APASL clinical practice guidelines on the management of acute kidney injury in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a syndrome that is characterized by the rapid development of organ failures predisposing these patients to a high risk of short-term early death. The main causes of organ failure in these patients are bacterial infections and systemic inflammation, both of which can be severe. For the majority of these patients, a prompt liver transplant is still the only effective course of treatment. Kidneys are one of the most frequent extrahepatic organs that are affected in patients with ACLF, since acute kidney injury (AKI) is reported in 22.8-34% of patients with ACLF. Approach and management of kidney injury could improve overall outcomes in these patients. Importantly, patients with ACLF more frequently have stage 3 AKI with a low rate of response to the current treatment modalities. The objective of the present position paper is to critically review and analyze the published data on AKI in ACLF, evolve a consensus, and provide recommendations for early diagnosis, pathophysiology, prevention, and management of AKI in patients with ACLF. In the absence of direct evidence, we propose expert opinions for guidance in managing AKI in this very challenging group of patients and focus on areas of future research. This consensus will be of major importance to all hepatologists, liver transplant surgeons, and intensivists across the globe.

Deceased Donor Liver Transplantation in India: First Report of 5-Y Outcomes.

BACKGROUND: Paucity of deceased donor livers has resulted in a 10-fold rise in living donor liver transplantations (LDLTs) performed in India over the past decade. Nonetheless, number of deceased donor liver transplantation (DDLT) performed has improved with the establishment of simplified legal framework for certification of brain death and organ donation. In this study, we present our outcomes of DDLT performed at various centers, comparing their outcomes and provide a snapshot of the increasing number of DDLT across the state over the years. METHODS: All consecutive patients who underwent liver transplants from January 2010 till December 2019 by our transplant team in the state of Tamil Nadu, India, were included in the study. The program was established initially at the primary hospital in the year 2010 and with the evolution of the initial experience, transplant programs were expanded to the others hospital from the year 2015. Preoperative clinical data, intraoperative characteristics, and posttransplant outcomes of DDLT were analyzed from our prospective database. RESULTS: A total of 362 DDLTs (331 adults, 31 children) were performed at 11 centers. Median (range) model for end-stage liver disease score was 16 (6-39). Forty-eight split, 11 combined liver kidney, and 4 auxiliary DDLTs were performed. One-, 3-, and 5-y survival was 87.2%, 80.4%, and 76.6% in adults and 80.6%, 80.6%, and 80.6% in children, respectively. CONCLUSIONS: In a country where over 80% of the LTs are performed as LDLT, we provide the first report of a heartening trend of increasing number of DDLT programs being established with excellent 5-y outcomes.

Liver Transplantation for Dengue-induced Acute Liver Failure.

Although liver involvement has been observed in over two-third cases of dengue viral infection, less than 1% cases progress to dengue-related acute liver failure (D-ALF). Various aspects of management of this disease remain debated including the need and timing of liver transplantation (LT). Moreover, the outcomes of LT for D-ALF have been suboptimal. We present four contrasting cases of D-ALF, two managed with LT and the other two conservatively to highlight the management dilemmas concerning LT in D-ALF. Based on our 4 cases, we would consider dengue shock syndrome, multisystem involvement and neurological deficit not completely accounted for by the ALF as potential contraindications for LT. These would need to be revisited on a case-to-case basis till larger studies define objective selection criteria for LT in D-ALF.

2023 Update of Indian National Association for Study of the Liver Consensus on Management of Intermediate and Advanced Hepatocellular Carcinoma: The Puri III Recommendations.

Hepatocellular carcinoma (HCC) presents significant treatment challenges despite considerable advancements in its management. The Indian National Association for the Study of the Liver (INASL) first published its guidelines to aid healthcare professionals in the diagnosis and treatment of HCC in 2014. These guidelines were subsequently updated in 2019. However, INASL has recognized the need to revise its guidelines in 2023 due to recent rapid advancements in the diagnosis and management of HCC, particularly for intermediate and advanced stages. The aim is to provide healthcare professionals with evidence-based recommendations tailored to the Indian context. To accomplish this, a task force was formed, and a two-day round table discussion was held in Puri, Odisha. During this event, experts in their respective fields deliberated and finalized consensus statements to develop these updated guidelines. The 2023 INASL guidelines offer a comprehensive framework for the diagnosis, staging, and management of intermediate and advanced HCC in India. They represent a significant step forward in standardizing clinical practices nationwide, with the primary objective of ensuring that patients with HCC receive the best possible care based on the latest evidence. The guidelines cover various topics related to intermediate and advanced HCC, including biomarkers of aggressive behavior, staging, treatment options, and follow-up care.

Fecal calprotectin in patients with liver cirrhosis.

BACKGROUND AND OBJECTIVES: Sepsis is the most challenging complication in patients with liver cirrhosis. It destabilizes patients leading to worsening of liver dysfunction and increased mortality. Intestinal bacterial dysbiosis, release of endotoxins, increased gut permeability and associated immune dysregulation have been described in cirrhotic patients with septic complications. Calprotectin is a major cytosolic protein secreted by the inflammatory cells and has been widely studied in patients with inflammatory bowel disease. We aimed at evaluating the role of fecal calprotectin (FCAL) in patients with liver cirrhosis. METHODS: A prospective, observational study on the utility of FCAL test was conducted in patients with liver cirrhosis. Fifteen milligrams of fecal specimen was collected and analyzed within 48 hours of hospitalization from patients with end-stage liver disease (ESLD), acute-on-chronic liver failure (ACLF) and at the time of outpatient visit for stable cirrhotics. Five healthy volunteers underwent FCAL test as control population. RESULTS: The mean FCAL (µg/g) level in healthy control (n = 5), stable cirrhotics (n = 10), ESLD (n = 10) and ACLF (n = 10) patients was 109.2 (95% CI: - 53.39 to 271.79), 143.3 (95% CI: 50.5-236.45), 176.9 (95% CI: 122.93-230.87) and 543.5 (95% CI: 207.09-879.91) (p = 0.005), respectively. Sepsis was identified in 13 (43.3%) patients. Area under the receiver-operating characteristics curve (AUROC) of FCAL was 0.80 (p = 0.005) and FCAL ≥ 200 µg/g (OR = 10.8, p = 0.006) was associated with sepsis. Nine (25.7%) patients expired. FCAL level was significantly higher in dead patients compared to survivors (mean, 493.67 (95% CI: 142.20-845.14) vs. 199.71 (95% CI: 99.84-299.59) µg/g,p = 0.005. CONCLUSIONS: FCAL levels are increased in patients with chronic liver disease, with highest level in ACLF. An FCAL level of ≥ 200 µg/g was associated with sepsis and mortality in cirrhotic patients. Larger studies are required to identify the role of FCAL in these patients. Early identification and initiation of anti-microbials may mitigate sepsis and reduce mortality.

Preventing Small-for-size Syndrome in Living Donor Liver Transplantation: Guidelines From the ILTS-iLDLT-LTSI Consensus Conference.

Small-for-size syndrome (SFSS) is a well-recognized complication following liver transplantation (LT), with up to 20% developing this following living donor LT (LDLT). Preventing SFSS involves consideration of factors before the surgical procedure, including donor and recipient selection, and factors during the surgical procedure, including adequate outflow reconstruction, graft portal inflow modulation, and management of portosystemic shunts. International Liver Transplantation Society, International Living Donor Liver Transplantation Group, and Liver Transplant Society of India Consensus Conference was convened in January 2023 to develop recommendations for the prediction and management of SFSS in LDLT. The format of the conference was based on the Grading of Recommendations, Assessment, Development, and Evaluation system. International experts in this field were allocated to 4 working groups (diagnosis, prevention, anesthesia, and critical care considerations, and management of established SFSS). The working groups prepared evidence-based recommendations to answer-specific questions considering the currently available literature. The working group members, independent panel, and conference attendees served as jury to edit and confirm the final recommendations presented at the end of the conference by each working group separately. This report presents the final statements and evidence-based recommendations provided by working group 2 that can be implemented to prevent SFSS in LDLT patients.

Frequent expression of PD-L1 in lymphocyte-rich hepatocellular carcinoma: A report of 4 cases.

BACKGROUND: Programmed death ligand 1 (PD-L1) is an immune checkpoint inhibitor. PD-L1 binds to its receptor programmed death receptor (PD-1) expressed by immune cells and plays a key role in regulating immune responses. Engagement of PD-L1 on cancer cells and PD-1 on immune cells avoid destruction of tumour cells by immune cells. Immunostaining with PD-L1 has been suggested as a biomarker predictive of antiPD-L1 immunotherapy. Lymphocyte-rich hepatocellular carcinoma (LrHCC) is a rare histological HCC subtype which is characterised by neoplastic epithelial cells intermixed with numerous immune cells. METHODS: Here in we investigated immunohistochemical PD-L1 expression in 4 cases of LrHCC. Tumour proportion score (TPS) and immune cell score was recorded. Immunophenotypic characterization of the tumour and inflammatory cells was also done. Epstein-Barr encoding region (EBER) in situ hybridization (ISH) assay as performed in all four tumours. RESULTS: Expression of PD-L1 was demonstrated in tumour epithelial cells and immune cells in all four cases. Incomplete to membranous staining was demonstrated in the tumour cells. Tumour proportion score (TPS) was 1.2-20 %. Immune cells demonstrated membranous and cytoplasmic immunostaining. Immune cell score was ≥1 % to >10 %. CONCLUSION: PD-L1 expression in both tumour and immune cells suggests distinct immunogenic feature and potential role of antiPD-L1 therapies in cases with inoperable disease.

Post-COVID-19 cholangiopathy: Current understanding and management options.

Post-coronavirus disease 2019 (COVID-19) cholangiopathy (PCC) is a rare but life-threatening complication of COVID-19 infection. PCC typically presents when patients recovering from the contagion and manifests as cholestasis in patients with no history of pre-existing liver disease. The pathogenesis of PCC is little understood. Hepatic injury in PCC could be mediated by the predilection of severe acute respiratory syndrome coronavirus 2 for cholangiocytes. Though PCC shows some resemblance to secondary sclerosing cholangitis in critically ill patients, it is considered as a separate and unique entity in the literature. Various treatment options like ursodeoxycholic acid, steroids, plasmapheresis, and endoscopic retrograde cholangiopancreatography guided interventions have been tried but with limited success. We have noticed significant improvement in liver function with antiplatelet therapy in a couple of patients. PCC can progress to end-stage liver disease necessitating liver transplantation. In this article, we discuss the current knowledge of PCC focusing on its pathophysiology, clinical manifestations, and management strategies.

Liver Cirrhosis and Portal Hypertension: How to Deal with Esophageal Varices?

The understanding of pathogenesis of portal hypertension in patients with liver cirrhosis continues to evolve. In addition to progressive fibrosis, cirrhosis is characterized by parenchymal extinction and vascular remodelling, causing architectural distortion. Existence of prothrombotic state and more recently, intestinal bacterial dysbiosis are recently described in the pathogenesis of portal hypertension. Clinically significant portal hypertension (CSPH) is an important prognostic milestone in patients with liver cirrhosis. This is a pre-symptomatic phase that predicts the development of varices, ascites and importantly increased risk of Hepatocellular carcinoma (HCC). CSPH is associated with significantly reduced survival. Endoscopic surveillance is necessary in these patients. Non-selective Beta-blocker is the preferred therapy for primary prophylaxis in the management of portal hypertension. Patients with acute variceal bleed should be resuscitated appropriately, followed by vasoactive drugs and endoscopic therapy. Early TIPS should be considered in those with refractory bleed or in endoscopic treatment failure. Application of artificial intelligence and machine learning may be useful in future for identifying patients at risk of variceal hemorrhage.

Outcome of Patients Waitlisted for Deceased Donor Liver Transplantation During COVID-19 Pandemic: A Single-Center Experience.

Background and aim: COVID-19 pandemic has strained several healthcare resources across the world. While liver transplantation (LT) is the only curative therapy for patients with end-stage liver disease, we aimed to determine the clinical outcome of patients waitlisted for deceased donor liver transplantation (DDLT) during COVID-19 pandemic. Methods: A retrospective comparative observational study of adult patients waitlisted for DDLT from January 2019 to January 2022 at our liver unit (Dr Rela Institute and Medical Center, Chennai, Tamil Nadu, India) was carried out. Patient demographics, disease etiology, Model for End-Stage Liver Disease - Sodium (MELD-Na) score were calculated for all patients listed during the study period. Clinical event was defined as number of DDLT, death in the absence of transplant, and patients awaiting LT were compared. Statistical analysis was performed with SPSS V24.0. Results: In total, 310 patients were waitlisted for DDLT, of whom 148, 63, and 99 patients listed during 2019, 2020, and 2021 (till January 2022), respectively; 22 (53.6%), 10 (24.3%), and 9 (21.9%) patients underwent DDLT in the year 2019, 2020, and 2021 (P = 0.000); 137 patients (44.19%) died on the DDLT waitlist of whom 41 (29.9%), 67 (48.9%), and 29 (21.1%) in the year 2019, 2020, and 2021 (P = 0.000), respectively. Waitlist mortality was significantly higher during the COVID first wave. Conclusion: COVID-19 pandemic has significantly impacted patients waitlisted for DDLT in India. With limited access to healthcare facilities and decreased organ donation rates during the pandemic, there was a considerable reduction in the patients waitlisted for DDLT, lesser number of patients underwent DDLT, and higher waitlist mortality during the pandemic year. Efforts to improve organ donation in India should be strongly implemented.

Identifying the early predictors of non-response to steroids in patients with flare of autoimmune hepatitis causing acute-on-chronic liver failure.

BACKGROUND AND AIMS: Early identification of non-response to steroids is critical in patients with autoimmune hepatitis (AIH) causing acute-on-chronic liver failure (ACLF). We assessed if this non-response can be accurately identified within first few days of treatment. METHODS: Patients with AIH-ACLF without baseline infection/hepatic encephalopathy were identified from APASL ACLF research consortium (AARC) database. Diagnosis of AIH-ACLF was based mainly on histology. Those treated with steroids were assessed for non-response (defined as death or liver transplant at 90 days for present study). Laboratory parameters, AARC, and model for end-stage liver disease (MELD) scores were assessed at baseline and day 3 to identify early non-response. Utility of dynamic SURFASA score [- 6.80 + 1.92*(D0-INR) + 1.94*(∆%3-INR) + 1.64*(∆%3-bilirubin)] was also evaluated. The performance of early predictors was compared with changes in MELD score at 2 weeks. RESULTS: Fifty-five out of one hundred and sixty-five patients (age-38.2 ± 15.0 years, 67.2% females) with AIH-ACLF [median MELD 24 (IQR: 22-27); median AARC score 7 (6-9)] given oral prednisolone 40 (20-40) mg per day were analyzed. The 90 day transplant-free survival in this cohort was 45.7% with worse outcomes in those with incident infections (56% vs 28.0%, p = 0.03). The AUROC of pre-therapy AARC score [0.842 (95% CI 0.754-0.93)], MELD [0.837 (95% CI 0.733-0.94)] score and SURFASA score [0.795 (95% CI 0.678-0.911)] were as accurate as ∆MELD at 2 weeks [0.770 (95% CI 0.687-0.845), p = 0.526] and better than ∆MELD at 3 days [0.541 (95% CI 0.395, 0.687), p < 0.001] to predict non-response. Combination of AARC score > 6, MELD score > 24 with SURFASA score ≥ - 1.2, could identify non-responders at day 3 (concomitant- 75% vs either - 42%, p < 0.001). CONCLUSION: Baseline AARC score, MELD score, and the dynamic SURFASA score on day 3 can accurately identify early non-response to steroids in AIH-ACLF.

Biphenotypic Immunohistochemical Features and NTRK1 Amplification in Intermediate Cell Carcinoma of the Liver.

Intermediate cell carcinoma is one of the rarest forms of primary liver cancer comprising relatively monomorphic populations of neoplastic epithelial cells demonstrating simultaneous positivity of both hepatocyte and cholangiocyte immunohistochemical markers. Here in, we describe an adult male patient who underwent left hepatectomy for a large liver tumor. The pathological and immunohistochemical analysis revealed the malignant primary liver cancer with intermediate cell morphology and mixed immunophenotypic features consistent with intermediate cell carcinoma. Furthermore, the genomic profiling using the Next-generation sequencing (NGS) platform demonstrated that there is a novel amplification with copy number gain 12 (12 gene copies) in the Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1) gene, being an oncogenic driver of intermediate cell carcinoma. This is the first case report with the amplification in NTRK1 and emphasizes the importance of molecular oncology.

COVID-19: Time for a clinical classification?

COVID-19 pandemic caused by SARS-CoV-2 virus has been around for 2 years causing significant health-care catastrophes in most parts of the world. The understanding of COVID-19 continues to expand, with multiple newer developments such as the presence of asymptomatic cases, feco-oral transmission, and endothelial dysfunction. The existing classification was developed before this current understanding. With the availability of recent literature evidences, we have attempted a classification encompassing pathogenesis and clinical features for better understanding of the disease process. The pathogenesis of COVID-19 continues to evolve. The spiked protein of the SARS-CoV-2 virus binds to ACE2 receptors causes direct cytopathic damage and hyperinflammatory injury. In addition to alveolar cells, ACE2 is also distributed in gastrointestinal tract and vascular endothelium. ACE2-SARS-CoV-2 interaction engulfs the receptors leading to depletion. Accumulation of Ang2 via AT1 receptor (AT1R) binding causes upregulation of macrophage activity leading to pro-inflammatory cytokine release. Interleukin-6 (IL-6) has been attributed to cause hyperinflammatory syndrome in COVID-19. In addition, it also causes severe widespread endothelial injury through soluble IL-6 receptors. Thrombotic complications occur following the cleavage and activation of von Willebrand factor. Based on the above understanding, clinical features, organ involvement, risk stratification, and disease severity, we have classified COVID-19 patients into asymptomatic, pulmonary, GI, and systemic COVID-19 (S-COVID-19). Studies show that the infectivity and prognosis are different and distinct amongst these groups. Systemic-COVID-19 patients are more likely to be critically ill with multi-organ dysfunction and thrombo-embolic complications.

Acute variceal bleeding portends poor outcomes in patients with acute-on-chronic liver failure: a propensity score matched study from the APASL ACLF Research Consortium (AARC).

BACKGROUND AND AIMS: Limited data exist regarding outcomes of acute variceal bleeding (AVB) in patients with acute-on-chronic liver failure (ACLF), especially in those with hepatic failure. We evaluated the outcomes of AVB in patients with ACLF in a multinational cohort of APASL ACLF Research Consortium (AARC). METHODS: Prospectively maintained data from AARC database on patients with ACLF who developed AVB (ACLF-AVB) was analysed. This data included demographic profile, severity of liver disease, and rebleeding and mortality in 6 weeks. These outcomes were compared with a propensity score matched (PSM) cohort of ACLF matched for severity of liver disease (MELD, AARC score) without AVB (ACLF without AVB). RESULTS: Of the 4434 ACLF patients, the outcomes in ACLF-AVB (n = 72) [mean age-46 ± 10.4 years, 93% males, 66% with alcoholic liver disease, 65% with alcoholic hepatitis, AARC score: 10.1 ± 2.2, MELD score: 34 (IQR: 27-40)] were compared with a PSM cohort selected in a ratio of 1:2 (n = 143) [mean age-44.9 ± 12.5 years, 82.5% males, 48% alcoholic liver disease, 55.7% alcoholic hepatitis, AARC score: 9.4 ± 1.5, MELD score: 32 (IQR: 24-40)] of ACLF-without AVB. Despite PSM, ACLF patients with AVB had a higher baseline HVPG than without AVB (25.00 [IQR: 23.00-28.00] vs. 17.00 [15.00-21.75] mmHg; p = 0.045). The 6-week mortality in ACLF patients with or without AVB was 70.8% and 53.8%, respectively (p = 0.025). The 6-week rebleeding rate was 23% in ACLF-AVB. Presence of ascites [hazard ratio (HR) 2.2 (95% CI 1.03-9.8), p = 0.026], AVB [HR 1.9 (95% CI 1.2-2.5, p = 0.03)], and MELD score [HR 1.7 (95% CI 1.1-2.1), p = 0.001] independently predicted mortality in the overall ACLF cohort. CONCLUSION: Development of AVB confers poor outcomes in patients with ACLF with a high 6-week mortality. Elevated HVPG at baseline represents a potential risk factor for future AVB in ACLF.

Nonalcoholic Steatohepatitis: A Rapidly Increasing Indication for Liver Transplantation in India.

Background and aims: Recently, there has been a considerable increase in patients with nonalcoholic fatty liver disease. Availability of high-efficacy drugs for hepatitis B and hepatitis C virus (HCV) infection may have changed the disease prevalence. We aimed to study the impact of this changing epidemiology in patients undergoing liver transplantation (LT) over a 10-year period. Methods: The study population was stratified into Period 1 (2009-2014) and Period 2 (2015-2019). Demographics, indications for LT and changes in the epidemiology between two periods were analysed. Aetiology-based posttransplant survival analysis was carried out. Results: Indication for LT among 1017 adult patients (277 in Period 1 and 740 in Period 2) showed a significant increase in nonalcoholic steatohepatitis (NASH; 85 [30.7%] and 311 [42%]; P = 0.001), decrease in hepatitis C (49 [17.7%] and 75 [10.1%]; P = 0.002), and increase in hepatocellular carcinoma from Period 1 to Period 2 (13 [26.5%] to 38 [50.7%]; P = 0.009) among HCV patients. Patients transplanted for NASH had a lower 5-year survival compared with viral hepatitis (75.9% vs 87.4%; P = 0.03). There was a strong association between coronary artery disease and NASH (hazard ratio = 1.963, 95% confidence interval, 1.19-3.22). Conclusion: NASH is the leading indication for liver transplantation in India, surpassing viral hepatitis in recent years.

Erratum to 'Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure' [J Clin Exp Hepatol 10 (2020) 477-517].

[This corrects the article DOI: 10.1016/j.jceh.2020.04.011.].

Versatility of Anabolic Androgenic Steroid-Induced Hepatotoxicity.

The modified derivatives of testosterone, termed as androgenic steroids are indicated in the management of hypogonadism, visceral obesity and metabolic disorders. Anabolic androgenic steroids (AASs) however are surreptitiously used by athletes and body builders for cosmetic purpose owing to their anabolic effects on muscle mass and strength. The unsurveilled use of AASs subjects these users to various side effects involving multiple systems such as the endocrine, genitourinary, hepatobiliary, central nervous, musculoskeletal and psychosocial system. The liver is a hormone-sensitive organ owing to abundance of androgen receptors and is vulnerable to a wide array of hepatotoxicity ranging from asymptomatic liver enzyme elevation to life-threatening subacute liver failure. The type of drug-induced liver injury (DILI) due to AASs can be hepatocellular injury, cholestasis, fatty liver disease, chronic vascular injury and neoplastic disease. Herein, we report three cases of AAS-related DILI associated with AAS abuse.

Hereditary Persistence of Alpha-Fetoprotein in Chronic Liver Disease-Confusing Genes!

Alpha-fetoprotein (AFP) is a glycoprotein secreted by the embryonic liver and is expressed in tumours with high mitotic index such as hepatocellular carcinoma (HCC) and germ cell tumours. Detection of elevated AFP is strongly associated with underlying HCC or occasionally germ cell tumour. Modest elevation of AFP can be observed in patients with chronic viral hepatitis particularly with active replication. Very rarely, incidental detection of raised AFP in a genetically susceptible individuals has been reported in the absence of the underlying malignant process. This condition is termed as hereditary persistence of AFP (HPAFP), a rare disorder with an autosomal dominant pattern of inheritance. HPAFP should be suspected in patients with high AFP in the absence of radiological evidence of HCC or germ cell tumour. The diagnosis is confirmed by the identification of AFP gene mutation. AFP gene is located in the long arm of chromosome 4. The most common single-nucleotide polymorphism in HPAFP is 119 G > A, rs587776861, interestingly reported only in six family clusters worldwide. Despite being described as a benign disorder, its implication in patients with underlying chronic liver disease needs further clarification. Here, we describe 3 patients in their forties with chronic liver disease and persistently elevated levels of AFP, where genetic studies confirmed HPAFP. None of our patients had HCC despite extensive investigations.