Hepatocellular carcinoma-the role of the underlying liver disease in clinical practice.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality. This particular type of cancer has the distinctive characteristic of mostly happening in individuals with an underlying liver disease. This makes the management of patients more challenging, since physicians must take into consideration two different conditions, the chronic liver disease and the tumor. The underlying liver disease has several implications in clinical practice, because different kinds of chronic liver disease can lead to varying degrees of risk of developing HCC, obstacles in surveillance, and differences in the efficacy of the treatment against HCC. A shift in the prevalence of liver diseases has been evident over the last few years, with viral hepatitis gradually losing the leading position as cause of HCC and metabolic dysfunction-associated steatotic liver disease gaining importance. Therefore, in an era of personalized medicine, it is imperative that physicians are aware of the underlying liver disease of individuals with HCC and its impact in the management of their tumors.

Impact of multidrug resistance on the management of bacterial infections in cirrhosis.

Patients with cirrhosis have an increased risk of infection and differently from other complications, that over the years are improving in their outcomes, infections in cirrhotic patients are still a major cause of hospitalization and death (up to 50% in-hospital mortality). Infections by multidrug-resistant organisms (MDRO) have become a major challenge in the management of cirrhotic patients with significant prognostic and cost-related impact. About one third of cirrhotic patients with bacterial infections is infected with MDR bacteria and their prevalence has increased in recent years. MDR infections have a worse prognosis compared to infections by non-resistant bacteria because they are associated with lower rate of infection resolution. An adequate management of cirrhotic patients with infections caused by MDR bacteria depends on the knowledge of some epidemiological aspects, such as the type of infection (spontaneous bacterial peritonitis, pneumonia, urinary tract infection and spontaneous bacteremia), bacteriological profile of antibiotic resistance at each health care unit and site of infection acquisition (community acquired, healthcare associated or nosocomial). Furthermore, regional variations in the prevalence of MDR infections determine that the choice of empirical antibiotic therapy must be adapted to the local microbiological epidemiology. Antibiotic treatment is the most effective measure to treat infections caused by MDRO. Therefore, optimizing antibiotic prescribing is critical to effectively treat these infections. Identification of risk factors for multidrug resistance is essential to define the best antibiotic treatment strategy in each case and the choice of an effective empirical antibiotic therapy and its early administration is cardinal to reduce mortality. On the other hand, the supply of new agents to treat these infections is very limited. Thus, specific protocols that include preventive measures must be implemented in order to limit the negative impact of this severe complication in cirrhotic patients.

Hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis.

Cirrhosis is an emerging major cause of the development of hepatocellular carcinoma (HCC), but in non-alcoholic fatty liver disease (NAFLD), up to 50% of patients with HCC had no clinical or histological evidence of cirrhosis. It is currently challenging to propose general recommendations for screening patients with NAFLD without cirrhosis, and each patient should be evaluated on a case-by-case basis based on the profile of specific risk factors identified. For HCC screening in NAFLD, a valid precision-based screening is needed. Currently, when evaluating this population of patients, the use of non-invasive methods can guide the selection of those who should undergo a screening and surveillance program. Hence, the objective of the present study is to review the epidemiology, the pathophysiology, the histopathological aspects, the current recommendations, and novel perspectives in the surveillance of non-cirrhotic NAFLD-related HCC.

Albumin administration in patients with cirrhosis: Current role and novel perspectives.

Mortality in cirrhosis is mostly associated with the development of clinical decompensation, characterized by ascites, hepatic encephalopathy, variceal bleeding, or jaundice. Therefore, it is important to prevent and manage such complications. Traditionally, the pathophysiology of decompensated cirrhosis was explained by the peripheral arterial vasodilation hypothesis, but it is currently understood that decompensation might also be driven by a systemic inflammatory state (the systemic inflammation hypothesis). Considering its oncotic and nononcotic properties, albumin has been thoroughly evaluated in the prevention and management of several of these decompensating events. There are formal evidence-based recommendations from international medical societies proposing that albumin be administered in individuals with cirrhosis undergoing large-volume paracentesis, patients with spontaneous bacterial peritonitis, those with acute kidney injury (even before the etiological diagnosis), and those with hepatorenal syndrome. Moreover, there are a few randomized controlled trials and meta-analyses suggesting a possible role for albumin infusion in patients with cirrhosis and ascites (long-term albumin administration), individuals with hepatic encephalopathy, and those with acute-on-chronic liver failure undergoing modest-volume paracentesis. Further studies are necessary to elucidate whether albumin administration also benefits patients with cirrhosis and other complications, such as individuals with extraperitoneal infections, those hospitalized with decompensated cirrhosis and hypoalbuminemia, and patients with hyponatremia.

Current impact of viral hepatitis on liver cancer development: The challenge remains.

Chronic infections due to hepatitis B and hepatitis C viruses are responsible for most cases of hepatocellular carcinoma (HCC) worldwide, and this association is likely to remain during the next decade. Moreover, viral hepatitis-related HCC imposes an important burden on public health in terms of disability-adjusted life years. In order to reduce such a burden, some major challenges must be faced. Universal vaccination against hepatitis B virus, especially in the neonatal period, is probably the most relevant primary preventive measure against the development of HCC. Moreover, considering the large adult population already infected with hepatitis B and C viruses, it is also imperative to identify these individuals to ensure their access to treatment. Both hepatitis B and C currently have highly effective therapies, which are able to diminish the risk of development of liver cancer. Finally, it is essential for individuals at high-risk of HCC to be included in surveillance programs, so that tumors are detected at an early stage. Patients with hepatitis B or C and advanced liver fibrosis or cirrhosis benefit from being followed in a surveillance program. As hepatitis B virus is oncogenic and capable of leading to liver cancer even in individuals with early stages of liver fibrosis, other high-risk groups of patients with hepatitis B are also candidates for surveillance. Considerable effort is required concerning these strategies in order to decrease the incidence and the mortality of viral hepatitis-related HCC.

Long-term albumin administration in patients with cirrhosis and ascites: A meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Ascites is a common complication of cirrhosis, and it is associated with increased mortality. The aim of this study was to evaluate the efficacy of long-term albumin administration in decreasing mortality and other complications of patients with cirrhosis and ascites. METHODS: A systematic review was performed using MEDLINE and Embase databases. Randomized controlled trials evaluating long-term albumin administration in patients with cirrhosis and ascites were considered eligible, as long as at least one of the following outcomes was evaluated: mortality, recurrence of ascites/need for paracentesis, refractory ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, gastrointestinal bleeding, or adverse events. Meta-analysis was performed using the random-effects model, through the Mantel-Haenszel method. The study protocol was registered at PROSPERO platform (CRD42019130078). RESULTS: The literature search yielded 1517 references. Five randomized controlled trials fulfilled the selection criteria and were included in this meta-analysis, involving 716 individuals. Patients receiving long-term albumin had significantly lower risk of recurrence of ascites/need for paracentesis when compared with controls (risk ratio = 0.56, 95% confidence interval = 0.48-0.67, P < 0.00001). There was no evidence of significant difference between the long-term albumin and control groups regarding mortality, refractory ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, gastrointestinal bleeding, or adverse events. CONCLUSIONS: Long-term albumin administration in patients with cirrhosis and ascites decreases recurrence of ascites/need for paracentesis. At this point, there is no evidence of significant benefits of long-term albumin administration regarding mortality or other complications of cirrhosis.

Primary prophylaxis of variceal bleeding in patients with cirrhosis: A comparison of different strategies.

Patients with cirrhosis and esophageal varices bleed at a yearly rate of 5%-15%, and, when variceal hemorrhage develops, mortality reaches 20%. Patients are deemed at high risk of bleeding when they present with medium or large-sized varices, when they have red signs on varices of any size and when they are classified as Child-Pugh C and have varices of any size. In order to avoid variceal bleeding and death, individuals with cirrhosis at high risk of bleeding must undergo primary prophylaxis, for which currently recommended strategies are the use of traditional non-selective beta-blockers (NSBBs) (i.e., propranolol or nadolol), carvedilol (a NSBB with additional alpha-adrenergic blocking effect) or endoscopic variceal ligation (EVL). The superiority of one of these alternatives over the others is controversial. While EVL might be superior to pharmacological therapy regarding the prevention of the first bleeding episode, either traditional NSBBs or carvedilol seem to play a more prominent role in mortality reduction, probably due to their capacity of preventing other complications of cirrhosis through the decrease in portal hypertension. A sequential strategy, in which patients unresponsive to pharmacological therapy would be submitted to endoscopic treatment, or the combination of pharmacological and endoscopic strategies might be beneficial and deserve further investigation.

Chronic liver failure-consortium acute-on-chronic liver failure and acute decompensation scores predict mortality in Brazilian cirrhotic patients.

AIM: To validate prognostic scores for acute decompensation of cirrhosis and acute-on-chronic liver failure in Brazilian patients. METHODS: This is a prospective cohort study designed to assess the prognostic performance of the chronic liver failure-consortium (CLIF-C) acute decompensation score (CLIF-C AD) and CLIF-C acute-on-chronic liver failure score (CLIF-C ACLF), regarding 28-d and 90-d mortality, as well as to compare them to other prognostic models, such as Model for End-Stage Liver Disease (MELD), MELD Sodium (MELD-Na), Child-Pugh (CP) score, and the CLIF-C Organ Failure score (CLIF-C OF). All participants were adults with acute decompensation of cirrhosis admitted to the Emergency Department of a tertiary hospital in southern Brazil. Prognostic performances were evaluated by means of the receiver operating characteristic (ROC) curves, area under the curves (AUC) and 95%CI. RESULTS: One hundred and thirteen cirrhotic patients were included. At admission, 18 patients had acute-on-chronic liver failure (ACLF) and 95 individuals had acute decompensation (AD) without ACLF, of which 24 eventually developed ACLF during the course of hospitalization (AD evolving to ACLF group). The AD group had significantly lower 28-d (9.0%) and 90-d (18.3%) mortality as compared to the AD evolving to ACLF group and to the ACLF group (both P < 0.001). On the other hand, 28-d and 90-d mortalities were not significantly different between AD evolving to ACLF group and ACLF group (P = 0.542 and P = 0.708, respectively). Among patients with ACLF, at 28 d from the diagnosis, CLIF-C ACLF was the only score able to predict mortality significantly better than the reference line, with an AUC (95%CI) of 0.71 (95%CI: 0.54-0.88, P = 0.021). Among patients with AD, all prognostic scores performed significantly better than the reference line regarding 28-d mortality, presenting with similar AUCs: CLIF-C AD score 0.75 (95%CI: 0.63-0.88), CP score 0.72 (95%CI: 0.59-0.85), MELD score 0.75 (95%CI: 0.61-0.90), MELD-Na score 0.76 (95%CI: 0.61-0.90), and CLIF-C OF score 0.74 (95%CI: 0.60-0.88). The same occurred concerning AUCs for 90-d mortality: CLIF-C AD score 0.70 (95%CI: 0.57-0.82), CP score 0.73 (95%CI: 0.62-0.84), MELD score 0.71 (95%CI: 0.59-0.83), MELD-Na score 0.73 (95%CI: 0.62-0.84), and CLIF-C OF score 0.65 (95%CI: 0.52-0.78). CONCLUSION: This study demonstrated that CLIF-C ACLF is the best available score for the prediction of 28-d mortality among patients with ACLF. CLIF-C AD score is also useful for the prediction of mortality among cirrhotic patients with AD not fulfilling diagnostic criteria for ACLF, but it was not superior to other well-established prognostic scores.

Hepatorenal syndrome: Current concepts related to diagnosis and management.

 Renal failure in cirrhotic patients is a very severe condition. Hepatorenal syndrome has the worst prognosis among all causes of kidney failure in such patients. Hepatorenal syndrome is diagnosed especially in cirrhotic patients with ascites who develop loss renal function, despite diuretic suspension and volume expansion with albumin and for whom other causes of kidney injury have been excluded. Patients with hepatorenal syndrome should be treated with a vasoconstrictor in combination with albumin as a bridge to receiving a liver transplant. The vasoconstrictor of choice is terlipressin or noradrenaline. In spite of higher drug-related costs associated to terlipressin, initial evidence demonstrates that, considering all direct medical costs involved, the treatment strategy using terlipressin is probably more economical than that using noradrenaline.

Noninvasive imaging assessment of non-alcoholic fatty liver disease: focus on liver scintigraphy.

Noninvasive diagnoses of nonalcoholic fatty-liver disease (NAFLD) involve the use of serologic markers and imaging methods, such as conventional ultrasonography (US), computed tomography, and magnetic resonance imaging. Although these methods are reliable for the noninvasive detection of moderate to severe fatty changes in the liver, they are not reliable for detecting nonalcoholic steatohepatitis (NASH) and fibrosis. New imaging technologies, such as US-based transient elastography, acoustic radiation force impulse and magnetic resonance-based elastography, can reportedly be used to determine the severity of liver fibrosis associated with NASH. In this context, the field of nuclear medicine through liver scintigraphy has recently been proposed, and is being explored for use in the diagnosis of NASH. More importantly, nuclear medicine may contribute to the distinction between simple steatosis and NASH. For example, the enhanced release of cytokines and the decrease in the phagocytic activity of Kupffer cells play important roles in the pathogenesis of NASH. Removal of technetium-99m colloid from circulation by Kupffer cell phagocytosis therefore provides a valuable imaging technique. Thus, nuclear medicine is poised to provide useful tools for the evaluation of patients with NAFLD. However, the evidence is still scarce, and more studies with larger samples are needed to identify their role before they are used in clinical practice.