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

Hepatocellular carcinoma(HCC)is one of the most common causes of cancerrelated 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.

Correction:Propensity-matched analysis of patients with intrahepatic cholangiocarcinoma or mixed hepatocellularcholangiocarcinoma and hepatocellular carcinoma undergoing a liver transplant

Rereading the article“Propensity-matched analysis of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma and hepatocellular carcinoma undergoing a liver transplant”(DOI:10.5306/wjco.v13.i8.688),published on August 24,we observe,with concern,that figures 3 and 4 are wrong.The authors have attached the correct figures for correction.

Immune aspects of hepatocellular carcinoma:From immune markers for early detection to immunotherapy

Hepatocellular carcinoma(HCC)is one of the most prevalent cancers and one of the main causes of cancer-related deaths worldwide.Most HCCs develop in an inflammatory microenvironment,and mounting evidence emphasizes the importance of immune aspects in hepatocarcinogenesis.In normal physiology,both innate and adaptive immune responses are responsible for eliminating malignantly transformed cells,thus preventing the development of liver cancer.However,in the setting of impaired natural killer cells and exhaustion of T cells,HCC can develop.The immunogenic features of HCC have relevant clinical implications.There is a large number of immune markers currently being studied for the early detection of liver cancer,which would be critical in order to improve surveillance programs.Moreover,novel immunotherapies have recently been proven to be effective,and the combination of atezolizumab and bevacizumab is currently the most effective treatment for advanced HCC.It is expected that in the near future different subgroups of patients will benefit from specific immunotherapy.The better we understand the immune aspects of HCC,the greater the benefit to patients through surveillance aiming for early detection of liver cancer,which allows for curative treatments,and,in cases of advanced disease,through the selection of the best possible therapy for each individual.

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.

Non-alcoholic fatty liver disease-related hepatocellular carcinoma:Is there a role for immunotherapy?

Hepatocellular carcinoma(HCC)is among the most common cancers and it is a major cause of cancer-related deaths.Non-alcoholic fatty liver disease(NAFLD)affects approximately one fourth of individuals worldwide and it is becoming one of the most important causes of HCC.The pathogenic mechanisms leading to NAFLD-related HCC are complex and not completely understood.However,metabolic,fibrogenic,oncogenic,inflammatory and immunological pathways seem to be involved.First-line therapy of advanced HCC has recently undergone major changes,since the combination of atezolizumab and bevacizumab was proven to increase survival when compared to sorafenib.Other immune-oncology drugs are also demonstrating promising results in patients with advanced HCC when compared to traditional systemic therapy.However,initial studies raised concerns that the advantages of immunotherapy might depend on the underlying liver disease,which seems to be particularly important in NAFLD-related HCC,as these tumors might not benefit from it.This article will review the mechanisms of NAFLD-related hepatocarcinogenesis,with an emphasis on its immune aspects,the efficacy of traditional systemic therapy for advanced NAFLD-related HCC,and the most recent data on the role of immunotherapy for this specific group of patients,showing that the management of this condition should be individualized and that a general recommendation cannot be made at this time.

Propensity-matched analysis of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma and hepatocellular carcinoma undergoing a liver transplant

BACKGROUND Cholangiocarcinoma(CC)is a rare tumor that arises from the epithelium of the bile ducts.It is classified according to anatomic location as intrahepatic,perihilar,and distal.Intrahepatic CC(ICC)is rare in patients with cirrhosis due to causes other than primary sclerosing cholangitis.Mixed hepatocellular carcinoma-CC(HCC-CC)is a rare neoplasm that shows histologic findings of both HCC and ICC within the same tumor mass.Due to the difficulties in arriving at the correct diagnosis,patients eventually undergo liver transplantation(LT)with a presumptive diagnosis of HCC on imaging when,in fact,they have ICC or HCC-CC.AIM To evaluate the outcomes of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma on pathological examination after liver transplant.METHODS Propensity score matching was used to analyze tumor recurrence(TR),overall mortality(OM),and recurrence-free survival(RFS)in LT recipients with pathologically confirmed ICC or HCC-CC matched 1:8 to those with HCC.Progression-free survival and overall mortality rates were computed with the Kaplan-Meier method using Cox regression for comparison.RESULTS Of 475 HCC LT recipients,1.7%had the diagnosis of ICC and 1.5%of HCC-CC on pathological examination of the explant.LT recipients with ICC had higher TR(46%vs 11%;P=0.006),higher OM(63%vs 23%;P=0.002),and lower RFS(38%vs 89%;P=0.002)than those with HCC when matched for pretransplant tumor characteristics,as well as higher TR(46%vs 23%;P=0.083),higher OM(63%vs 35%;P=0.026),and lower RFS(38%vs 59%;P=0.037)when matched for posttransplant tumor characteristics.Two pairings were performed to compare the outcomes of LT recipients with HCC-CC vs HCC.There was no significant difference between the outcomes in either pairing.CONCLUSION Patients with ICC had worse outcomes than patients undergoing LT for HCC.The outcomes of patients with HCC-CC did not differ significantly from those of patients with HCC.

Hepatocellular carcinoma in nonalcoholic fatty liver disease:A growing challenge

Nonalcoholic fatty liver disease(NAFLD)is the most common cause of liver disease worldwide,and its prevalence increases continuously.As it predisposes to hepatocellular carcinoma both in the presence and in the absence of cirrhosis,it is not surprising that the incidence of NAFLD-related hepatocellular carcinoma would also rise.Some of the mechanisms involved in hepatocarcinogenesis are particular to individuals with fatty liver,and they help explain why liver cancer develops even in patients without cirrhosis.Genetic and immune-mediated mechanisms seem to play an important role in the development of hepatocellular carcinoma in this population.Currently,it is consensual that patients with NAFLD-related cirrhosis should be surveilled with ultrasonography every 6 mo(with or without alpha-fetoprotein),but it is known that they are less likely to follow this recommendation than individuals with other kinds of liver disease.Moreover,the performance of the methods of surveillance are lower in NAFLD than they are in other liver diseases.Furthermore,it is not clear which subgroups of patients without cirrhosis should undergo surveillance.Understanding the mechanisms of hepatocarcinogenesis in NAFLD could hopefully lead to the identification of biomarkers to be used in the surveillance for liver cancer in these individuals.By improving surveillance,tumors could be detected in earlier stages,amenable to curative treatments.

Liver transplantation and alcoholic liver disease:History,controversies,and considerations

Alcohol consumption accounts for 3.8% of annual global mortality worldwide, and the majority of these deaths are due to alcoholic liver disease(ALD), mainly alcoholic cirrhosis. ALD is one of the most common indications for liver transplantation(LT). However, it remains a complicated topic on both medical and ethical grounds, as it is seen by many as a "self-inflicted disease". One of the strongest ethical arguments against LT for ALD is the probability of relapse. However, ALD remains a common indication for LT worldwide. For a patient to be placed on an LT waiting list, 6 mo of abstinence must have been achieved for most LT centers. However, this "6-mo rule" is an arbitrary threshold and has never been shown to affect survival, sobriety, or other outcomes. Recent studies have shown similar survival rates among individuals who undergo LT for ALD and those who undergo LT for other chronic causes of end-stage liver disease. There are specific factors that should be addressed when evaluating LT patients with ALD because these patients commonly have a high prevalence of multisystem alcohol-related changes. Risk factors for relapse include the presence of anxiety or depressive disorders, short pre-LT duration of sobriety, and lack of social support. Identification of risk factors and strengthening of the social support system may decrease relapse among these patients. Family counseling for LT candidates is highly encouraged to prevent alcohol consumption relapse. Relapse has been associated with unique histopathological changes, graft damage, graft loss, and even decreased survival in some studies. Research has demonstrated the importance of a multidisciplinary evaluation of LT candidates. Complete abstinence should be attempted to overcome addiction issues and to allow spontaneous liver recovery. Abstinence is the cornerstone of ALD therapy. Psychotherapies, including 12-step facilitation therapy, cognitive-behavioral therapy, and motivational enhancement therapy, help support abstinence. Nutritional therapy helps to reverse muscle wasting, weight loss, vitamin deficiencies, and trace element deficiencies associated with ALD. For muscular recovery, supervised physical activity has been shown to lead to a gain in muscle mass and improvement of functional activity. Early LT for acute alcoholic hepatitis has been the subject of recent clinical studies, with encouraging results in highly selected patients. The survival rates after LT for ALD are comparable to those of patients who underwent LT for other indications. Patients that undergo LT for ALD and survive over 5 years have a higher risk of cardiorespiratory disease, cerebrovascular events, and de novo malignancy.

Low platelet count: Predictor of death and graft loss after liver transplantation

BACKGROUND The impact of platelets on liver transplantation(LT) is well recognized, but not completely understood. Platelets exert dichotomous effects on the graft and on the patient. On the one hand, they are essential for primary hemostasis and tissue repair and regeneration. On the other hand, they support ischemia/reperfusion injury and inflammatory processes. Recent evidence has shown a new role for platelet count(PC) in predicting outcomes after LT.AIM To evaluate if low PC is a predictor of short-and long-term outcomes after LT.METHODS Four hundred and eighty consecutive LT patients were retrospectively assessed.PC from the preoperative to the seventh postoperative day(POD) were considered. C-statistic analysis defined the ideal cutoff point for PC. Cox regression was performed to check whether low PC was a predictor of death,retransplantation or primary changes in graft function within one year after LT.RESULTS The highest median PC was 86 × 109/L [interquartile range(IQR) = 65–100 ×109/L] on seventh POD, and the lowest was 51 × 109/L(IQR = 38–71 × 109/L) on third POD. The C-statistic defined a PC < 70 × 109/L on fifth POD as the ideal cutoff point for predicting death and retransplantation. In the multivariate analysis, platelets < 70 × 109/L on 5 POD was an independent risk factor for death at 12 mo after LT [hazard ratio(HR) = 2.01; 95% confidence interval(CI) 1.06-3.79;P = 0.031]. In the Cox regression, patients with PC < 70 × 109/L on 5 POD had worse graft survival rates up to one year after LT(HR = 2.76; 95%CI 1.52-4.99; P =0.001).CONCLUSION PC < 70 × 109/L on 5 POD is an independent predictor of death in the first year after LT. These results are in agreement with other studies that indicate that low PC after LT is associated with negative outcomes.