Hepatorenal Syndrome Type 1: From Diagnosis Ascertainment to Goal-Oriented Pharmacotherapy

Hepatorenal syndrome type 1 (HRS-1) is a serious form of acute kidney injury (AKI) that affects individuals with advanced cirrhosis with ascites. Prompt and accurate diagnosis is essential for effective implementation of therapeutic measures that can favorably alter its clinical course. Despite decades of investigation, HRS-1 continues to be primarily a diagnosis of exclusion. While the diagnostic criteria dictated by the International Club of Ascites (ICA) provide a useful framework to approach the diagnosis of HRS-1, they do not fully reflect the complexity of clinical scenarios that is often encountered in patients with cirrhosis and AKI. Thus, diagnostic uncertainty is often faced. In particular, the distinction between HRS-1 and acute tubular injury (ATI) is challenging with the currently available clinical tools. Because treatment of HRS-1 differs from that of ATI, distinguishing these 2 causes of AKI has direct implications in management. Therefore, the use if the ICA criteria should be enhanced with a more individualized approach and attention to the other phenotypic aspects of HRS-1 and other types of AKI. Liver transplantation is the most effective treatment for HRS-1 but it is only available to a small fraction of the affected patients worldwide. Thus, pharmacological therapy is necessary. Vasoconstrictors aimed to increase mean arterial pressure constitute the most effective approach. Administration of intravenous albumin is an established co-adjuvant therapy. However, the risk for fluid overload in patients with cirrhosis with AKI is not negligible and interventions intended to expand or remove volume should be tailored to the specific needs of the patient. Norepinephrine and terlipressin are the most effective vasoconstrictors and their use should be determined by availability, ease of administration and attention to optimal risk/benefit balance for each clinical scenario.

Diastolic Dysfunction Is a Predictor of Poor Survival in Patients with Decompensated Cirrhosis

Background. Left ventricular diastolic dysfunction (LVDD) appears to be the earliest cardiac disturbance in cirrhosis patients. There are many previous reports reporting the significance of severity of LVDD on the outcome of liver transplantation or TIPS insertion, a few Indian studies have addressed the role of LVDD on survival in decompensated cirrhosis. The objective of this study is to assess the effect of LVDD on the survival of decompensated cirrhotic patients. Methods. We prospectively evaluated 92 decompensated cirrhotic patients from April 2015 to March 2017 at IMS and SUM Hospital, Bhubaneswar, India. 2D echocardiography with tissue Doppler imaging was used to evaluate cardiac function, as per the American society of echocardiography guidelines. The primary endpoint was to evaluate the effect of LVDD on overall mortality. Results. Ninety-two decompensated cirrhotic patients were evaluated in this prospective cohort study. Twenty-eight out of 92 patients (30%) died due to liver-related complications after a follow-up of 24 months. The decompensated cirrhotic patients with MELD score ≥ 15 had a significantly higher E / e ′ ratio ( 11.94 ± 4.24 vs. 8.74 ± 3.32 , p < 0.001 ) suggesting severe LV dysfunction in advanced cirrhosis. Patients with E / e ′ ratio > 10 had significantly higher MELD score and Child-Pugh score ( 19.88 ± 7.72 vs. 14.31 ± 5.83 ; 10.25 ± 1.74 vs. 9.02 ± 1.74 , p < 0.01 , respectively) as compared to the E / e ′ ratio < 10 group. In Cox proportional hazard multivariate analysis, E / e ′ ≥ 10 (HR 2.72, 95% CI 1.07-6.9, p = 0.03 ) and serum albumin (HR 0.32, 95% CI 0.14-0.7, p < 0.01 ) were found to be independent predictors of mortality in decompensated cirrhotic patients. Conclusion: The presence of LVDD and low serum albumin were independent predictors of mortality in decompensated cirrhotic patients. Hence, LVDD is an indicator of advanced cirrhosis and mortality.

Limitations and Possibilities of Transarterial Chemotherapeutic Treatment of Hepatocellular Carcinoma

Because diagnostic tools for discriminating between hepatocellular carcinoma (HCC) and advanced cirrhosis are poor, HCC is often detected in a stage where transarterial chemoembolization (TACE) is the best treatment option, even though it provides a poor survival gain. Despite having been used worldwide for several decades, TACE still has many limitations. First, there is a vast heterogeneity in the cellular composition and metabolism of HCCs as well as in the patient population, which renders it difficult to identify patients who would benefit from TACE. Often the delivered drug does not penetrate sufficiently selectively and deeply into the tumour and the drug delivery system is not releasing the drug at an optimal clinical rate. In addition, therapeutic effectiveness is limited by the crosstalk between the tumour cells and components of the cirrhotic tumour microenvironment. To improve this widely used treatment of one of our most common and deadly cancers, we need to better understand the complex interactions between drug delivery, local pharmacology, tumour targeting mechanisms, liver pathophysiology, patient and tumour heterogeneity, and resistance mechanisms. This review provides a novel and important overview of clinical data and discusses the role of the tumour microenvironment and lymphatic system in the cirrhotic liver, its potential response to TACE, and current and possible novel DDSs for locoregional treatment.

Cellular and Molecular Mechanism of Liver Fibrosis: A Critical Insight

Diseases are there, some are curable but certain diseases are life threatening. The dreadfulness of liver fibrosis created much attention in 21st century among pharmaceutical researchers. Usually liver fibrosis is asymptomatic and patients with advanced cirrhosis symptoms will have limited scope for reversibility. Recognition of asymptomatic individuals by considering them as critical is the fundamental step to control the liver-related morbidity and mortality. By reviewing the previous mortality analysis around the globe it is reported that liver fibrosis is the second leading cause of mortality in US, fifth most common cause of death in Germany, UK as well as tenth most frequent cause of fatality in India and around 10 lakh patients are diagnosed globally in every year. Liver fibrosis often leads to cirrhosis, hepatocellular carcinoma and progress towards liver failure which results due to excessive deposition of extracellular matrix (ECM) proteins, especially collagen type-1 contributed by hepatic stellate cells. The current study is based on for analyzing the molecular basis of liver fibrosis so that, it will be helpful for finding its route cause in cellular level which will guide as a future direction for developing new theranostic approaches for the early diagnosis of liver fibrosis.

Impact of lifestyle interventions targeting physical exercise and caloric intake on cirrhosis regression in rats

In patients, advanced cirrhosis only regresses partially once the etiological agent is withdrawn. Animal models for advanced cirrhosis regression are missing. Lifestyle interventions (LI) have shown to improve steatosis, inflammation, fibrosis and portal pressure in liver disease. We aimed at characterizing cirrhosis regression after etiological agent removal in experimental models of advanced cirrhosis and to study the impact of different LI on it. Advanced cirrhosis was induced in rats either by CCl4 or by thioacetamide (TAA) administration. Systemic and hepatic hemodynamics, liver fibrosis, hepatic stellate cell (HSC) activation, hepatic macrophage infiltration and metabolic profile were evaluated after 48h, 4 weeks or 8 weeks of etiological agent removal. The impact of LI consisting in caloric restriction (CR) or moderate endurance exercise (MEE) during the 8-week regression process was analyzed. The effect of MEE was also evaluated in early cirrhotic and in healthy rats. A significant reduction in portal pressure (PP), liver fibrosis and HSC activation was observed during regression. However, these parameters remained above those in healthy animals. During regression, animals markedly worsened their metabolic profile. CR although preventing those metabolic disturbances did not further reduce PP, hepatic fibrosis or HSC activation. MEE also prevented metabolic disturbances, without enhancing, but even attenuating the reduction of PP, hepatic fibrosis and HSC activation achieved by regression. MEE also worsened hepatic fibrosis in early-TAA cirrhosis and in healthy rats.

Perspective: The Mechanobiology of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the second most deadly primary cancer in the world and is thus a major global health challenge. HCC primarily develops in patients with an underlying chronic liver disease, the vast majority with advanced cirrhosis, characterized by increased matrix deposition and liver stiffness. Liver stiffness is highly associated with cancer development and poor patient outcome and is measured clinically to assess cancer risk; cirrhotic livers greatly exceed the threshold stiffness shown to alter hepatocyte cell behavior and to increase the malignancy of cancer cells. Recent studies have shown that cirrhotic liver cells have highly irregular nuclear morphologies and that nuclear deformation mediates mechanosensitive signaling. Separate research has shown that nuclear deformation can increase genetic instability and the accumulation of DNA damage in migrating cancer cells. We hypothesize that the mechanical changes associated with chronic liver disease are drivers of oncogenesis, activating mechanosensitive signaling pathways, increasing rates of DNA damage, and ultimately inducing malignant transformation.