DPMAS in the Management of Severe Acute Liver Injury

To examine the incidence of hepatitis E (HepE) in individuals with acute liver injury severe enough to warrant treatment at a transplant unit. Hepatitis E virus (HEV) is an emerging pathogen in developed countries causing severe illness, particularly in immunocompromised patients or those with underlying chronic liver disease. HepE infection is often under diagnosed, as clinicians can be reluctant to test patients who have not travelled to regions traditionally considered hyperendemic for HepE. There are few data regarding the significance of HEV in patients with very severe acute liver injury in developed countries. Eighty patients with acute severe liver injury attending the Scottish Liver Transplant unit were tested for HEV and anti-HEV IgG and IgM. Severe acute liver injury was defined as a sudden deterioration in liver function confirmed by abnormal liver function tests and coagulopathy or presence of hepatic encephalopathy. Eighty percent of these patients were diagnosed with paracetomol overdose. No patients had a history of chronic or decompensated chronic liver disease at time of sampling. IgG positive samples were quantified against the World Health Organization anti-HEV IgG standard. Samples were screened for HEV viral RNA by quantitative reverse transcription polymerase chain reaction. Four cases of hepatitis E were identified. Three of the four cases were only diagnosed on retrospective testing and were initially erroneously ascribed to drug-induced liver injury and decompensated chronic liver disease, with the cause of the decompensation uncertain. One case was caused by HEV genotype 1 in a traveller returning from Asia, the other three were autochthonous and diagnosed on retrospective testing. In two of these cases (where RNA was detected) HEV was found to be genotype 3, the most prevalent genotype in developed countries. Three patients survived, two of whom had been misdiagnosed as having drug induced liver injury. The fourth patient died from sepsis and liver failure precipitated as a result of hepatitis E infection and previously undiagnosed cirrhosis. Histopathology data to date is limited to mainly that seen for endemic HepE. All patients, with the exception of patient 1, demonstrated characteristics of HepE infection, as seen in previously described locally acquired cases. In patients with acute severe liver injury, HEV testing should be part of the initial diagnostic investigation algorithm irrespective of suspected initial diagnosis, age or travel history.

A Multicenter Study Into Causes of Severe Acute Liver Injury

Oral Azole Antifungal Medications and Risk of Acute Liver Injury, Overall and by Chronic Liver Disease Status

INTRODUCTION:The aim of this study was to determine the role of hepatitis E virus (HEV) infection in a large cohort of prospectively enrolled patients with severe acute liver injury (ALI).METHODS:Serum samples from 594 consecutive adults enrolled between 2008 and 2018 in the US Acute Liver Failure Study Group ALI registry were tested for anti-HEV IgM and anti-HEV IgG levels. Those with detectable anti-HEV IgM underwent further testing for HEV RNA using real-time polymerase chain reaction.RESULTS:The median age of patients was 38 years; 41% were men and 72% Caucasian. Etiologies of ALI included acetaminophen hepatotoxicity (50%), autoimmune hepatitis (8.9%), hepatitis B virus (8.9%), and idiosyncratic drug-induced liver injury (7.9%). Overall, 62 patients (10.4%) were negative for anti-HEV IgM but positive for IgG, whereas only 3 men (0.5%) were positive for both anti-HEV IgM and IgG. These 3 cases were initially diagnosed as having indeterminate, HEV, and hepatitis B virus-related ALI. One of these patients had detectable HEV RNA genotype 3, and another anti-HEV IgM+ patient had detectable HEV antigens by immunohistochemistry on liver biopsy. On multivariate modeling, older (odds ratio: 1.99) and non-Caucasian subjects (odds ratio: 2.92) were significantly more likely to have detectable anti-HEV IgG (P < 0.0001).DISCUSSION:Acute HEV infection is an infrequent cause of ALI in hospitalized North American adults. The anti-HEV IgG+ patients were significantly older and more likely to be non-Caucasian. These data are consistent with other population-based studies that indicate exposure to HEV in the general US population is declining over time and might reflect a cohort effect.

Idiopathic Acute Liver Injury in Paediatric Outpatients: Incidence and Signal Detection in Two European Countries

Background. Coronavirus disease 2019 (COVID-19) has been associated with acute liver injury presenting as increased liver enzymes, specifically alanine aminotransferase (ALT) and aspartate aminotransferase (AST). There is limited data in the prevalence of liver injury in COVID-19. We aim to determine the prevalence of acute liver injury among COVID-19 patients admitted in a tertiary hospital in the Philippines. Methods. The study is a single center, retrospective cohort of all COVID-19 patients with baseline AST and ALT admitted at St. Luke’s Medical Center - Quezon City from January 2020 to December 2021. The population was divided into those with normal liver enzymes, mild (AST and/or ALT 1-3 times ULN), and severe (AST and/or ALT &gt;3x ULN) acute liver injury. Association of liver injury to clinical outcome, COVID-19 disease severity, and length of hospital stay were determined. Among those with elevated AST/ALT, comparison of the levels before and after treatment with hepatoprotective agents were evaluated. Results. Among the 669 patients included in the analysis, 448 (67%) developed liver injury of which 50 (7.5%) had severe liver injury and 398 (59.5%) developed mild liver injury. Chi squared analysis showed that acute liver injury (OR:2.64,CI:1.90-3.69,p&lt;0.01) was associated with COVID-19 severity. However, acute liver injury was not associated with clinical outcome (p = 0.347) and length of hospital stay (p = 0.317). There was no association between the use of hepatoprotective agents and changes in level of transaminases (p=0.087). Conclusion. This study revealed that mild liver injury is commonly found in patients with COVID-19 infection. Severity of liver injury is significantly associated with COVID-19 severity, but not with clinical outcome and length of hospital stay. In this study, treatment with hepatoprotective agents did not lead to a decrease in liver enzymes. Further evaluation is needed to recognize those patients at higher risk of complications and identify effective therapies in providing better clinical outcomes. Keywords. Acute Liver Injury, COVID-19 disease, Hepatoprotective Agents

In 2004, we implemented a referral system for patients with acute liver injury (ALI) based on an established formula that estimates the risk of progression to acute live failure (ALF); however, the benefits of the system for patients with severe acute liver injury (SLI) remain unclear. We have evaluated the clinical significance of the referral system for SLI patients. Patients with ALI/SLI who were consecutively and prospectively listed on the system between 2004 and 2018 were analyzed. Of the 371 ALI/SLI/ALF patients on the system, 124 satisfied the criteria for SLI; 34 of these 124 progressed to SLI after registration. Multivariate analysis using age, sex, AST, ALT, creatinine, total bilirubin, prothrombin, presence of hepatic encephalopathy (HE), and SLI at registration revealed that HE was associated with high mortality. Among the 23 patients who developed HE, five who progressed to SLI after registration showed an increased time to HE development compared with patients who had SLI at the time of registration. However, there was no significant difference in survival time after HE development. We concluded that early identification of SLI patients using the referral system increased the time from SLI diagnosis to HE development.

We present a unique case of biopsy-proven syphilitic hepatitis which presented as severe acute liver injury with significant elevation in aminotransferases and bilirubin, and improved with antibiotic therapy. However, the patient returned weeks after initial presentation with new-onset acute liver injury and had developed hypergammaglobulinemia, positive autoantibody titers, and repeat liver biopsy demonstrating interface hepatitis, supporting a diagnosis of autoimmune hepatitis. He had an otherwise unrevealing etiologic workup, and responded to glucocorticoid therapy. We believe that syphilitic hepatitis and its treatment subsequently triggered an immunogenic response, leading to autoimmune hepatitis. Autoimmune hepatitis is a chronic liver disease thought to manifest as a result of predisposing genetic factors in combination with environmental insults, especially hepatotropic pathogens. Syphilis is a sexually transmitted disease caused by Treponema pallidum that has been associated with autoimmunity and the development of autoantibodies. We propose that in the setting of syphilitic hepatitis, a molecular mimicry event resulting from structural similarities between T. pallidum and liver antigens, as well as impaired regulatory T-cell function, led to the breakdown of immune tolerance and the onset of autoimmune hepatitis. To support this hypothesis, further molecular analyses and case series are necessary to determine if syphilitic hepatitis and its treatment are risk factors for the onset of autoimmune hepatitis. Autoimmune hepatitis should be considered early as the cause of acute liver injury in susceptible patients with risk factors for the disease, as prompt recognition and appropriate treatment may prevent progression of liver injury and result in improved outcomes.

Introductionl´atteinte hépatique aiguë sévère (AHAS) est une inflammation aiguë du foie avec des perturbations des marqueurs d´atteinte hépatique et des signes d´insuffisance hépatocellulaire (ictère et INR supérieur à 1,5) selon définition de l´association européenne pour l'étude du foie.Le facteur qui conditionne le pronostic de l´AHAS reste l´apparition d´une encéphalopathie hépatique (EH). L´objectif de ce travail est de rechercher les facteurs prédictifs du développement de l´EH au cours de l´AHAS.Méthodesil s´agit d´une étude observationnelle rétrospective entre janvier 2000 et décembre 2019. Nous avons réalisé une étude analytique comparant les deux groupes en fonction de l´apparition ou non d´une EH.Résultatscinquante-neuf patients ont été colligés. La survenue d'une EH était observée chez 15 patients (25,4%). Les facteurs prédictifs de la survenue d´une EH en analyse univariée étaient un délai de consultation supérieur à 9 jours, un taux d´INR supérieur à 2,45, un taux de bilirubine supérieur à 230 μmol/l, créatininémie supérieur à 60,5 μmol/l, un taux d'urée supérieur à 5,5 mmol/l et un score MELD supérieur à 26,5 (p=0,023, p = 0,017, p = 0,0001, p=0,049, p = 0,0001, p = 0,0001 respectivement). L´hépatite auto-immune et la cause indéterminée étaient associées à l´apparition d´une EH (respectivement p=0,003 et p=0,044). En analyse multivariée, l´étiologie auto-immune et un taux d´urée supérieur à 5,5 mmol/l étaient significativement associés à la survenue d´une EH.Conclusionla survenue de l´EH est le résultat de l´interférence de plusieurs facteurs associant des paramètres biologiques comme l´INR, la bilirubinémie, la fonction rénale et l´étiologie en cause.

Acute liver injury is a serious clinical syndrome with multiple causes and unclear pathological process. Here, CCl4‐ and D‐galactosamine/lipopolysaccharide (D‐gal/LPS)‐induced acute liver injury was established to explore the cell death patterns and determine whether or not liver regeneration occurred. In CCl4‐induced hepatic injury, three phases, including the early, progressive, and recovery phase, were considered based on alterations of serum transaminases and liver morphology. Moreover, in this model, cytokines exhibited double‐peak fluctuations; apoptosis and pyroptosis persisted throughout all phases; autophagy occurred in the early and the progressive phases; and sufficient and timely hepatocyte regeneration was observed only during the recovery phase. All of these phenomena contribute to mild liver injury and subsequent regeneration. Strikingly, only the early and progressive phases were observed in the D‐gal/LPS model. Slight pyroptosis occurred in the early phase but diminished in the progressive phase, while apoptosis, reduced autophagy, and slight but subsequently diminished regeneration occurred only during the progressive phase, accompanied by a strong cytokine storm, resulting in severe liver injury with high mortality. Taken together, our work reveals variable modes and dynamics of cell death and regeneration, which lead to different consequences for mild and severe acute liver injury, providing a helpful reference for clinical therapy and prognosis.

Background: Myxedema crisis, which occurs due to hypothyroidism, is a rare and life-threatening condition that can lead to severe myocardial infarction and lethal arrhythmia, as presented in this case. Case Presentation: A 63-year-old man presented with typical prolonged chest pain, palpitations leading to near syncope, severe fatigue, loss of appetite, dizziness, and somnolence 2 days before admission. The patient exhibited somnolence, hypotension, thin eyebrows, and pretibial pitting edema. Electrocardiography revealed sinus rhythm with a prolonged QT interval, inferolateral-anterior ischemia, and a troponin-T value five times above the upper limit of normal. Therefore, the working diagnosis included non–ST-elevation myocardial infarction Killip IV, severe biventricular heart failure, severe acute kidney injury, and severe acute liver injury. On the third day of treatment, the patient experienced two consecutive episodes of unstable ventricular tachycardia and one episode of return of spontaneous circulation cardiac arrest. Thyroid examination incidentally revealed severe hypothyroidism with severe hyperkalemia. After other causes were excluded, the diagnosis of myxedema crisis was assumed. Oral thyroid therapy, levothyroxine (100 µg once daily), was administered. Within 3 days of initiating all treatments, the patient experienced significant hemodynamic improvement, improved kidney function, and normalization of liver function, accompanied by the disappearance of dyspnea, chest pain, and edema, with a compos mentis status. The patient was discharged with stable hemodynamics without support on the tenth day of treatment and underwent a coronary computed tomography angiography at an outpatient facility, which showed near-normal coronary results. The patient has been on routine follow-up for almost 1 year with levothyroxine (50 µg once daily) and has recently demonstrated good left ventricular function (ejection fraction=50%) and good functional capacity on an exercise test. Conclusion: Clinicians should consider hypothyroidism crisis in the differential diagnosis for myocardial infarction, heart failure, and lethal arrhythmia, and treatment should be initiated immediately.

Induction of Hepatic Tissue-Type Plasminogen Activator and Type 1 Plasminogen Activator–Inhibitor Gene Expressions and Appearance of Their Translation Products in the Bile Following Acute Liver Injury in Rats

Heat stroke (HS) is a life-threatening condition characterized by hyperthermia and multiple organ failure. Mild to moderate hepatocellular injury is a well-documented complication but severe liver injury and acute liver failure are rare. There are neither established criteria nor optimal timing for liver transplantation and conservative management seems to be the cornerstone treatment. The authors report a case of a patient with severe liver injury related to HS who recovered completely under conservative treatment.LEARNING POINTSHyperthermia, neurologic dysfunction and recent exposure to hot weather or physical exertion should raise the suspicion of heat stroke (HS).Fast and effective cooling is the cornerstone of treatment, along with support of organ dysfunction. Antipyretics have no role in HS management.Conservative treatment has been described as being successful in the management of patients with HS that manifest severe acute liver injury (ALI) and acute liver failure (ALF). However, early referral to a liver transplantation centre is essential to guide treatment.

Salvage effect of the vascular endothelial growth factor on chemically induced acute severe liver injury in rats

Acute liver injury in the setting of acute fulminant hepatitis caused by the hepatitis B virus(HBV) can occur both during primary infection and after chronic HBV reactivation. Guidelines recommend considering antiviral therapy in both cases. Antiviral therapy with a nucleoside analog may be beneficial in patients with acute liver failure from acute HBV infection, though not all studies have shown a benefit. This is a case of a 53-year-old woman with a past medical history of untreated hepatitis C with undetectable viral load and right breast cancer status post lumpectomy, who presented to the emergency department with complaints of yellowish skin and sclera discoloration with right upper quadrant pain for one week. She was a known intravenous drug abuser and binge alcohol user. Her labs were positive for hepatitis B, hepatitis E, and hepatitis C viruses. She also had elevated liver enzymes with hyperbilirubinemia showing severe acute liver injury. Computed tomography of the abdomen and pelvis with contrast was normal, and the abdominal ultrasound showed homogenous echotexture of the liver without a focal lesion. The patient was diagnosed with acute fulminant hepatitis B. After initial hemodynamic stabilization, N-acetylcysteine (NAC) and tenofovir were started, and transaminases were followed. Liver function tests showed a downtrend, and, in a few weeks, they came to baseline. Hepatitis B viral load became undetectable as well.Acute hepatitis B infection is seldom treated. The presented case depicts the use of tenofovir in the setting of severe acute liver injury due to hepatitis B. Starting antiviral therapy (especially tenofovir disoproxil fumarate) early in the disease course was shown to have very assuring results with complete resolution of symptoms and normalization of liver function tests. The treatment protocol for acute HBV deserves further investigation.