A Rare Cause of Acute on Chronic Liver Failure (ACLF): Bakuchi-Induced Liver Injury.

Psoralea corylifolia Linn (Bakuchi or Babchi), commonly known as purple fleabane, is a popular herb used in Ayurvedic traditional medicine. Its seeds, called Fructus Psoraleae, are traditionally used for treating leprosy, vitiligo, and psoriasis in the absence of empirical evidence. We report the first case of acute on chronic liver failure (ACLF) caused by Bakuchi, a well-documented hepatotoxic agent, in a middle-aged female. Her liver function deteriorated progressively which prompted us to go for a liver biopsy which was consistent with diagnosis of herb-induced liver injury after excluding all competing causes. Fortunately, the patient improved gradually after herb withdrawal and supportive care. Patients with underlying chronic liver disease (CLD) should be aware of risks in using untested herbal formulations. This case emphasizes the need for increased surveillance to formulate guidelines regarding the regulation and informed use of herbal supplements in patients with chronic liver disease.

Ashwagandha-induced liver injury-A case series from India and literature review.

BACKGROUND: Ashwagandha herb is commonly used in Ayurveda and a "fad" dietary supplement for a host of indications based on low levels of evidence. Recently, ashwagandha was implicated in multiple reports of herb-induced liver injury (HILI), mainly from the United States. We present the first, and currently largest, series of ashwagandha-HILI from multiple centers in India. METHODS: We retrospectively analyzed the respective institutional electronic medical records for ashwagandha-HILI. Patients consuming ashwagandha as part of multiherbal formulations or along with other known hepatotoxic supplements or medicines were excluded. All patients underwent a detailed diagnostic workup to exclude competing causes reasonably. Where possible, the implicated herbal formulation was retrieved and subjected to chemical analysis. RESULTS: Out of 23 patients with liver injury from ashwagandha (January 2019 to December 2022), we report 8 patients with single-ingredient formulation-related HILI. Study cohort was male predominant, and cholestatic hepatitis was the commonest presentation. Five patients had underlying chronic liver disease; 3 presented with acute-on-chronic liver failure, and all 3 died on follow-up. In others, the liver injury was prolonged, nonetheless self-limiting. Liver biopsy revealed cholestatic features predominantly with hepatocellular necrosis and lymphocyte/eosinophil predominant portal-based inflammation. One patient progressed to chronic HILI. Chemical analysis revealed only natural phytochemicals without adulteration or contamination. CONCLUSIONS: Ashwagandha-HILI presents with cholestatic hepatitis and can lead to the syndrome of acute-on-chronic liver failure with high mortality in those with pre-existing liver disease. Educating the public on avoiding the use of potentially toxic and unrecommended herbal supplements can help mitigate the avoidable liver disease burden in the community.

Palliative Care for Patients with End-Stage Liver Disease.

End-stage liver disease (ESLD) is the culmination of progression of chronic liver disease to cirrhosis, decompensation, and chronic liver failure, featuring portal hypertension or hepatocellular failure-related complications. Liver transplantation offers improved long-term survival for these patients but is negatively influenced by donor availability, financial constraints in developing countries, active substance abuse, progression of disease or malignancy on wait-list, sepsis and extrahepatic organ involvement. In this context, palliative care (PC), an interdisciplinary medical practice that aim to prevent and relieve suffering, offers best possible quality of life and is not limited to end-of-life care. It also encompasses achievable goals such as symptom control and aggressive disease-modifying treatments or interventions that beneficially alter the natural course of the disease to offer curative intend. In this narrative review, we discuss the prognostic factors that define disease course in ESLD, various indications and challenges in PC for advanced cirrhosis and management options for major symptom burden in patients with ESLD based on evidence-based best practice.

Gut Microbiome and Alcohol-associated Liver Disease.

Changes in gut microbiota (GM) may be associated with the causation and progression of multiple liver diseases such as metabolic-associated liver disease, alcohol-associated liver disease (ALD), alcohol-associated hepatitis (AH), primary biliary cholangitis, primary sclerosing cholangitis, autoimmune liver disease, and most importantly, complications of cirrhosis and portal hypertension such as hepatic encephalopathy (HE), infection, and hepatocellular carcinoma. ALD includes simple steatosis, steatohepatitis, AH, cirrhosis, and acute-on-chronic liver failure. Alcohol consumption is associated with GM changes even before ALD development, and continued alcohol intake results in progressive dysbiosis and development of clinical events such as AH, infection, and HE. The composition and function of GM, specific changes in bacterial communities, and the functional metabolism of GM are affected in the spectrum of ALD, as revealed using high-throughput sequencing. It was reported in preliminary studies that modulation of disrupted GM improves adverse clinical events and ameliorates disease progression in ALD. In this review, we exhaustively discuss the preclinical and clinical studies on GM in ALD and critically discuss GM modulation and its effects based on various human and animal models of ALD.

Gut Barrier and Microbiota in Cirrhosis.

Gut microbiota and their homeostatic functions are central to the maintenance of the intestinal mucosal barrier. The gut barrier functions as a structural, biological, and immunological barrier, preventing local and systemic invasion and inflammation of pathogenic taxa, resulting in the propagation or causation of organ-specific (liver disease) or systemic diseases (sepsis) in the host. In health, commensal bacteria are involved in regulating pathogenic bacteria, sinister bacterial products, and antigens; and help control and kill pathogenic organisms by secreting antimicrobial metabolites. Gut microbiota also participates in the extraction, synthesis, and absorption of nutrient metabolites, maintains intestinal epithelial integrity and regulates the development, homeostasis, and function of innate and adaptive immune cells. Cirrhosis is associated with local and systemic immune, vascular, and inflammatory changes directly or indirectly linked to perturbations in quality and quantity of intestinal microbiota and intestinal mucosal integrity. Dysbiosis and gut barrier dysfunction are directly involved in the pathogenesis of compensated cirrhosis and the type and severity of complications in decompensated cirrhosis, such as bacterial infections, encephalopathy, extrahepatic organ failure, and progression to acute on chronic liver failure. This paper reviews the normal gut barrier, gut barrier dysfunction, and dysbiosis-associated clinical events in patients with cirrhosis. The role of dietary interventions, antibiotics, prebiotics, probiotics, synbiotics, and healthy donor fecal microbiota transplantation (FMT) to modulate the gut microbiota for improving patient outcomes is further discussed.

Critical Updates on Chronic Hepatitis B Virus Infection in 2021.

Chronic hepatitis B virus (HBV) infection is a global healthcare burden in the form of chronic liver disease, cirrhosis, liver failure and liver cancer. There is no definite cure for the virus and even though extensive vaccination programs have reduced the burden of liver disease in the future population, treatment options to eradicate the virus from the host are still lacking. In this review, we discuss in detail current updates on the structure and applied biology of the virus in the host, examine updates to current treatment and explore novel and state-of-the-art therapeutics in the pipeline for management of chronic HBV. Furthermore, we also specifically review clinical updates on HBV-related acute on chronic liver failure (ACLF). Current treatments for chronic HBV infection have seen important updates in the form of considerations for treating patients in the immune tolerant phase and some clarity on end points for treatment and decisions on finite therapy with nucleos(t)ide inhibitors. Ongoing cutting-edge research on HBV biology has helped us identify novel target areas in the life cycle of the virus for application of new therapeutics. Due to improvements in the area of genomics, the hope for therapeutic vaccines, vector-based treatments and focused management aimed at targeting host integration of the virus and thereby a total cure could become a reality in the near future. Newer clinical prognostic tools have improved our understanding of timing of specific treatment options for the catastrophic syndrome of ACLF secondary to reactivation of HBV. In this review, we discuss in detail pertinent updates regarding virus biology and novel therapeutic targets with special focus on the appraisal of prognostic scores and treatment options in HBV-related ACLF.

Hepatocellular Carcinoma in 2021: An Exhaustive Update.

Primary liver cancer is a challenging global health concern with an estimated more than a million persons to be affected annually by the year 2025. The commonest type is hepatocellular carcinoma (HCC), which has been increasing in incidence the world over, mostly due to chronic viral hepatitis B infection. In the last decade, paradigm changes in the etiology, understanding of molecular biology, and pathogenesis, including the role of gut microbiota; medical and surgical treatments, and outcome trends are notable. The application of omics-based technology has helped us unlock the molecular and immune landscape of HCC, through which novel targets for drug treatment such as immune-checkpoint inhibitors have been identified. Novel tools for the surveillance and diagnosis of HCC include protein-, genomics-, and composite algorithm-based clinical/biomarker panels. Magnetic resonance imaging-based novel techniques have improved HCC diagnosis through ancillary features that enhance classical criteria while positron emission tomography has shown value in prognostication. Identification of the role of gut microbiota in the causation and progression of HCC has opened areas for novel therapeutic research. A select group of patients still benefit from modified surgical and early interventional radiology treatments. Improvements in radiotherapy protocols, identification of parameters of futility among radiological interventions, and the emergence of novel first-line systemic therapies that include a combination of antiangiogenic and immune-checkpoint inhibitors have seen a paradigm change in progression-free and overall survival. The current review is aimed at providing exhaustive updates on the etiology, molecular biology, biomarker diagnosis, imaging, and recommended treatment options in patients with HCC.

Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure.

Acute liver failure (ALF) is not an uncommon complication of a common disease such as acute hepatitis. Viral hepatitis followed by antituberculosis drug-induced hepatotoxicity are the commonest causes of ALF in India. Clinically, such patients present with appearance of jaundice, encephalopathy, and coagulopathy. Hepatic encephalopathy (HE) and cerebral edema are central and most important clinical event in the course of ALF, followed by superadded infections, and determine the outcome in these patients. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a crucial role in the pathogenesis, and several therapies aim to correct this abnormality. The role of newer ammonia-lowering agents is still evolving. These patients are best managed at a tertiary care hospital with facility for liver transplantation (LT). Aggressive intensive medical management has been documented to salvage a substantial proportion of patients. In those with poor prognostic factors, LT is the only effective therapy that has been shown to improve survival. However, recognizing suitable patients with poor prognosis has remained a challenge. Close monitoring, early identification and treatment of complications, and couseling for transplant form the first-line approach to manage such patients. Recent research shows that use of dynamic prognostic models is better for selecting patients undergoing liver transplantation and timely transplant can save life of patients with ALF with poor prognostic factors.

Indian National Association for the Study of the Liver Consensus Statement on Acute Liver Failure (Part 1): Epidemiology, Pathogenesis, Presentation and Prognosis.

Acute liver failure (ALF) is an infrequent, unpredictable, potentially fatal complication of acute liver injury (ALI) consequent to varied etiologies. Etiologies of ALF as reported in the literature have regional differences, which affects the clinical presentation and natural course. In this part of the consensus article designed to reflect the clinical practices in India, disease burden, epidemiology, clinical presentation, monitoring, and prognostication have been discussed. In India, viral hepatitis is the most frequent cause of ALF, with drug-induced hepatitis due to antituberculosis drugs being the second most frequent cause. The clinical presentation of ALF is characterized by jaundice, coagulopathy, and encephalopathy. It is important to differentiate ALF from other causes of liver failure, including acute on chronic liver failure, subacute liver failure, as well as certain tropical infections which can mimic this presentation. The disease often has a fulminant clinical course with high short-term mortality. Death is usually attributable to cerebral complications, infections, and resultant multiorgan failure. Timely liver transplantation (LT) can change the outcome, and hence, it is vital to provide intensive care to patients until LT can be arranged. It is equally important to assess prognosis to select patients who are suitable for LT. Several prognostic scores have been proposed, and their comparisons show that indigenously developed dynamic scores have an edge over scores described from the Western world. Management of ALF will be described in part 2 of this document.

Granulocyte Colony-Stimulating Factor Use in Decompensated Cirrhosis: Lack of Survival Benefit.

BACKGROUND: Granulocyte colony-stimulating factor (GCSF) has been utilized in decompensated cirrhosis (DC) for improving transplant-free survival (TFS). Data from multiple centers are conflicting with regard to patient outcomes. In this retrospective study, we present our 'real-world experience' of GCSF use in a large group of DC. METHODS: From September 2016 to September 2018, 1231 patients with cirrhosis were screened, of which 754 were found to have decompensation(s). Seventy-three patients with active ascites, jaundice, or both completed GCSF treatment (10 mcg/kg per day for 5 days, followed by 5 mcg/kg/day once every third day for total 12 doses). Per-protocol analysis (n = 56) was performed to study clinical events, liver disease severity, and outcomes at 3, 6, and 12 months after treatment. Modified intention-to-treat (mITT, n = 100) analysis was performed to study overall survival at 180 days. Outcomes were compared with a matched historical control (HC) group (n = 24). RESULTS: Nine (16%, n = 56), 24 (43%, n = 56), and 36 (75%, n = 48) patients died at 3, 6, and 12-month follow-up after GCSF. The commonest cause of death was sepsis (53%) followed by progressive liver failure (33%). Nine percent of patients developed hepatocellular carcinoma on follow-up at the end of 1 year. Acute variceal bleeds, overt hepatic encephalopathy, intensive unit admissions, and liver disease severity scores were higher after treatment at the end of 1 year. The Child-Pugh score >11 and model for end-stage liver disease-sodium score >25 and > 20 predicted worse outcomes at all time points and at 6 and 12 months after GCSF, respectively. Compared to a matched HC group, patients receiving GCSF had higher mortality (75% vs 46%, P = 0.04) at one year. mITT analysis revealed poor overall survival at 6 months compared to HCs (48% vs 75%, P = 0.04). CONCLUSION: Survival in DC was shorter than what was expected in the natural history of the disease after GCSF use.

Ayurveda Herbal Medicine-induced Liver Cirrhosis.

We present the rare case of a young male with sinusoidal obstruction syndrome due to Ayurvedic herbal medicine which he took for management of bilateral leg swelling associated with protein-losing enteropathy due to intestinal lymphangiectasia. The patient developed progressive sinusoidal fibrosis leading to cirrhosis on long term follow-up. In a diagnosis that took three years to conclude, we showcase serial liver biopsies that reveal the rare disease progression. Complementary and alternative medicine use among apparently healthy population is a potentially modifiable risk factor for liver diseases, in the presence of adequate public health education from concerned authorities.

Branch Duct-type Intraductal Papillary Mucinous Neoplasm Presenting as Paraneoplastic Small Plaque Para-psoriasis.

To present and discuss a novel association between branch duct-type intraductal papillary mucinous neoplasm and paraneoplastic parapsoriasis. We present the case of a middle-aged male presenting with skin lesions that were suggestive of parapsoriasis, resistant to treatment, and in whom a diagnosis of branch-type intraductal papillary mucinous neoplasm of the pancreas was eventually made. A curative Whipple's surgery led to complete resolution of the skin lesions within 3 weeks. Paraneoplastic parapsoriasis in association with intraductal papillary mucinous pancreatic neoplasm has never been reported before.