Severe Liver Injury Research Articles

Circulating miRNA-192 and miR-29a as Disease Progression Biomarkers in Hepatitis C Patients with a Prevalence of HCV Genotype 3.

MicroRNAs miR-29a and miR-192 are involved in inflammatory and fibrotic processes of chronic liver disease, and circulating miR-29a is suggested to diagnose fibrosis progression due to hepatitis C virus (HCV) infection. This study aimed to evaluate the expression profile of circulating miR-192 and 29a in a patient cohort with a high frequency of HCV genotype-3. A total of 222 HCV blood samples were collected and serum were separated. Patients were classified into mild, moderate, and severe liver injury based on their Child-Turcotte-Pugh CTP score. RNA was isolated from the serum and used for quantitative real-time PCR. The HCV genotype-3 (62%) was the predominant HCV genotype. In HCV patients, the serum miR-192 and miR-29a levels were significantly upregulated in comparison to healthy controls (p = 0.0017 and p = 0.0001, respectively). The progression rate of miR-192 and 29a in the patient group with mild was highly upregulated compared to patients with moderate and severe hepatitis infection. The ROC curve of miR-192 and miR-29a of moderate liver disease had a significant diagnostic performance compared to the other HCV-infected groups. The increase in miR-29a and miR-192 serum levels was even slightly higher in patients with HCV genotype-3 than in non-genotype-3 patients. In conclusion, serum miR-192 and miR-29a levels significantly increased during the progression of chronic HCV infection. The marked upregulation in patients with HCV genotype-3 suggests them as potential biomarkers for hepatic disease, independently of the HCV genotype.

Adverse effects and potential mechanisms of fluxapyroxad in Xenopus laevis on carbohydrate and lipid metabolism

Fungicides are one of significant contributing factors to the rapid decline of amphibian species worldwide. Fluxapyroxad (FLX), an effective and broad-spectrum succinate dehydrogenase inhibitor fungicide, has attracted major concerns due to its long-lasting in the environment. However, the potential toxicity of FLX in the development of amphibians remains mostly unknown. In this research, the potential toxic effects and mechanisms of FLX on Xenopus laevis were investigated. In the acute toxicity test, the 96 h median lethal concentration (LC50) of FLX in X. laevis tadpoles was 1.645 mg/L. Based on the acute toxicity result, tadpoles at the stage 51 were exposed to 0, 0.00822, 0.0822, and 0.822 mg/L FLX during 21 days. Results demonstrated that FLX exposure led to an apparent delay in the growth and development of tadpoles and associated with severe liver injury. Additionally, FLX induced glycogen depletion and lipid accumulation in the liver of X. laevis. The biochemical analysis of plasma and liver indicated that FLX exposure could perturb liver glucose and lipid homeostasis by altering enzyme activity related to glycolysis, gluconeogenesis, fatty acid synthesis, and oxidation. Consistent with the biochemical result, FLX exposure altered the liver transcriptome profile, and the enrichment analysis of differential expression genes highlighted the adverse effects of FLX exposure on steroid biosynthesis, PPAR signaling pathway, glycolysis/gluconeogenesis, and fatty acid metabolism in the tadpole liver. Overall, our study was the first to reveal that sub-lethal concentrations of FLX could induce liver damage and produce obvious interference effects on carbohydrate and lipid metabolism of Xenopus, providing new insight into the potential chronic hazards of FLX for amphibians.

Type I and II interferons induce granulopoiesis and correlate with organ damage during infection-induced shock

Abstract The mechanisms that drive pathology in infection-induced shock are not well understood. The tick-borne pathogen Ixodes ovatuserhlichia (IOE) induces severe inflammation, vascular damage, liver injury, and death. Mice that lack the receptor for type I IFN, or receptors for both type I and II IFNs, improves survival by 50–70 and 90%, respectively. IOE infection induced a significant increase in circulating granulocytes that depended on both type I and II IFNs. We also observed an IFN-dependent increase in eosinophils and basophils in the bone marrow in IOE-infected C57BL/6TA (WT). Although IOE infection induced an increase in bone marrow IL-5 and GM-CSF levels independent of IFN signaling, bone marrow concentrations of IL-3 and IL-13, both known to promote eosinophil differentiation and survival, increased in an IFNAR-dependent manner. Furthermore, we demonstrate an infection- and IFN-dependent increase of CCL3 and CCL5, two chemokines that promote eosinophil activation and migration. While bone marrow and blood eosinophils and basophils were increased, we observed a specific depletion of eosinophils in WT liver at day 7 post-IOE infection, correlating with increased cell death and severe liver pathology. In contrast, basophil frequencies were increased in IOE-infected WT mice. Additionally, Ifnar-deficient and Ifnar-Ifngr-deficient mice exhibited normal eosinophil and basophil frequencies and reduced liver inflammation, similar to uninfected mice. Together, our data reveal an IFN-driven cytokine and chemokine response that correlates with rampant granulopoiesis and mortality and provide evidence that IFN-induced eosinophil activation may contribute to vascular leak and liver damage in infection-induced shock. Supported by grants from NIH R35GM131842

A Hepatic Manifestation of Anorexia Nervosa.

Anorexia nervosa can cause severe liver injury as manifested in AST and ALT levels in the thousands.The slow reintroduction of enteral feeding can reverse liver injury.The mechanism is unclear but autophagocytosis of liver cells likely contributes to this phenomenon.

Increased TG to HDL-C ratio is associated with severity of drug-induced liver injury

We investigated the relationship between dyslipidemia and drug-induced liver injury (DILI), especially the level of triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) in severe DILI. In this single-centered retrospective study, of 326 patients with DILI, 221 patients were analyzed. Control groups include medication using group and acute hepatitis B group. The relationship between dyslipidemia and DILI was estimated. Demographic and clinical features were analyzed. Dyslipidemia and TG/HDL-C ratios were compared between DILI and control groups, DILI mild group and severe group. The area under the receiver-operating characteristic curve (AUC) was used to evaluate the credibility of the relationship and to find cut-off points. Dyslipidemia is related to DILI when compared with medication using control group (AOR 4.60; 95% CI 2.81–7.54; P < 0.01) and compared with acute hepatitis B group (AOR 2.12; 95% CI 1.37–3.29; P < 0.01). Dyslipidemia is associated with the severity of DILI (AOR 25.78; 95% CI 7.63–87.1; P < 0.01). TG/HDL-C ratio is higher in DILI group than that of medication using control group, also higher in severe DILI group than that of mild DILI group. AUCs for TG/HDL-C ratio to indicate the severity of DILI was 0.89 (P < 0.05), the cut-off point was 2.35. Dyslipidemia and TG/HDL-C ratio were related to DILI occurrence. Severe liver injury in DILI was associated with dyslipidemia and elevated TG/HDL-C ratio.

Fpr2-/- Mice Developed Exacerbated Alcohol-Associated Liver Disease.

Alcohol-associated liver disease (ALD) is the most common chronic liver disease and carries a significant healthcare burden. ALD has no long-term treatment options aside from abstinence, and the mechanisms that contribute to its pathogenesis are not fully understood. This study aimed to investigate the role of formyl peptide receptor 2 (FPR2), a receptor for immunomodulatory signals, in the pathogenesis of ALD. WT and Fpr2-/- mice were exposed to chronic-binge ethanol administration and subsequently assessed for liver injury, inflammation, and markers of regeneration. The differentiation capacity of liver macrophages and the oxidative burst activity of neutrophils were also examined. Compared to WT, Fpr2-/- mice developed more severe liver injury and inflammation and had compromised liver regeneration in response to ethanol administration. Fpr2-/- mice had fewer hepatic monocyte-derived restorative macrophages, and neutrophils isolated from Fpr2-/- mice had diminished oxidative burst capacity. Fpr2-/- MoMF differentiation was restored when co-cultured with WT neutrophils. Loss of FPR2 led to exacerbated liver damage via multiple mechanisms, including abnormal immune responses, indicating the crucial role of FPR2 in ALD pathogenesis.

Characterization of Hypomagnesemia in Alcoholic Hepatitis Patients and Its Association with Liver Injury and Severity Markers.

Hypomagnesemia has been documented in alcohol-associated liver disease (ALD). This study aims to characterize hypomagnesemia in alcoholic hepatitis (AH) patients and identify its response with liver injury and severity markers. A total of 49 male and female AH patients with an age range of 27-66 years were enrolled in this study. Patients were grouped by MELD: MiAH (mild AH < 12 [n = 5]), MoAH (12 ≤ moderate AH ≤ 19 [n = 13]), and SAH (severe AH ≥ 20 [n = 31]). Patients were also evaluated by MELD grouping as non-severe (MELD ≤ 19 [n = 18]) and severe (MELD ≥ 20 [n = 31]). Data were collected on demographics (Age; BMI), drinking history (AUDIT; LTDH), liver injury (ALT; AST), and liver severity (Maddrey's DF; MELD; AST:ALT). Serum magnesium (SMg) levels were tested as SOC lab (normal ≥ 0.85 ≤ 1.10 mmol/L). SMg was deficient in each group; the lowest in the MoAH patients. The true positivity of SMg values were at a good performance level when compared between severe and non-severe AH patients (AUROC: 0.695, p = 0.034). We found that the SMg level < 0.78 mmol/L could predict severe AH (sensitivity = 0.100 and 1-specificity = 0.000) at this true positivity, and subsequently analyzed patients with SMg < 0.78 mmol/L (Gr.4) and ≥0.78 mmol/L (Gr.5). Between Gr.4 and Gr.5, there were clinically as well as statistically significant differences in disease severity as defined by MELD, Maddrey's DF, and ABIC scores. This study demonstrates the utility of SMg levels to identify AH patients who may have progressed to severe status. The extent of magnesium response in AH patients also corresponded significantly with the prognosis of liver disease. Physicians suspecting AH in patients with recent heavy drinking may use SMg as an indicator to guide further testing, referrals, or treatment.

The Effect of Angioembolization vs Open Exploration for Moderate to Severe Blunt Liver Injuries on Mortality

Burton, Vicki; Schneider, Andrew B MD; Raff, Lauren MD, FACS; Reid, Trista Day Snyder MD, FACS; Gbolahan Charles, Anthony MBBS, FACS; Gallaher, Jared Robert MD, FACS Author Information

Acute severe hepatitis as a presenting symptom in clinically stable patients admitted with SARS-CoV-2 Omicron infection.

Suggested mechanisms for SARS-CoV-2 direct liver infection have been proposed by others to involve both cholangiocytes and hepatocytes. Early clinical studies have highlighted abnormal liver biochemistry with COVID-19 infection as often not being severe, with elevated liver enzymes <5X the upper limit of normal. Liver enzymes were evaluated and compared in patients admitted with a diagnosis of COVID-19 in a deidentified Internal Medicine-Medical Teaching Unit/hospitalist admission laboratory database. Comparisons in the incidence of severe liver injury (alanine aminotransferase >10 times upper limit of normal) were made for patients with pre-Omicron SARS-CoV-2 (November 30, 2019, to December 15, 2021) and Omicron SARS-CoV-2 (December 15, 2021, to April 15, 2022). Comprehensive hospital health records were also reviewed for the 2 patient cases discussed. One patient had a liver biopsy that was evaluated with H&E and immunohistochemistry staining using an antibody against COVID-19 spike protein. The evaluation of a deidentified admissions laboratory database found the incidence of severe liver injury was 0.42% with Omicron versus 0.30% with pre-Omicron variants of COVID-19. In both patient cases discussed, abnormal liver biochemistry and a negative comprehensive workup strongly suggest COVID-19 as the cause of severe liver injury. In the one patient with liver biopsy, immunohistochemistry staining suggests SARS-CoV-2 presence in the portal and lobular spaces in association with immune cell infiltration. The Omicron variant of SARS-CoV-2 should be considered in the differential diagnosis of severe acute liver injury. Our observation suggests that this new variant, either through direct liver infection and/or mediating immune dysfunction, can result in severe liver injury.

Features of Liver Injury in COVID-19 Pathophysiological, Biological and Clinical Particularities

The outbreak of the coronavirus pandemic in March 2020 has caused unprecedented pressure on public health and healthcare. The spectrum of COVID-19 onset is large, from mild cases with minor symptoms to severe forms with multi-organ dysfunction and death. In COVID-19, multiple organ damage has been described, including lung damage, acute kidney injury, liver damage, stroke, cardiovascular and digestive tract disorders. The aspects of liver injury are different, sometimes presenting with only a slight increase in liver enzymes, but sometimes with severe liver injury, leading to acute liver failure requiring liver transplantation. In patients with chronic liver disease, especially liver cirrhosis, immune dysfunction can increase the risk of infection. Immune dysfunction has a multifactorial physiopathological mechanism, implying a complement system and macrophage activation, lymphocyte and neutrophil activity dysfunction, and intestinal dysbiosis. This review aims to evaluate the most relevant studies published in the last years related to the etiopathogenetic, biochemical, and histological aspects of liver injury in patients diagnosed with COVID-19. Liver damage is more evident in patients with underlying chronic liver disease, with a significantly higher risk of developing severe outcomes of COVID-19 and death. Systemic inflammation, coagulation disorders, endothelial damage, and immune dysfunction explain the pathogenic mechanisms involved in impaired liver function. Although various mechanisms of action of SARS-CoV-2 on the liver cell have been studied, the impact of the direct viral effect on hepatocytes is not yet established.

373 Identification of potential targets for immunotherapy in a cynomolgus macaque model of Ebola virus disease

OBJECTIVES/GOALS: Ebola virus infection causes severe disease and liver injury in humans. Macrophages contribute to inflammatory signaling and are prevalent in the liver. We assessed the activation status, including therapeutic target expression, of hepatic macrophages. METHODS/STUDY POPULATION: We compared formalin-fixed, paraffin-embedded liver tissue from terminal Ebola virus-infected and uninfected control cynomolgus macaques, a gold-standard model for human disease. We characterized region-specific protein and whole transcriptome expression in these tissues using GeoMx Digital Spatial Profiling. Macrophage (CD68+) and leukocyte (CD45+) accumulation in liver tissue was quantified by immunofluorescence image analysis using digital pathology software. RESULTS/ANTICIPATED RESULTS: Macrophage-specific (CD68+) regions in the liver of Ebola virus-infected macaques demonstrated a shift towards an inflammatory gene expression profile, as compared to those from healthy control tissue. These regions showed differential expression of monocyte/macrophage differentiation, antigen presentation, and T cell activation gene sets, which were associated with decreased MHC-II allele expression. Moreover, macrophage-specific regions in the infected macaques showed enriched expression of genes or proteins associated with known immunomodulatory therapeutics, including S100A9, IDO1, and CTLA-4. DISCUSSION/SIGNIFICANCE: These data demonstrate that hepatic macrophages express an inflammatory phenotype, that their ability to present antigens to the adaptive immune system may be impaired, and that they express therapeutically targetable markers for immunomodulation of these cells during Ebola virus infection.

Association of Liver Function Serum Markers and Unfavorable Outcomes in Traumatic Liver Injury Patients

OBJECTIVE To evaluate serum markers in liver function tests (LFT) at various intervals after traumatic liver injury to identify serum markers associated with unfavorable outcomes. METHODS A retrospective cohort analysis was conducted of trauma center patients older than 18 years with traumatic liver injury. Liver function test (LFT) results of patients with favorable and unfavorable outcomes were compared at different post-injury time points. Statistical significance was established as p-value less than 0.05. RESULTS Of the 206 patients with severe liver injuries in the unfavorable outcome group, 119 (57.8%) needed intervention. Aspartate amino-transferase (AST) and alanine transaminase (ALT) were seen to increase in correlation with injury severity at initial admission. On days 1-5 and 6-10 after admission, the unfavorable outcome group had a slower decline in AST. In the unfavorable group, total bilirubin (TB) and direct bilirubin (DB) levels rose significantly 5 days after the injury and were higher than normal with a higher odds ratio (OR) of unfavorable outcome 11-15 days after injury in multivariable analysis [OR (95% confidence intervals): 2.7 (1.02-7.37) and 6.9 (1.08-44.14), respectively]. CONCLUSIONS Liver function tests can help identify individuals at risk for traumatic liver injury complications. Elevated levels of TB and DB are statistically significantly associated with adverse outcomes, particularly after day 5 following the injury. Early repeating LFT in first five days after injury may be less beneficial in determining patient risk. Blood test results may be affected by the amount of fluid resuscitation, particularly on the first day of admission in cases of high- grade injuries. KEYWORDS aspartate aminotransferase, liver injury, liver function test, unfavorable outcome, alanine transaminase, bilirubin

In silico structure prediction and molecular docking analyses to reveal potential binding domain of Hepatitis B virus genotype A2

Hepatitis B Virus (HBV) infects the hepatocytes to cause serious liver diseases. HBeAg regulates the response of immune system to the intracellular capsid act as T-cell tolerogen. The immune response regulation may predispose to chronicity during perinatal infections to prevent the severe liver injuries. Various in silico approaches including comparative modeling, threading approach and ab initio approach were employed for the prediction of 3D structures of the selected protein followed by the validation of the predicted structures through Errat, Procheck and Anolea. The predicted 3D structure of HBeAg revealed overall quality factor of 95.9184%. Interestingly, it was observed that only 1.97% residues were present in outlier region while 98.03% in favored and allowed region. Molecular docking analyses were performed and the attempt was for the identification of novel ligands for HBeAg. The reported compound may regulate the activity and act as regulator of HBeAg. Interestingly, least binding energy of -7.1 Kcal/mol was observed in the reported compound and high binding affinity to predict the binding residues (Asp-51, Phe-53, Val-56, Arg-57, Met-95, Ala-98, Asn-103, Arg-111, Asp-112, Val-115, Val-118 and Asn-119). The function determination of the selected target protein is due to the identification of effective binding sites in protein structures. The reported compound may act as potent molecule and the predicted structure is reliable for the functional studies and structural insights.

Unity is Strenght: Multidisciplinary Approach to a Severe Liver and Pancreatic Injury

Unity is Strenght: Multidisciplinary Approach to a Severe Liver and Pancreatic Injury

Hepatoprotective and anti-inflammatory effects of entecavir or probiotics on Oxaliplatin-Induced Liver Injury in the rats

Oxaliplatin (OXA), a current cancer chemotherapeutic, has low efficacy and is linked to serious adverse effects, including liver damage. We anticipated that probiotics and entecavir would help reduce OXA-induced liver damage because the pathophysiology of drug-induced liver damage is thought to be related to the disordered gut microbiota. Twenty-four rats were used in this study and divided into 4 groups: control group (n=6), OXA group (n=6), entecavir (ENT) group (n=6), and probiotics (PRO) group (n=6). After 3 weeks, all rats were sacrificed, and blood samples were analyzed for alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), interleukin 6 (IL-6), and IL-1. Serum measurement of biochemical parameters showed a significant increase in ALP in the OXA group compared to the control group (p&lt;0.0001). The treatment with ENT or PRO along with OXA alleviated these changes. Significant elevation of serum ALT (p=0.041) and non-significant (p=0.210) increase of AST was observed in OXA-treated rats as compared with control rats. The administration of ENT or PRO along OXA restored these changes, but they did not reach the levels of control rats. Significant elevations of serum IL-1 (p=0.024) and a non-significant (p=0.114) increase of IL-6 were observed in OXA-treated rats compared to control rats. The administration of ENT or PRO along OXA reduced inflammatory cytokines' levels but they did not return to the baseline. The treatment with ENT or PRO was beneficial in reducing the severity of OXA-induced liver injury, likely by reducing inflammatory responses and liver function tests.

Bipotent transitional liver progenitor cells contribute to liver regeneration

Following severe liver injury, when hepatocyte-mediated regeneration is impaired, biliary epithelial cells (BECs) can transdifferentiate into functional hepatocytes. However, the subset of BECs with such facultative tissue stem cell potential, as well as the mechanisms enabling transdifferentiation, remains elusive. Here we identify a transitional liver progenitor cell (TLPC), which originates from BECs and differentiates into hepatocytes during regeneration from severe liver injury. By applying a dual genetic lineage tracing approach, we specifically labeled TLPCs and found that they are bipotent, as they either differentiate into hepatocytes or re-adopt BEC fate. Mechanistically, Notch and Wnt/β-catenin signaling orchestrate BEC-to-TLPC and TLPC-to-hepatocyte conversions, respectively. Together, our study provides functional and mechanistic insights into transdifferentiation-assisted liver regeneration.

Issues of intensive care and liver transplantation tactics in fulminant liver failure

Fulminant liver failure is usually characterized as severe acute liver injury with encephalopathy and synthetic dysfunction (international normalized ratio [INR] ≥1.5) in a patient without cirrhosis or previous liver disease. Management of patients with acute liver failure includes ensuring that the patient is cared for appropriately, monitoring for worsening liver failure, managing complications, and providing nutritional support. Patients with acute liver failure should be treated at a liver transplant center whenever possible. Serial laboratory tests are used to monitor the course of a patient's liver failure and to monitor for complications. It is necessary to monitor the level of aminotransferases and bilirubin in serum daily. More frequent monitoring (three to four times a day) of blood coagulation parameters, complete blood count, metabolic panels, and arterial blood gases should be performed. For some causes of acute liver failure, such as acetaminophen intoxication, treatment directed at the underlying cause may prevent the need for liver transplantation and reduce mortality. Lactulose has not been shown to improve overall outcomes, and it can lead to intestinal distention, which can lead to technical difficulties during liver transplantation. Early in acute liver failure, signs and symptoms of cerebral edema may be absent or difficult to detect. Complications of cerebral edema include increased intracranial pressure and herniation of the brain stem. General measures to prevent increased intracranial pressure include minimizing stimulation, maintaining an appropriate fluid balance, and elevating the head of the patient's bed. For patients at high risk of developing cerebral edema, we also offer hypertonic saline prophylaxis (3%) with a target serum sodium level of 145 to 155 mEq/L (level 2C). High-risk patients include patients with grade IV encephalopathy, high ammonia levels (&gt;150 µmol/L), or acute renal failure, and patients requiring vasopressor support. Approximately 40 % of patients with acute liver failure recover spontaneously with supportive care. Predictive models have been developed to help identify patients who are unlikely to recover spontaneously, as the decision to undergo liver transplant depends in part on the likelihood of spontaneous recovery of the liver. However, among those who receive a transplant, the one-year survival rate exceeds 80 %, making this treatment the treatment of choice in this difficult patient population.

Reduction of emodin-8-O-ß-D-glucoside content participates in processing-based detoxification of polygoni multiflori radix

BackgroundThe occurrence of severe liver injury by the herbal medicine Polygoni Multiflori Radix (PMR) has drawn significant attention. The fact that processing attenuates PMR-induced hepatotoxicity has been well accepted, but the mechanisms are still ambiguous. PurposeThis study aimed to illuminate the mechanism of processing-based attenuation of PMR hepatotoxicity. MethodsThe contents of emodin-8-O-β-d-glucoside (EG) and emodin (EMD) in raw and processed PMR were quantified. The difference in toxicokinetic behaviors of EG and EMD was determined in vivo, and the disposition properties of EG were investigated in vitro and in vivo. ResultsDecreased EG content was found in processed (black bean) PMR. Processed PMR showed reduced adverse effects relative to raw PMR. In addition, less hepatic protein adduction derived from EMD was produced in mice after exposure to processed PMR than that in animals receiving raw PMR. Glucose transporters SGLT1 and GLUT2 participated in the absorption of EG, and effective hydrolysis of EG to EMD took place in the intestinal epithelial cells during the process of absorption. Cytosolic broad-specificity β-glucosidase and lactase phlorizin hydrolase, as well as intestinal flora, participated in the hydrolysis of EG. The circulated EMD resulting from the deglycosylation of EG executed the hepatotoxic action. ConclusionEG is a pre-toxin and can be metabolically activated to EMD participating in the hepatotoxic event. The reduction of EG content due to processing is a key mechanistic factor that initiates the detoxification of PMR.

Inflammasome and pyroptosis in autoimmune liver diseases.

Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and IgG4-related sclerosing cholangitis (IgG4-SC) are the four main forms of autoimmune liver diseases (AILDs), which are all defined by an aberrant immune system attack on the liver. Most previous studies have shown that apoptosis and necrosis are the two major modes of hepatocyte death in AILDs. Recent studies have reported that inflammasome-mediated pyroptosis is critical for the inflammatory response and severity of liver injury in AILDs. This review summarizes our present understanding of inflammasome activation and function, as well as the connections among inflammasomes, pyroptosis, and AILDs, thus highlighting the shared features across the four disease models and gaps in our knowledge. In addition, we summarize the correlation among NLRP3 inflammasome activation in the liver-gut axis, liver injury, and intestinal barrier disruption in PBC and PSC. We summarize the differences in microbial and metabolic characteristics between PSC and IgG4-SC, and highlight the uniqueness of IgG4-SC. We explore the different roles of NLRP3 in acute and chronic cholestatic liver injury, as well as the complex and controversial crosstalk between various types of cell death in AILDs. We also discuss the most up-to-date developments in inflammasome- and pyroptosis-targeted medicines for autoimmune liver disorders.

A261 SEVERE ACUTE LIVER INJURY SECONDARY TO WILSON’S DISEASE: A CASE REPORT AND REVIEW OF THE LITERATURE

Abstract Background Wilson’s disease is autosomal recessive and rare (prevalence 1/30000-1/50000) caused by mutations in the ATP7B gene involved in copper excretion. Copper deposition drives hepatic injury, along with neuropsychiatric-ophthalmologic, and hematologic symptoms. Leipzig criteria greater than 4 establishes the diagnosis. Purpose We report a case of severe liver injury secondary to probable Wilson’s disease. Method Literature review of diagnosis, management including emerging therapies was performed using PubMed. Result(s) A 29-year-old otherwise healthy male with no family history of liver disease presented with abdominal pain, jaundice, and severe acute liver injury (ALT 1534 U/L ALP 114 U/L bilirubin 113 umol/L) initially misdiagnosed as hepatitis A in community urgent care. He had worsening liver injury (ALT 1809 U/L bilirubin 411 umol/L), with normal INR and no encephalopathy over an additional 3 weeks and was admitted to our tertiary care centre for further work up. History did not reveal viral prodromes, herbals or natural remedies. CBD oil was the only potential exposure, though longstanding use of the same brand argued against this as a cause. Chronic liver disease workup was negative (viral hepatitides, SARS-CoV-2, alpha-1-antitrypsin, acetaminophen level, iron profile, and comprehensive Mitogen autoantibody panel). Patent vasculature on Doppler US. Liver biopsy showed diffuse lobular inflammation, hepatocyte necrosis, 30% parenchymal involvement, primarily lymphocytes with some eosinophils and plasma cells, and no viral inclusions suggesting acute hepatitis with drugs or viral hepatitis as etiologies. The 24-hour urine copper was elevated at 2.19 umol/d (&amp;lt;0.80). Biopsy copper dry weight 60mcg/g (N&amp;lt;50; &amp;gt;250 diagnostic). Normal ceruloplasmin 0.30g/L and serum copper 25.8 umol/L. MRI brain not suggestive of Wilson’s disease, no Kayser-Fleischer rings on Ophthalmology assessment, and no hemolysis. Given a Leipzig score of 3 suggesting possible Wilson’s disease he was started on penicillamine 1500mg daily. Five weeks later he had serologic (ALT 1061 U/L bilirubin 128 umol/L) improvement, yet elevated elastography at 22kPa IQR 5% likely due to inflammation. Given coverage issues, he was switched to compassionate trientine 500mg BID with further improvement (ALT 347 U/L bilirubin 26 umol/L). Sequencing for ATP7B gene mutations are pending (Blueprint Genetics). Conclusion(s) Wilson’s disease should be considered in those with hepatic or neuropsychiatric symptoms, transaminases in the 1000s or acute liver failure. Treatment is lifelong with typically good prognosis and is fatal if untreated. Treatment options include chelators D-penicillamine (first line, with side effects including proteinuria and worsened neurological symptoms) and trientine (fewer side effects). Zinc prevents copper absorption and can be used in asymptomatic patients. Transplant in acute liver failure and end-stage liver disease is guided by the King’s score. Several novel therapies including gene therapy are in development. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared