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.

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.

Treatment and prognostic implications of strong PD-L1 expression in primary hepatic sarcomatoid carcinoma.

Primary hepatic sarcomatoid carcinoma (HSC) is an extremely rare and aggressive subtype of primary liver cancer. HSC has uncertain pathogenesis and dismal prognosis with overall survival of only 8.3 months. The molecular alterations of HSC are also not well understood. In this study, the authors describe a patient who presented with a large liver mass. The patient underwent complete surgical resection and histological examination demonstrated HSC, infiltrating the stomach. PD-L1 was strongly positive in the tumor cells. The patient was started on anti-PD-L1 immunotherapy postsurgery and is doing well 15 months after surgical resection. Tumor whole exome sequencing revealed genetic alterations in TP53, NF2 and MAGEC3 genes, indicating their potential role in tumor development.

Primary sarcomatoid cancer of the liver is a rare type of severe cancer that generally has a very poor prognosis. People diagnosed with primary sarcomatoid of the liver normally survive for only a few months. Surgery is not very effective in treating this type of cancer and recurrence is common even after complete removal. In this paper, the authors report a patient who presented to them with a large liver tumor. The patient underwent operation and the tumor was completely removed from the liver. Pathological testing of the tumor revealed it was severe primary sarcomatoid liver cancer. The patient was started on an immunotherapy treatment. The treatment enhanced the ability of the body's immune system to fight cancer. The patient is doing well 15 months after the operation, which might mean that this type of immunotherapy treatment after surgery helps prolong the life of people diagnosed with primary sarcomatoid cancer of the liver.

Update on the Pathology of Pediatric Liver Tumors: A Pictorial Review.

Liver tumors in children are uncommon and show remarkable morphologic heterogeneity. Pediatric tumors may arise from either the epithelial or mesenchymal component of the liver and rarely may also show both lines of differentiation. Both benign and malignant liver tumors have been reported in children. The most common pediatric liver tumors by age are benign hepatic infantile hemangiomas in neonates and infants, malignant hepatoblastoma in infants and toddlers, and malignant hepatocellular carcinoma in teenagers. Here, we provide an up-to-date review of pediatric liver tumors. We discuss the clinical presentation, imaging findings, pathology, and relevant molecular features that can help in the correct identification of these tumors, which is important in managing these children.

Outcomes of pediatric liver transplantation for progressive familial intrahepatic cholestasis.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a heterogenous group of inherited hepatocellular disorders and the clinical aspects, role of liver transplantation (LT), and its outcomes remain largely unelucidated. We present our data of LT for each type of PFIC and compare their early, and long-term outcomes, highlighting their individual differences and management strategies. METHODS: Prospectively collected data over a decade (2011-2022) of children with PFIC who underwent LT was analyzed. The groups (PFIC 1-4) were compared with regard to early and long-term outcomes including attainment of catch-up growth. RESULTS: Of 60 children with PFIC who underwent LT, 13, 11, 31 & 5 were of PFIC 1, 2, 3 & 4, respectively. There were no significant differences in gender, PELD scores, BMI, type of grafts, cold and warm ischemia times, intraoperative blood loss, and morbidity among the groups. Post-LT chronic diarrhea was observed in 6 (46.1%) children with PFIC-I, and of them, 3 (23%) developed graft steatohepatitis. Three of these children underwent total internal biliary diversion (TIBD) and on 1-year follow-up, their graft steatosis resolved and they attained catch-up growth. Catch-up growth was significantly poorer in the PFIC1 group (44.4% vs. 88%, 90%, 100% p < .001). Overall 1- and 5-year patient survival of the four PFIC groups (1-4) were 69.2%, 81.8%, 96.8%, 100% & 69.2%, 81.8%, 96.8%, 100%, respectively. CONCLUSION: Ours is the largest to-date series of LT for PFIC illustrating their short- and long-term outcomes. While the results for the whole cohort were excellent, those after LT for PFIC1 was relatively poorer as reflected by catch-up growth, graft steatosis, and post-LT diarrhea, which can be optimized by the addition of TIBD during LT.

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.

Experience With Establishing a Robotic Donor Hepatectomy Program for Pediatric Liver Transplantation.

BACKGROUND: The benefits of minimal invasive donor hepatectomy, especially for left lateral sectionectomy (LLS) have been unequivocally demonstrated. Moreover, donors in pediatric liver transplantation (LT) are usually parents who need to recover quickly to take care of the child. There are inherent limitations to conventional laparoscopic surgery including surgeon's experience with advanced laparoscopic surgery and steep learning curve which limits the wide application of minimal invasive donor hepatectomy. We share our experience of establishing a program of robotic donor hepatectomy (RDH) and achieving proficiency in performing RDH for pediatric LT. METHODS: Data were prospectively collected of consecutive LLS RDH based on a structured learning algorithm. Donor and recipient outcomes were analyzed. RESULTS: Seventy-five consecutive cases of LLS RDH were performed. The median primary warm ischemia time was 6 min (interquartile range [IQR]: 5-7 min). No major complications (grade ≥IIIb Clavien-Dindo) were noted in the cohort. There were no emergency conversion to open surgery and neither were there postoperative explorations through a laparotomy. Seven grafts were hyper-reduced and 5 required venoplasty. Two recipients died because of severe sepsis and multiorgan failure. Major complications occurred in 15 children (20%), none of which were attributable to RDH. Median hospital stay of the donors and recipients was 5 d (IQR: 5-6) and 12 d (IQR: 10-18) respectively. CONCLUSIONS: We share our experience of starting a RDH program for pediatric LT. We highlight the challenges and our learning algorithm to spur teams on the cusp of starting robotic transplant programs.

Pathologic and Immunophenotypic Characterization of Syncytial Giant Cell Variant of Pediatric Hepatocellular Carcinoma. A Distinct Subtype.

INTRODUCTION: Hepatocellular carcinoma (HCC) in pediatrics has a uniformly poor prognosis. Complete surgical resection or liver transplantation remain the only curative options. In contrast to adult HCC, literature on pediatric HCC is sparse and a majority of the distinct subtypes are undefined with regards to their histology, immunohistochemistry and prognosis. CASE REPORT: Two infants, one with biliary atresia and another with transaldolase deficiency, underwent living donor liver transplants. Explant-liver histopathology revealed tumor with diffuse neoplastic syncytial giant cell pattern. Immunophenotypic characterization highlighted expression of epithelial cell adhesion molecule, alpha fetoprotein and metallothionein. CONCLUSION: HCC with syncytial giant cells variant can occur in infants with underlying liver disease, specifically in our experience, with biliary atresia and another with transaldolase deficiency.

Anatomical variations of left hepatic vein and outflow reconstruction techniques in pediatric living donor liver transplantation.

Anatomical variations of left hepatic vein are observed in nearly a third of left lateral segment (LLS) donors in living donor liver transplantation. However, there is a paucity of studies and no structured algorithm for customized outflow reconstruction in LLS grafts with variant anatomy. Analysis of a prospectively collected database of 296 LLS pediatric living donor liver transplantation was done to identify different venous drainage patterns of segments 2 (V2) and 3 (V3). Left hepatic vein anatomy was classified into 3 types: type 1 (n = 270, 91.2%): V2 and V3 joined to form a common trunk which drains into the middle hepatic vein/inferior vena cava (IVC), subtype 1a length of trunk ≥9 mm and subtype 1b length of trunk <9 mm; type 2(n = 6, 2%): V2 and V3 drain independently into IVC; type 3 (n = 20, 6.8%): V2 and V3 drain into IVC and middle hepatic vein respectively. Analysis of postoperative outcomes between LLS grafts with single and reconstructed multiple outflows showed no difference in the occurrence of hepatic vein thrombosis/stenosis, major morbidity (P = .91), and 5-year survival (log-rank P = .562). This classification is a simple yet effective tool for preoperative donor assessment, and we propose a schema for the customized reconstruction of LLS grafts with excellent and consistently reproducible outcomes.

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.

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.

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.

Hilar Fibropolycystic Liver Disease of Unknown Etiology: A Revelation from the Explant Liver.

Fibropolycystic diseases of the liver comprise a spectrum of disorders affecting bile ducts of various sizes and arise due to an underlying ductal plate malformation (DPM). We encountered a previously unreported variant of DPM, the hilar fibropolycystic disease which we diagnosed in the explant liver. A 2-year-old boy was referred for liver transplantation with a diagnosis of biliary atresia (BA) and failed Kasai portoenterostomy (KPE). He had cirrhosis with portal hypertension along with synthetic failure indicated by coagulopathy and hypoalbuminemia. The child underwent liver transplant successfully. The explant liver had fibropolycystic disease confined to the perihilar liver and hilum. No pathogenic mutation was detected by whole exome sequencing. Fibropolycystic liver disease may represent a peculiar anatomical variant, which can be diagnosed by careful pathological examination of the explant liver. The neonatal presentation of hilar fibropolycystic liver disease can be misdiagnosed as BA.

Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review.

Cholangiocarcinomas are a heterogeneous group of highly aggressive cancers that may arise anywhere within the biliary tree. There is a wide geographical variation with regards to its incidence, and risk-factor associations which may include liver fluke infection, primary sclerosing cholangitis, and hepatolithiasis amongst others. These tumours are classified into intrahepatic, perihilar and distal based on their anatomical location. Morphologically, intrahepatic cholangiocarcinomas are further sub-classified into small and large duct variants. Perihilar and distal cholangiocarcinomas are usually mucin-producing tubular adenocarcinomas. Cholangiocarcinomas develop through a multistep carcinogenesis and are preceded by dysplastic and in situ lesions. While clinical characteristics and management of these tumours have been extensively elucidated in literature, their ultra-structure and tumour biology remain relatively unknown. This review focuses on the current knowledge of pathological characteristics, molecular alterations of cholangiocarcinoma, and its precursor lesions (including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm).

Erratum: Hilar Fibropolycystic Liver Disease of Unknown Etiology: A Revelation from the Explant Liver.

[This corrects the article DOI: 10.1055/s-0040-1716829.].

Liver Transplantation Society of India Guidelines for the Management of Acute Liver Injury Secondary to Yellow Phosphorus-Containing Rodenticide Poisoning Using the Modified Delphi Technique of Consensus Development.

BACKGROUND: Acute liver failure caused by the ingestion of yellow phosphorus-containing rodenticide has been increasing in incidence over the last decade and is a common indication for emergency liver transplantation in Southern and Western India and other countries. Clear guidelines for its management are necessary, given its unpredictable course, potential for rapid deterioration and variation in clinical practice. METHODS: A modified Delphi approach was used for developing consensus guidelines under the aegis of the Liver Transplantation Society of India. A detailed review of the published literature was performed. Recommendations for three areas of clinical practice, assessment and initial management, intensive care unit (ICU) management and liver transplantation, were developed. RESULTS: The expert panel consisted of 16 clinicians, 3 nonclinical specialists and 5 senior advisory members from 11 centres. Thirty-one recommendations with regard to criteria for hospital admission and discharge, role of medical therapies, ICU management, evidence for extracorporeal therapies such as renal replacement therapy and therapeutic plasma exchange, early predictors of need for liver transplantation and perioperative care were developed based on published evidence and combined clinical experience. CONCLUSION: Development of these guidelines should help standardise care for patients with yellow phosphorus poisoning and identify areas for collaborative research.

Pediatric metabolic liver diseases: Evolving role of liver transplantation.

Metabolic liver diseases (MLD) are the second most common indication for liver transplantation (LT) in children. This is based on the fact that the majority of enzymes involved in various metabolic pathways are present within the liver and LT can cure or at least control the disease manifestation. LT is also performed in metabolic disorders for end-stage liver disease, its sequelae including hepatocellular cancer. It is also performed for preventing metabolic crisis', arresting progression of neurological dysfunction with a potential to reverse symptoms in some cases and for preventing damage to end organs like kidneys as in the case of primary hyperoxalosis and methyl malonic acidemia. Pathological findings in explant liver with patients with metabolic disease include unremarkable liver to steatosis, cholestasis, inflammation, variable amount of fibrosis, and cirrhosis. The outcome of LT in metabolic disorders is excellent except for patients with mitochondrial disorders where significant extrahepatic involvement leads to poor outcomes and hence considered a contraindication for LT. A major advantage of LT is that in the post-operative period most patients can discontinue the special formula which they were having prior to the transplant and this increases their well-being and improves growth parameters. Auxiliary partial orthotopic LT has been described for patients with noncirrhotic MLD where a segmental graft is implanted in an orthotopic position after partial resection of the native liver. The retained native liver can be the potential target for future gene therapy when it becomes a clinical reality.

Renal Dysfunction in Cirrhosis: Critical Care Management.

Cirrhotic patients with manifestations of the end-stage liver disease have a high risk for developing renal dysfunction even with minor insults. The development of renal dysfunction increases the morbidity and mortality of these patients. Causes of renal dysfunction in cirrhotics can be due to hepatorenal syndrome (HRS) or acute kidney injury (AKI) resulting from prerenal, renal, and postrenal causes. Development of pretransplant renal dysfunction has been shown to affect post-liver transplantation outcomes. Early detection and aggressive strategies for the prevention of further progression of renal dysfunction seem to decrease the morbidity and improve survival in this group of patients. This article aims to outline the pathogenesis of renal dysfunction in cirrhosis, etiological factors, and evaluation of renal dysfunction, strategies for aggressive therapy for renal dysfunction, the indications of renal replacement therapy (RRT) in this group of patients, and the various modalities of RRT with their merits and demerits. A thorough understanding of the pathogenesis, early detection, and aggressive corrective measures for AKI can prevent further progression. In conclusion, a good knowledge of treatment modalities available for renal dysfunction in cirrhosis and institution of timely interventions can significantly improve survival in this group of patients. KEY MESSAGES: Development of renal dysfunction in cirrhotics increases the morbidity and mortality of these patients and results in poor outcomes after liver transplantation. Early detection and aggressive strategies for the prevention of further progression of renal dysfunction seem to decrease the morbidity and improve survival in this group of patients. HOW TO CITE THIS ARTICLE: Rajakumar A, Appuswamy E, Kaliamoorthy I, Rela M. Renal Dysfunction in Cirrhosis: Critical Care Management. Indian J Crit Care Med 2021;25(2):207-214.