The Story of Ammonia in Liver Disease: An Unraveling Continuum.

Hyperammonemia and liver disease are closely linked. Most of the ammonia in our body is produced by transamination and deamination activities involving amino acid, purine, pyrimidines, and biogenic amines, and from the intestine by bacterial splitting of urea. The only way of excretion from the body is by hepatic conversion of ammonia to urea. Hyperammonemia is associated with widespread toxicities such as cerebral edema, hepatic encephalopathy, immune dysfunction, promoting fibrosis, and carcinogenesis. Over the past two decades, it has been increasingly utilized for prognostication of cirrhosis, acute liver failure as well as acute on chronic liver failure. The laboratory assessment of hyperammonemia has certain limitations, despite which its value in the assessment of various forms of liver disease cannot be negated. It may soon become an important tool to make therapeutic decisions about the use of prophylactic and definitive treatment in various forms of liver disease.

Porto-sinusoidal Vascular Disease: Classification and Clinical Relevance.

Non-cirrhotic portal hypertension (NCPH) is a well-recognized clinico-pathological entity, which is associated with clinical signs and symptoms, imaging, and endoscopic features of portal hypertension (PHT), in absence of cirrhosis. In patients with NCPH without known risk factors of PHT or extrahepatic portal vein thrombosis, the condition is called idiopathic non-cirrhotic portal hypertension (INCPH). There are multiple infectious, immune related causes, systemic diseases, drug and toxin exposures, haematological disorders, and metabolic risk factors that have been associated with this INCPH. However, the causal pathogenesis is still unclear. The Vascular liver disorders interest group group recently proposed porto-sinusoidal vascular disease (PSVD) as a syndromic entity, which provides definite histopathological criteria for diagnosis of NCPH (table 1). The three classical histo-morphological lesions specific for PSVD include obliterative portal venopathy, nodular regenerative hyperplasia, and incomplete septal fibrosis. The PSVD definition includes patients with portal vein thrombosis, PVT, and even those without PHT, thus broadening the scope of diagnosis to include patients who may have presented early, prior to haemodynamic changes consistent with PHT. However, this new diagnosis has pros and cons. The cons include mandating invasive liver biopsy to assess the PSVD histological triad in all patients with NCPH, an erstwhile clinical diagnosis in Asian patients. In addition, the natural history of the subclinical forms of PSVD without PHT and linear progression to develop PHT is unknown yet. In this review, we discuss the diagnosis and treatment of INCPH/PSVD, fallacies and strengths of the old and new schema, pathobiology of this disease, and clinical correlates in an Asian context. Although formulation of standardised diagnostic criteria is useful for comparison of clinical cohorts with INCPH/PSVD, prospective clinical validation in global cohorts is necessary to avoid misclassification of vascular disorders of the liver.

A Study of Impact of Fixed-Dose Albumin Infusion on Outcome in Patients With Cirrhosis and Infection: A Randomized Open-label Clinical Trial.

Background and aim: Antibiotics and albumin infusion constitute the standard of treatment in patients with decompensated cirrhosis who have spontaneous bacterial peritonitis (SBP). Recent studies have also shown that the use of albumin in patients with advanced liver disease who have infections other than SBP leads to the resolution of acute and chronic liver failure and prevents the development of nosocomial infections. The recommended dose of albumin for these patients is out of reach for many in resource-limited settings like India. The evidence for this recommendation is also scarce. This study aimed to assess the efficacy of a lower dose of albumin infusion in addition to antibiotics on short-term mortality and morbidity in patients with cirrhosis and infections. Patients and methods: A prospective, open-label, randomized control study was performed. Consecutive patients with cirrhosis and infections were randomized in a 2:1 ratio into two groups: group A (116) and group B (58) patients. In addition to antibiotics and standard medical therapy, group A was given albumin in a dose of 20 g/day for five days, and group B was given the recommended dose (1.5 g/kg/body weight and 1 g/kg body weight on days one and three, respectively). The primary outcome was in-hospital mortality. Secondary outcomes were improvements in clinical and laboratory parameters. Results: Except for etiology, all the baseline clinical and laboratory variables in both groups were comparable. The in-hospital mortality in groups A and B was (11 [10.67%] vs. 6 [10.09%], (P = 0.965). The duration of hospitalization, 30-day mortality, improvement in shock and sensorium, and absolute improvements in serum creatinine, international normalized ratio (INR), and serum bilirubin were also comparable in both groups. Conclusion: Low-dose albumin infusion in patients with cirrhosis and infections can have the same results as standard-dose albumin and can be used in resource-limited situations. Clinical trial registration number: CTRI/2020/03/023794.

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.

Position statement from the Indian Society of Gastroenterology, Cardiological Society of India, Indian Academy of Neurology and Vascular Society of India on gastrointestinal bleeding and endoscopic procedures in patients on antiplatelet and/or anticoagulant therapy.

Antiplatelet and/or anticoagulant agents (collectively known as antithrombotic agents) are used to reduce the risk of thromboembolic events in patients with conditions such as atrial fibrillation, acute coronary syndrome, recurrent stroke prevention, deep vein thrombosis, hypercoagulable states and endoprostheses. Antithrombotic-associated gastrointestinal (GI) bleeding is an increasing burden due to the growing population of advanced age with multiple comorbidities and the expanding indications for the use of antiplatelet agents and anticoagulants. GI bleeding in antithrombotic users is associated with an increase in short-term and long-term mortality. In addition, in recent decades, there has been an exponential increase in the use of diagnostic and therapeutic GI endoscopic procedures. Since endoscopic procedures hold an inherent risk of bleeding that depends on the type of endoscopy and patients' comorbidities, in patients already on antithrombotic therapies, the risk of procedure-related bleeding is further increased. Interrupting or modifying doses of these agents prior to any invasive procedures put these patients at increased risk of thromboembolic events. Although many international GI societies have published guidelines for the management of antithrombotic agents during an event of GI bleeding and during urgent and elective endoscopic procedures, no Indian guidelines exist that cater to Indian gastroenterologists and their patients. In this regard, the Indian Society of Gastroenterology (ISG), in association with the Cardiological Society of India (CSI), Indian Academy of Neurology (IAN) and Vascular Society of India (VSI), have developed a "Guidance Document" for the management of antithrombotic agents during an event of GI bleeding and during urgent and elective endoscopic procedures.

Indian National Association for Study of the Liver (INASL) Guidance Paper on Nomenclature, Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease (NAFLD).

Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease globally and in India. The already high burden of NAFLD in India is expected to further increase in the future in parallel with the ongoing epidemics of obesity and type 2 diabetes mellitus. Given the high prevalence of NAFLD in the community, it is crucial to identify those at risk of progressive liver disease to streamline referral and guide proper management. Existing guidelines on NAFLD by various international societies fail to capture the entire landscape of NAFLD in India and are often difficult to incorporate in clinical practice due to fundamental differences in sociocultural aspects and health infrastructure available in India. A lot of progress has been made in the field of NAFLD in the 7 years since the initial position paper by the Indian National Association for the Study of Liver on NAFLD in 2015. Further, the ongoing debate on the nomenclature of NAFLD is creating undue confusion among clinical practitioners. The ensuing comprehensive review provides consensus-based, guidance statements on the nomenclature, diagnosis, and treatment of NAFLD that are practically implementable in the Indian setting.

Gallstone Disease in Cirrhosis-Pathogenesis and Management.

Gallstones are more common in patients with cirrhosis of the liver, and the incidence increases with severity of liver disease. Pigment stones are the most frequent type of gallstones (GSs) in cirrhotics, and majority remain asymptomatic. Hepatitis C virus infection and nonalcoholic fatty liver disease are the underlying etiologies of liver diseases that most often associated with GSs. Multiple altered mechanisms in cirrhosis such as chronic hemolysis due to hypersplenism, reduced bile acid synthesis and transport, decreased cholesterol secretion, decreased apolipoprotein A-I and A-II secretion, gallbladder hypo-motility, autonomic dysfunction, and portal hypertension collectively lead to increased risk of lithogenesis. Asymptomatic GSs should be followed up closely and offered laparoscopic cholecystectomy once symptomatic in Child-Pugh class A and B patients. The model for the end-stage liver disease score is the best predictor of the outcome after cholecystectomy. In patients of Child-Pugh class C, conservative or minimally invasive approaches should be used to treat complications of GSs.

Overview of Complications in Cirrhosis.

Background: Cirrhosis is the outcome of chronic liver disease of any etiology due to progressive liver injury and fibrosis. Consequently, cirrhosis leads to portal hypertension and liver dysfunction, progressing to complications like ascites, variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, cirrhotic cardiomyopathy, sarcopenia, hepatocellular carcinoma, and coagulation disorders. End-stage liver disease leads to an impaired quality of life, loss of social and economic productivity, and reduced survival. Methods: This narrative review explains the pathophysiology of complications of cirrhosis, the diagnostic approach and innovative management, with focus on data from India. A comprehensive literature search of the published data was performed in regard with the spectrum, diagnosis, and management of cirrhosis and its complications. Results: There is a change in the epidemiology of metabolic syndrome, lifestyle diseases, alcohol consumption and the spectrum of etiological diagnosis in patients with cirrhosis. With the advent of universal vaccination and efficacious long-term viral suppression agents for chronic hepatitis B, availability of direct-acting antiviral agents for chronic hepatitis C, and a booming liver transplantation programme across the country, the management of complications is essential. There are several updates in the standard of care in the management of complications of cirrhosis, such as hepatorenal syndrome, hepatocellular carcinoma, and hepatic encephalopathy, and new therapies that address supportive and palliative care in advanced cirrhosis. Conclusion: Prevention, early diagnosis, appropriate management of complications, timely transplantation are cornerstones in the management protocol of cirrhosis and portal hypertension. India needs improved access to care, outreach of public health programmes for viral hepatitis care, health infrastructure, and disease registries for improved healthcare outcomes. Low-cost initiatives like immunization, alcohol cessation, awareness about liver diseases, viral hepatitis elimination, and patient focused decision-making algorithms are essential to manage liver disease in India.

Extrahepatic Manifestations in Alcoholic Liver Disease.

Though liver is the most commonly affected organ in patients with chronic and excessive intake of alcohol, no organ is immune to toxic effects of alcohol and patients with alcohol-related liver disease (ALD) can suffer from a wide list of extrahepatic manifestations involving gastrointestinal tract, central and peripheral nervous systems, cardio vascular system, musculo-skeletal system, disruption of nutritional status, endocrinological abnormalities, hematological abnormalities and immune dysfunction. These extrahepatic organ involvements are usually overlooked by hepatologists and physicians who are mostly focused on managing life threatening complications of ALD. As a result, there is delayed diagnosis, delay in the initiation of appropriate treatment and late referral to other specialists. Some of these manifestations are of utmost clinical importance (e.g. delirium tremans and Wernicke's encephalopathy) because an early diagnosis and treatment can lead to full recovery while delayed or no treatment can result in death. On the other hand, several extrahepatic manifestations are of prognostic significance (such as alcoholic cardiomyopathy and malignancies) in which there is an increased risk of morbidity and mortality. Hence, a clear understanding and awareness of the extrahepatic manifestations of ALD is quintessential for proper management of these patients.

Clinical Implications, Evaluation, and Management of Hyponatremia in Cirrhosis.

Hyponatremia is the most common electrolyte abnormality in patients with decompensated cirrhosis on Liver Transplantation (LT) waiting list. Most of these patients have dilutional or hypervolemic hyponatremia secondary to splanchnic vasodilatation. Excessive secretion of the antidiuretic hormone also plays an important role. Hypervolemic hyponatremia is commonly associated with refractory ascites, spontaneous bacterial peritonitis, and hepatic encephalopathy. Although uncommon, the use of diuretics and laxatives can cause hypovolemic hyponatremia that is characterized by the striking absence of ascites or pedal edema. Clinical features are often nonspecific and depend on the acuity of onset rather than the absolute value of serum sodium. Symptoms may be subtle, including nausea, lethargy, weakness, or anorexia. However, rarely patients may present with confusion, seizures, psychosis, or coma. Treatment includes discontinuation of diuretics, beta-blockers, and albumin infusion. Hypertonic saline (3%) infusion may be used in patients with very low serum sodium (<110 mmol/L) or when patients present with seizures or coma. Short-term use of Vasopressin (V2) receptor antagonists may also be used to normalize sodium levels prior to LT. However, all these measures may be futile, and LT remains the definite treatment in these patients to improve survival. In this review, we describe the classification, pathogenesis of hyponatremia, and its clinical implications in patients with cirrhosis. Approach to these patients along with management will also be discussed briefly.

Treatment of Muscle Cramps in Patients With Cirrhosis of Liver: A Systematic Review.

Background: Muscle cramps are witnessed in 22-88% of patients with cirrhosis of liver and frequently lead to sleep disturbance with an appalling impact on quality of life. Despite such a high prevalence, there is lack of evidence-based management protocol due to scarcity of trials on treatment options in the literature. This study aimed to review systematically the available therapeutic options for muscle cramps in patients with cirrhosis of liver. Methods: A systematic review of the relevant databases (PubMed, Scopus, Embase, and Web of Science) to identify treatments for muscle cramps in patients with hepatic cirrhosis was performed. Studies meeting the selection criteria were reviewed and assessed for risk of bias and analyzed. Results: Twenty-four publications were identified as eligible for inclusion in this systematic review. Seven randomized controlled trials (RCTs) and 17 prospective studies were included. Taurine, methocarbamol, baclofen, and orphenadrine are relatively safer and effective treatment option for muscle cramps in cirrhosis on the basis of recently conducted RCTs. Moreover, l-carnitine, branched-chain amino acids (BCAAs), pregabalin, zinc, and vitamin D are also safe and showed beneficial effects on muscle cramps. However, studies on vitamin E revealed contradictory results. Conclusion: Taurine, BCAAs, orphenadrine, and baclofen are safe and well-tolerated treatment options for muscle cramps in cirrhosis. However, well-designed randomized controlled clinical trials are the need of the hour to determine the most suitable treatment options for skeletal muscle cramps in patients with cirrhosis of liver.

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.].

Hepatogenous Diabetes: A Primer.

As liver is one of the primary organs involved in glucose homeostasis, it is not surprising that patients with liver dysfunction in chronic liver disease usually develop impaired glucose tolerance and subsequently overt diabetes later in their natural course. Diabetes that develops after the onset of cirrhosis of liver is usually referred to as hepatogenous diabetes (HD). It is an underrecognized and a hallmark endocrinological event in chronic liver disease. HD is associated with a higher risk of developing hepatic decompensations, such as ascites, variceal bleeding, hepatic encephalopathy, renal dysfunction, refractory ascites, and hepatocellular carcinoma along with reduced survival rates than normoglycemic patients with cirrhosis of liver. It is quite different from type 2 diabetes mellitus with the absence of classical risk factors, dissimilar laboratory profiles, and decreased incidence of microvascular complications. Furthermore, the management of patients with HD is challenging because of altered pharmacokinetics of most antidiabetic drugs and increased risk of hypoglycemia and other adverse effects. Hence, a clear understanding of the epidemiology, pathophysiology, clinical implications, laboratory diagnosis, and management of HD is essential for both hepatologists as well as endocrinologists, which is narrated briefly in this review.

Tobacco, Cigarettes, and the Liver: The Smoking Gun.

The association between alcohol and liver disease, including alcoholic hepatitis, cirrhosis, acute-on-chronic liver failure, and hepatocellular carcinoma, has been well described, but the same cannot be said for the association between smoking, water pipe or tobacco chewing. A review of cumulative evidence suggests that smoking is independently a risk factor for liver fibrosis and contributes to carcinogenesis in HCC. Smoking-related fibrosis has been reported in patients with nonalcoholic fatty liver disease, primary biliary cholangitis, alcoholic liver disease and chronic viral hepatitis. Heavy smoking leads to systemic inflammation, oxidative stress, insulin resistance, and results in tissue hypoxia, as well as free radical damage. Other than damaging the liver, patients also suffer from the systemic effects of the 4000 chemicals associated with tobacco, which include nitrosamines, aromatic hydrocarbons, nicotine, nornicotine, and other alkaloids. These include respiratory ailments, cancer of the lungs, oral cavity, esophagus, pancreas and colon, atherosclerotic vascular disease, and stroke.

Sickle Hepatopathy.

Sickle hepatopathy is an umbrella term describing various pattern of liver injury seen in patients with sickle cell disease. The disease is not uncommon in India; in terms of prevalence, India is second only to Sub-Saharan Africa where sickle cell disease is most prevalent. Hepatic involvement in sickle cell disease is not uncommon. Liver disease may result from viral hepatitis and iron overload due to multiple transfusions of blood products or due to disease activity causing varying changes in vasculature. The clinical spectrum of disease ranges from ischemic injury due to sickling of red blood cells in hepatic sinusoids, pigment gall stones, and acute/chronic sequestration syndromes. The sequestration syndromes are usually episodic and self-limiting requiring conservative management such as antibiotics and intravenous fluids or packed red cell transfusions. However, rarely these episodes may present with coagulopathy and encephalopathy like acute liver failure, which are life-threatening, requiring exchange transfusions or even liver transplantation. However, evidence for their benefits, optimal indications, and threshold to start exchange transfusion is limited. Similarly, there is paucity of the literature regarding the end point of exchange transfusion in this scenario. Liver transplantation may also be beneficial in end-stage liver disease. Hydroxyurea, the antitumor agent, which is popularly used to prevent life-threatening complications such as acute chest syndrome or stroke in these patients, has been used only sparingly in hepatic sequestrations. The purpose of this review is to provide insights into epidemiology of sickle cell disease in India and pathogenesis and classification of hepatobiliary involvement in sickle cell disease. Finally, various management options including exchange transfusion, liver transplantation, and hydroxyurea in hepatic sequestration syndromes will be discussed in brief.