification of non-responders to corticosteroids.

The present narrative review on albumin dialysis provides evidence-based and expert opinion guidelines for clinicians caring for adult patients with different types of liver failure. The review was prepared by an expert panel of 13 members with liver and ntensive care expertise in extracorporeal liver support therapies for the management of patients with liver failure. The coordinating committee developed the questions according to their importance in the management of patients with liver failure. For each indication, experts conducted a comprehensive review of the literature aiming to identify the best available evidence and assessed the quality of evidence based on the literature and their experience. Summary statements and expert’s recommendations covered all indications of albumin dialysis therapy in patients with liver failure, timing and intensity of treatment, efficacy, technical issues related to the device and safety. The panel supports the data from the literature that albumin dialysis showed a beneficial effect on hepatic encephalopathy, refractory pruritus, renal function, reduction of cholestasis and jaundice. However, the trials lacked to show a clear beneficial effect on overall survival. A short-term survival benefit at 15 and 21 days respectively in acute and acute-on-chronic liver failure has been reported in recent studies. The technique should be limited to patients with a transplant project, to centers experienced in the management of advanced liver disease. The use of extracorporeal albumin dialysis could be beneficial in selected patients with advanced liver diseases listed for transplant or with a transplant project. Waiting future large randomized controlled trials, this panel experts’ statements may help careful patient selection and better treatment modalities.

A 68-year-old male with a history of end-stage renal disease and latent tuberculosis on isoniazid (INH), and no psychiatric history presented with a five-day history of anorexia, fatigue, and nausea. Physical exam in the emergency department was notable for somnolence, right upper extremity tremor, and diffuse abdominal pain. Initial workup revealed an anion gap metabolic acidosis with elevated lactate, prompting admission to the general ward for empiric IV antibiotics for suspected bacteremia from his permacath. Within a few hours of admission, he became increasingly encephalopathic and had two episodes of copious hematemesis. Repeat studies revealed a cholestatic pattern of liver injury and new-onset coagulopathy. With an overall clinical picture consistent with fulminant hepatic failure, our pharmacy team initiated a comprehensive pill count of all his medications, which established that he had been inadvertently taking up to six times the recommended dose of INH. With INH discontinuation and supportive therapy, he improved and was discharged on hospital day eight. Our experience provides lessons in the timely recognition and management of this rarely reported toxidrome in the United States.

Background: Surgical treatment of massive hepatic formations is an acute problem of operative hepatology, often being the only way to increase the life expectancy of patients. However, even nowadays, liver surgeries are considered to be traumatic, high-risk interventions due to the development of a potent body stress response induced by tissue damage, risk of severe intra- and postoperative complications, and high mortality. High mortality rates, especially after extensive liver resections, are more often associated with bleeding, bile flow from a liver section with the subsequent development of peritonitis, intoxication, and post-hepatectomy liver failure. The aim of this study was to perform intraoperative, post-resection prevention of acute liver failure (ALF) by applying cyanocobalamin in the experiment. Methods and Results: The study included 96 sexually mature male Wistar rats, which were divided into 4 groups, 24 animals in each group. A conventional 70% hepatectomy was performed on animals of all groups. Prevention of post-hepatectomy liver failure (PHLF) was not performed in animals of the control group (CG) 1; animals of CG2 received 1 ml of 0.9% sodium chloride solution that was injected into the preserved hepatic lobes intraoperatively; animals of the experimental group (EG)1 received 10 intrahepatic injections of 0.1 ml of cyanocobalamin (200 μg/ml); animals of EG2 received 1ml of cyanocobalamin (200 μg/ml) intraperitoneally. The general condition of the animals (activity, appetite), healing time of the postoperative wound, and weight of the regenerated liver were assessed after the experiment. Biochemical methods included assessment of the indices of the cytolysis syndrome, cholestatic syndrome, the syndrome of hepatic cell failure, as well as the analysis of oxidative stress parameter and sevaluation of the expression of transforming growth factor beta ( TGF-β). On Day 5 after hepatic resection, a significant improvement in the general condition of the animals (increased appetite and activity) was noted in EG1 and EG2. Intraoperative, intrahepatic administration of cyanocobalamin can increase the TGF-β expression by 2.5-3 times, affecting the proliferative activity of hepatocytes and providing recovery to 96.15±4.31% of the initial liver weight by Day 14 after hepatectomy Conclusion: Intraoperative, intrahepatic administration of cyanocobalamin prevents the development of ALF in the early postoperative period and ensures restoration of the anatomical and functional integrity of the liver.

Background: Abnormal liver function has been reported in patients with COVID-19 infection. The aim of our study was to report on the prevalence of liver injury in our cohort, to evaluate the association of mild versus severe liver injury with mortality in COVID-19 patients and to scrutinize the temporal pattern of viral detection and liver injury. Methods: We present data from a German cohort of 147 SARS-CoV-2 infected patients. The patients were divided into 3 groups according to their liver status during treatment. The first group included patients without elevated alanine aminotransferase or bilirubin, the third group patients meeting the biochemical criteria of acute liver failure (ALF), and the second group all other patients. Results: Liver injury was detected in 75 (50.7%) and 93 (63%) patients by admission and during treatment, respectively. ALF was associated with the male sex, younger age, and higher BMI. Mortality was associated with the presence of ALF (OR = 9.423, 95% CI: 2.410–36.858) in contrast to milder liver injury (OR 1.101, 95% CI: 0.435–2.791). In 30% of patients with mild liver injury and in 50% of ALF patients, peak liver injury was observed at a time point when the virus was no longer detectable in the respiratory tract. Conclusion: Mild liver injury was not associated with worse outcome in our cohort, and the pattern of liver injury did not fit well to the theory of SARS-CoV-2 directly causing liver impairment. Instead, severe liver injury in our cohort was associated multiple-organ failure and acute vascular events.

Introduction. Hepatitis A is the most common cause of acute hepatitis in children. Wilson disease (WD) is a rare autosomal recessive condition that can result in chronic liver disease. Hepatitis A may be a trigger in the onset of WD. Case presentation. We report the case of a previously healthy 7-year-old girl, admitted in our clinic for upper digestive hemorrhage, jaundice and increased abdomen in volume. The onset of the disease was 1 month before when she was diagnosed with hepatitis A. The laboratory tests at the time of admission pointed out anemia, increased inflammatory biomarkers, conjugated hyperbilirubinemia, hypoalbuminemia, hepatic cytolysis, elevated alkaline phosphatase levels, hyponatremia, and severe coagulopathy. The abdominal ultrasound showed hepatomegaly, inhomogeneous structure, granular echogenicity, with micronodules, diameter of the portal vein 9 mm, altered portal vein pulsatility, splenomegaly and ascites. The upper digestive endoscopy revealed hyperemia and edema of the gastric mucosa, adherent gastric clots, incipient varices of the gastric fornix. The echocardiography showed mild pleural and pericardial effusion. We ruled out hepatitis B, hepatitis C, toxoplasma, rubella, herpes virus, Epstein Barr virus, cytomegalovirus, but also autoimmune hepatitis. Based on the low levels of ceruloplasmin and serum copper, and the positive D-penicilamine test associated to gastric varices and portal hypertension, we established the diagnosis of WD. The ophthalmology and neurological consults found no pathological changes. The patient’s clinical and biochemical evolution was favorable after the initiation of chelation therapy. Conclusion. Though rare, the association between hepatitis A and WD can result in acute liver failure and death, especially in previously healthy children.

Acute liver failure (ALF) is a fatal liver disease characterized by severe hepatocyte destruction. MicroRNAs (miRNAs/miRs) have been reported to serve a key role in a number of liver diseases. Therefore, the aim of the present study was to investigate the role and underlying mechanism of miR‑214 in ALF. ALF murine and hepatocyte models were established using D‑galactosamine (D‑GalN) and lipopolysaccharide (LPS) or D‑GalN + tumor necrosis factor (TNF)‑α, respectively. The expression levels of miR‑214 and Bax were detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and/or western blotting. Furthermore, an automatic biochemical analyzer was used to measure the levels of aspartate aminotransferase (AST) or alanine aminotransferase (ALT). The levels of TNF‑α and interleukin (IL)‑6 were detected by ELISA and RT‑qPCR. In addition, TUNEL staining and flow cytometry were used to analyze cell apoptosis, and the protein expression of caspase‑3 was determined by western blotting. It was identified that the levels of AST and ALT were increased and that hepatocyte apoptosis was enhanced in the D‑GalN/LPS‑stimulated group compared with the control. Furthermore, higher expression of caspase‑3 was observed in the D‑GalN/LPS‑stimulated group. In addition, it was demonstrated that miR‑214 was downregulated, while Bax was upregulated in D‑GalN/LPS‑stimulated mice and D‑GalN/TNF‑α‑stimulated BNLCL2 cells. Moreover, in D‑GalN/TNF‑α‑stimulated BNLCL2 cells, miR‑214 overexpression suppressed apoptosis and decreased TNF‑α and IL‑6 levels, and these effects were reversed by the Bax plasmid. It was also identified that overexpression of miR‑214 significantly decreased Bax mRNA and protein expression levels in vitro. Collectively, the present results suggested that miR‑214 inhibited hepatocyte apoptosis during ALF development via targeting Bax, thus indicating that miR‑214 may be a potential target for ALF treatment.

Drug induced liver injury (DILI) is a common cause of acute liver injury. Paracetamol, also known as acetaminophen, is a widely used anti-pyretic that has long been established to cause liver toxicity once above therapeutic levels. Hepatotoxicity from paracetamol overdose, whether intentional or non-intentional, is the most common cause of DILI in the United States and remains a global issue. Given the increased prevalence of combination medications in the form of pain relievers and antihistamines, paracetamol can be difficult to identify and remains a significant cause of acute hepatotoxicity, as evidenced by its contribution to over half of all acute liver failure cases in the United States. This is especially concerning given that, when co-ingested with other medications, the rise in serum paracetamol levels may be delayed past the 4-hour post-ingestion mark that is currently used to determine patients that require medical therapy. This review serves to describe the clinical and pathophysiologic features of hepatotoxicity secondary to paracetamol and provide an update on current available knowledge and treatment options.

Background Currently the treatment of choice for critical liver failure is liver transplantation. Liver failure is treated conservatively until a matching liver donor becomes available. The therapeutic plasma exchange (TPE) plays an important role as a bridge to transplantation by removing accumulated toxins from patient plasma, as well as restoring the coagulation profile. Method This was a retrospective study on critically ill liver disease patients who underwent TPE from January 2012 to September 2015. The data were collected for the analyses of coagulation parameters, liver function tests, renal function tests, model for end-stage liver disease (MELD) scores, mortality, and hospital stay. Results In the study duration, a total of 45 patients with critical liver disease underwent therapeutic plasma exchange. The TPE resulted in a statistically significant reduction in the bilirubin level, aspartate aminotransferase (AST), alanine aminotransferase (ALT), prothrombin time (PT), international normalized ratio (INR), serum ferritin level and MELD scores. Higher MELD scores in both pre- and post-TPE were associated with higher mortality during the hospital stay. Conclusion The TPE is safe and well-tolerated, and it improves coagulation profile and liver function tests in critically ill liver disease patients, but the overall survival remains low.

Background: Mesenchymal stem cells (MSCs) migrate and transmigrate to acute liver failure (ALF) area due to vascular endothelial growth factor (VEGF) stimulation as an attractant molecule then actively giving the paracrine signaling and or differentiating into primary hepatocytes, however the best route of MSCs transplanted to liver injury area remains unclear. Aim: In this study we compare intravenous (IV) and intraperitoneal (IP) route of MSCs administration by analyzing serum glutamic pyruvic transaminase (SGPT), serum glutamic-oxaloacetic transaminase (SGOT) and bilirubin level as improvement markers of liver function and VEGF as attractant-proliferation molecule on days 2 and 5. Materials and methods: Eighteen male Sprague-Dawley rats weighting 200 g were used in this study. They were divided in three study groups: vehicle control, IP and IV groups. The IV group was treated by MSCs at dose 1×106 by lateral tail vein injection and IP group received 1×106 MSCs via IP injection. The level of SGPT, SGOT and bilirubin were measured by an automatic analyzer, the VEGF level using enzyme-linked immunosorbent assay (ELISA), while the CD73 expression was evaluated using immunohistochemistry. Results: This study showed that IV injection of MSCs was more efficient for increasing liver function than IP treatment group that confirmed by the observed significant decrease in SGPT, SGOT and bilirubin level on days 2 and 5 (p Conclusion: Our result conclude that an IV administration of MSCs was more efficacious than the IP administration for liver injury regeneration.&nbsp

Liver-type fatty acid binding protein (FABP1) has previously been demonstrated to improve prognostic discrimination in acetaminophen (APAP)-induced ALF but has not been investigated in other etiologies of ALF. AIM: To determine whether FABP1 levels (early: admission or late: days 3-5) are associated with 21-day transplant-free survival in non-APAP ALF. METHODS: FABP1 was measured in serum samples from 384 ALF patients (n = 88 transplant-free survivors (TFS), n = 296 died/LT-NTFS) using solid-phase enzyme-linked immunosorbent assay and analyzed with US ALFSG registry data. RESULTS: Of 384 ALF patients (autoimmune hepatitis n = 125, drug-induced liver injury n = 141, Hepatitis B n = 118), 177 (46%) patients received LT. Early FABP1 levels were significantly higher in ALF patients requiring vasopressor support (203.4 vs. 76.3 ng/mL) and renal replacement therapy (203.4 vs. 78.8 ng/mL; p

BACKGROUND Acute liver failure (ALF) and acute-on-chronic liver (ACLF) carry high short-term mortality rate, and may result from a wide variety of causes. Plasma exchange has been shown in a randomized control trial to improve survival in ALF especially in patients who did not receive a liver transplant. Other cohort studies demonstrated potential improvement in survival in patients with ACLF. AIM To assess utility of plasma exchange in liver failure and its effect on mortality in patients who do not undergo liver transplantation. METHODS Databases MEDLINE via PubMed, and EMBASE were searched and relevant publications up to 30 March, 2019 were assessed. Studies were included if they involved human participants diagnosed with liver failure who underwent plasma exchange, with or without another alternative non-bioartificial liver assist device. RESULTS Three hundred twenty four records were reviewed, of which 62 studies were found to be duplicates. Of the 262 records screened, 211 studies were excluded. Fifty-one articles were assessed for eligibility, for which 7 were excluded. Twenty-nine studies were included for ALF only, and 9 studies for ACLF only. Six studies included both ALF and ACLF patients. A total of 44 publications were included. Of the included publications, 2 were randomized controlled trials, 14 cohort studies, 12 case series, 16 case reports. All of three ALF studies which looked at survival rate or survival days reported improvement in outcome with plasma exchange. In two out of four studies where plasma exchange-based liver support systems were compared to standard medical treatment (SMT) for ACLF, a biochemical improvement was seen. Survival in the non-transplanted patients was improved in all four studies in patients with ACLF comparing plasma exchange vs SMT. Using the aforementioned studies, plasma exchange based therapy in ACLF compared to SMT improved survival in non-transplanted patients at 30 and 90-d with a pooled OR of 0.60 (95%CI 0.46-0.77, P < 0.01). CONCLUSION The level of evidence for use of high volume plasma exchange in selected ALF cases is high. Plasma exchange in ACLF improves survival at 30-and 90-d in non-transplanted patients. Further well-designed randomized control trials will need to be carried out to ascertain the optimal duration and amount of plasma exchange required and assess if the use of high volume plasma exchange can be extrapolated to patients with ACLF.

Acute liver failure (ALF) associated with malignant infiltration of the liver is rare and its pathological and radiologic features remain poorly described. An 87-year-old man was admitted to our hospital for anorexia for several days, high-grade fever from the previous day, and liver dysfunction but suddenly died on day 3 of hospitalization due to ventricular fibrillation. The patient was diagnosed at autopsy with malignant diffuse large B-cell lymphoma. To the best of our knowledge, this report represents a valuable addition to the ALF literature describing a case of ALF associated with diffuse large B-cell lymphoma diagnosed at autopsy.

Introduction: Liver transplantation is the only viable treatment with a proven survival benefit for acute liver failure (ALF). Donor organ shortage is, however, a major hurdle; hence, alternative approaches that enable liver regeneration and target acute severe hepatocellular damage are necessary.Areas covered: This article sheds light on therapeutic targets for liver regeneration and considers their therapeutic potential. ALF following extensive hepatocyte damage and small-for-size syndrome (SFSS) are illuminated for the reader while the molecular mechanisms of liver regeneration are assessed in accordance with relevant therapeutic strategies. Furthermore, liver background parameters and predictive biomarkers that might associate with liver regeneration are reviewed.Expert opinion: There are established and novel experimental strategies for liver regeneration to prevent ALF resulting from SFSS. Granulocyte-colony stimulating factor (G-CSF) is a promising agent targeting liver regeneration after acute severe injury. Autophagy and hepatocyte senescence represent attractive new targets for liver regeneration in acute severe hepatic injury. Liver support strategies, including tissue engineering, constitute novel regenerative means; the success of this is dependent on stem cell research advances. However, there is no firm clinical evidence that these supportive strategies may alleviate hepatocellular damage until liver transplantation becomes available or successful self-liver regeneration occurs.

Acute liver failure is characterized by the rapid development of liver dysfunction and remarkably high mortality. Accumulating evidence suggests that soyasaponin possesses potential anti-inflammatory activities. Here, we aimed to investigate the potential role of soyasaponin II in acute liver failure and establish the underlying mechanism. Methods: Lipopolysaccharide/D-galactosamine (LPS/GalN) was employed to induce acute liver failure. We applied liquid chromatography and mass spectrometry (LC/MS) to characterize the changes of soyasaponin II levels in the cecal content and liver. Transcriptomics and proteomics analysis were used to evaluate the functional molecule mediated by soyasaponin II in macrophages. Results: LPS/GalN administration markedly decreased fecal and hepatic soyasaponin II levels. Soyasaponin II treatment protected mice against LPS/GalN induced acute liver injury. Additionally, soyasaponin II markedly diminished Y-Box Binding Protein 1 (YB-1) phosphorylation and nuclear translocation, Nlrp3 inflammasome priming, and interleukin 1β (Il-1β) production in macrophages. Phosphorylated YB-1 could activate Nlrp3 mRNA transcription by binding the promoter region. Finally, immunofluorescence analysis showed elevated p-YB-1 nuclear translocation in macrophages of acute liver failure patients compared to controls. Conclusion: Our data shows that soyasaponin II which serves as a novel inhibitor for YB-1 phosphorylation and Nlrp3 inflammasome priming could protect mice against LPS/GalN induced acute liver failure.

Patients with liver diseases are in a rebalanced state of hemostasis, due to simultaneous decline in pro- and anticoagulant factors. This balance seems to remain even in the sickest patients, but is less stable and might destabilize when patients develop disease complications. Patients with acute decompensation of cirrhosis, acute-on-chronic liver failure, or acute liver failure often develop complications associated with changes in the hemostatic system, such as systemic inflammation. Systemic inflammation causes hemostatic alterations by adhesion and aggregation of platelets, release of von Willebrand factor (VWF), enhanced expression of tissue factor, inhibition of natural anticoagulant pathways, and inhibition of fibrinolysis. Laboratory tests of hemostasis in acutely-ill liver patients may indicate a hypocoagulable state (decreased platelet count, prolongations in prothrombin time and activated partial thromboplastin time, decreased fibrinogen levels) due to decreased synthetic liver capacity or consumption, or a hypercoagulable state (increased VWF levels, hypofibrinolysis in global tests). Whether these changes are clinically relevant and should be corrected with antithrombotic drugs or blood products is incompletely understood. Inflammation and activation of coagulation may cause local ischemia, progression of liver disease, and multiorgan failure. Anti-inflammatory treatment in acutely-ill liver patients may be of potential interest to prevent thrombotic or bleeding complications and halt progression of liver disease.

Background Mesenchymal stem cell (MSC) transplantation is emerging as a promising cell therapeutic strategy in acute liver failure (ALF) clinical research. The potency of MSCs to migrate and engraft into targeted lesions could largely determine their clinical efficacy, in which chemokine/receptor axes play a crucial role. Unfortunately, the downregulation of chemokine receptors expression after in vitro expansion results in a poor homing capacity of MSCs. Methods By evaluating the chemokine expression profile in the liver of ALF patients and ALF mice, we found that CCL2 expression was highly upregulated in damaged livers, while the corresponding receptor, CCR2, was lacking in cultured MSCs. Thus, we genetically modified MSCs to overexpress CCR2 and investigated the targeted homing capacity and treatment efficacy of MSCCCR2 compared to those of the MSCvector control. Results In vivo and ex vivo near-infrared fluorescence imaging showed that MSCCCR2 rapidly migrated and localized to injured livers in remarkably greater numbers following systemic infusion, and these cells were retained in liver lesions for a longer time than MSCvector. Furthermore, MSCCCR2 exhibited significantly enhanced efficacy in the treatment of ALF in mice, which was indicated by a dramatically improved survival rate, the alleviation of liver injury with reduced inflammatory infiltration and hepatic apoptosis, and the promotion of liver regeneration. Conclusions Altogether, these results indicate that CCR2 overexpression enhances the targeted migration of MSCs to damaged livers, improves their treatment effect, and may provide a novel strategy for improving the efficacy of cell therapy for ALF.

Lipids are organic compounds insoluble in water with a variety of metabolic and non-metabolic functions. They not only represent an efficient energy substrate but can also act as key inflammatory and anti-inflammatory molecules as part of a network of soluble mediators at the interface of metabolism and the immune system. The role of endogenous bioactive lipid mediators has been demonstrated in several inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, cancer). The liver is unique in providing balanced immunotolerance to the exposure of bacterial components from the gut transiting through the portal vein and the lymphatic system. This balance is abruptly deranged in liver failure syndromes such as acute liver failure and acute-on-chronic liver failure. In these syndromes, researchers have recently focused on bioactive lipid mediators by global metabonomic profiling and uncovered the pivotal role of these mediators in the immune dysfunction observed in liver failure syndromes explaining the high occurrence of sepsis and subsequent organ failure. Among endogenous bioactive lipids, the mechanistic actions of three classes (eicosanoids, pro-resolving lipid mediators and lysophospholipids) in the pathophysiological modulation of liver failure syndromes will be the topic of this narrative review. Furthermore, the therapeutic potential of lipid-immune pathways will be described.

The Qingchangligan formula (QCLGF) is a traditional Chinese medicine that has significant clinical potential for patients with acute liver failure (ALF). However, the experimental evidence of the effect of QCLGF on ALF and the associated mechanisms remain elusive. We aimed to evaluate the function of QCLGF in ALF and the underlying mechanism. ALF was induced in rats by intraperitoneal injection of D-GalN (1100 mg/kg). The Qingchangligan formula was administered to the rats (6.725 g/kg · d) for 5 days, and the model group and the control group were given the same amount of physiological saline. Then 16S rRNA gene sequencing, high performance gas chromatography-mass spectrometry (GC-MS), and RNA-seq analysis were performed on the samples. The levels of ALT and AST in the ALF rats were abnormal (5322.08 ± 566.27 U/L and 7655.95 ± 1238.08 U/L, respectively) compared with the normal control (98.98 ± 6.90 U/L and 99.63 ± 10.94 U/L, respectively). The levels of ALT and AST in the QCLGF rats (2997.67 ± 469.24 U/L and 4158.40 ± 596.07 U/L, respectively) were closer the normal control group. Liver HE staining showed that the degree of liver damage in the QCLGF rats was lighter than that in the ALF rats. The overall structure of the gut microbiota after ALF was significantly altered, including Proteobacteria, Blautia, Romboutsia, Parabacteroides, UCG-008, Parasutterella, Ruminococcus, norank_f:Lachnospiraceae, the Eubacterium_xylanophilum_group, Oscillibacter, and Eisenbergiella. QCLGF balanced the structure and abundance of intestinal flora. The levels of D(+)galactose, isopropyl beta-D-1-thiogalactopyranoside and D-mannitol were lighter in the plasma of the ALF rats than in the normal control rats, but there were significantly elevated levels of those metabolites in the QCLGF rats. The gene expression changed significantly in the ALF rats. QCLGF regulated the expression of THBS1 and the KEGG pathways of carbohydrate metabolism, lipid metabolism, signal transduction, the immune system, and infectious disease: bacterial. QCLGF may alleviating intestinal flora disorder, regulating galactose metabolism and downregulating the expression of THBS1 to alleviate D-GalN induced acute liver failure.

Einleitung: Das hepatorenale Syndrom (HRS) ist eine schwerwiegende Komplikation bei fortgeschrittener Leberfunktionsstörung mit hoher Letalität. Trotz aufwendiger intensivmedizinischer Behandlung ist eine irreversible Schädigung der Leber häufig. Allerdings ist eine Regeneration der Leberfunktion möglich, wenn die ursächliche Erkrankung überwunden werden kann. In dieser Zeit muss die Leberfunktion passager unterstützt werden (bridge to recovery). Dafür stehen verschiedene extrakorporale Verfahren zur zur Verfügung. Zu den am besten untersuchten artifiziellen Verfahren zählen MARS® und Prometheus®. Für beide wurde eine effektive Elimination von wasser- und proteingebundenen Toxinen ohne signifikante Beeinträchtigung der Hämodynamik nachgewiesen. Es gibt Hinweise, dass das HRS unter Prometheus®-Therapie etwas günstiger beeinflusst wird. Ziel dieser Studie war es, deren Wirksamkeit bei HRS-Patienten zu prüfen und festzustellen, ob Prometheus® hier einen Vorteil gegenüber der Standardbehandlung hat. Material und Methode: Wir führten eine retrospektive Datenanalyse an 114 Patienten durch, die im Zeitraum 2006-2013 mit Prometheus® behandelt wurden. Die Patienten wurden anhand des Auftretens eines HRS in zwei Gruppen unterteilt (HRS+/HRS-). Primäre Endpunkte waren das 28-Tage-Überleben sowie die Beurteilung der Leber- und Nierenfunktion. Verschiedene intensivmedizinische Scores (MELD, SOFA, APACHE II) und Surrogatmarker (u.a. Kreatinin, Bilirubin) wurden ausgewertet. Die Letalität wurde mit der über die Scores prognostizierten verglichen. Darauf basierend wurde eine randomisierte, klinisch kontrollierte Pilotstudie mit 17 Patienten für die Dauer von 2 Wochen durchgeführt. Primärer Endpunkt war die Evaluation der Leber- und Nieren-funktion nach Studienende. Ergebnisse: In der retrospektiven Datenanalyse unterschieden sich die Basisparameter nicht zwischen den zwei Gruppen (HRS+/-). Die Gruppe HRS+ wies aber einen höheren MELD auf. Bezüglich des 28-Tage-Überlebens zeigte sich kein Unterschied zwischen den Gruppen. Allerdings zeigte eine Subgruppenanalyse von Patienten mit MELD>30 eine tendenziell bessere Wirksamkeit der Prometheus®-Therapie in der Gruppe HRS+ im Vergleich zu HRS-. 8 Die Letalität wurde im Vergleich der drei Scores am besten durch Apache II prognostiziert. Kreatinin- und Bilirubinlevel wurden in beiden Gruppen durch Prometheus® deutlich reduziert. In der Pilotstudie wurden Kreatinin- und Bilirubinlevel in beiden Gruppen verlässlich reduziert. Dieser Trend zeigte sich auch noch 7 und 14 Tage nach Therapieende. Es gab keinen Unterschied zwischen Prometheus®- und Standardtherapie. Zusammenfassung: Unsere Studie bestätigt, dass Prometheus® insbesondere bei schwer betroffenen Patienten möglicherweise einen positiven Effekt in der Behandlung des HRS haben kann. Die Daten weisen darauf hin, dass die genaue Indikationsstellung des Einsatzes entscheidend für den Therapieerfolg im Vergleich zur Standardtherapie zu sein scheint., Introduction: The hepatorenal syndrome (HRS) is a serious complication of advanced liver dysfunction with high mortality. Despite extensive intensive medical treatment, irreversible damage to the liver is common. However, regeneration of liver function is possible if the causative disease can be overcome. During this time, the liver function must be passively supported..Various extracorporeal procedures for temporary support of liver function have been developed in recent years. MARS® and Prometheus® are among the best investigated artificial procedures. Both methods are proved to effectively eliminate water- and protein-bound toxins without significant impairment of hemodynamics. Some studies suggest better outcomes for HRS when using Prometheus®. Here, we aimed to test the efficacy of Prometheus® in HRS patients and determine whether Prometheus® is more effective than standard treatment. Material and method: We conducted a retrospective data analysis on 114 patients treated with Prometheus® during 2006 and 2013. Patients were divided into two groups: HRS+ and HRS-. Primary endpoints were 28-day survival and assessment of liver and kidney function. Various intensive care scores (MELD, SOFA, APACHE II) and surrogate markers (including creatinine, bilirubin) were evaluated. Actual mortality was compared with the mortality probability predicted by the scores. Based on these results, a randomized, clinically controlled pilot study was conducted with 17 patients for 14 days. Primary endpoint was the evaluation of liver and kidney function at end of study. Results: In the retrospective analysis basic parameters did not differ between the two groups (HRS+/-). However, the HRS+ group showed a higher MELD. While there was no overall difference in 28-day survival between the groups, a subgroup analysis of patients with MELD>30 showed that the Prometheus® therapy tended to be more effective in the HRS+ group. In a comparison of the three scores, lethality was best predicted by Apache II. Creatinine and bilirubin levels were clearly reduced by Prometheus® in both groups. In the pilot study, creatinine and bilirubin levels were also reliably reduced in both groups. This trend was still evident 7 and 14 days after the end of therapy. There was no difference between Prometheus® and standard therapy. Summary: Our study confirms that Prometheus® may have a positive effect in the treatment of HRS, especially in severely affected patients. Our data indicate that Prometheus is more effective than standard therapy, but specific indication is crucial for therapeutic success.

BACKGROUND & AIMS: Acetaminophen (APAP) overdose remains a frequent cause of acute liver failure, which is generally accompanied by increased levels of serum bile acids (BAs). However, the pathophysiological role of BAs remains elusive. Herein, we investigated the role of BAs in APAP-induced hepatotoxicity. METHODS: We performed intravital imaging to investigate BA transport in mice, quantified endogenous BA concentrations in the serum of mice and patients with APAP overdose, analyzed liver tissue and bile by mass spectrometry and MALDI-mass spectrometry imaging, assessed the integrity of the blood-bile barrier and the role of oxidative stress by immunostaining of tight junction proteins and intravital imaging of fluorescent markers, identified the intracellular cytotoxic concentrations of BAs, and performed interventions to block BA uptake from blood into hepatocytes. RESULTS: Prior to the onset of cell death, APAP overdose causes massive oxidative stress in the pericentral lobular zone, which coincided with a breach of the blood-bile barrier. Consequently, BAs leak from the bile canaliculi into the sinusoidal blood, which is then followed by their uptake into hepatocytes via the basolateral membrane, their secretion into canaliculi and repeated cycling. This, what we termed 'futile cycling' of BAs, led to increased intracellular BA concentrations that were high enough to cause hepatocyte death. Importantly, however, the interruption of BA re-uptake by pharmacological NTCP blockage using Myrcludex B and Oatp knockout strongly reduced APAP-induced hepatotoxicity. CONCLUSIONS: APAP overdose induces a breach of the blood-bile barrier which leads to futile BA cycling that causes hepatocyte death. Prevention of BA cycling may represent a therapeutic option after APAP intoxication. LAY SUMMARY: Only one drug, N-acetylcysteine, is approved for the treatment of acetaminophen overdose and it is only effective when given within ∼8 hours after ingestion. We identified a mechanism by which acetaminophen overdose causes an increase in bile acid concentrations (to above toxic thresholds) in hepatocytes. Blocking this mechanism prevented acetaminophen-induced hepatotoxicity in mice and evidence from patients suggests that this therapy may be effective for longer periods after ingestion compared to N-acetylcysteine.

Herbal and dietary supplements (HDS) are increasingly used worldwide for numerous, mainly unproven health benefits. The HDS industry is poorly regulated compared to prescription medicines and most products are easily obtainable. Drug induced liver injury (DILI) is a well-recognized entity associated with prescription and over the counter medications and many reports have emerged of potential HDS-related DILI. There is considerable geographic variability in the risk and severity of DILI associated with HDS but the presentation of severe liver injury is similar with a hepatocellular pattern accompanied by jaundice. This type of injury can lead to acute liver failure and the need for liver transplantation. Patients will often fail to mention their use of HDS, considering it natural and therefore harmless. Hence physicians should understand that these products can be associated with DILI and explicitly ask about HDS use in any patient with otherwise unexplained acute liver injury.

Background Yellow phosphorus (YP) is a protoplasmic poison that causes acute liver failure (ALF) for which liver transplantation is the definitive modality. Hereby, we present our clinical data on the role of plasma exchange (PE) in ALF due to YP poisoning when liver transplantation is not readily available. Methods Our study is a prospective observational type, conducted between January 2017 and January 2020, which included patients with ALF due to YP poisoning requiring PE. Clinical features, quantity of poison consumed, and laboratory data before and after PE were noted, and the outcome was documented. Results This study had 10 patients. The mean age was 30 years. The ratio of male to female being 1.5:1. The amount of YP consumed (median) was 10 gm. Six patients consumed ≤10 gm and four consumed >10 gm. The mean of total PE sessions was 3.3. Seven patients (70%) had recovery from ALF, out of which five had consumed