Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Risk factors for HCC include chronic hepatitis B and hepatitis C, alcohol addiction, metabolic liver ...disease (particularly nonalcoholic fatty liver disease) and exposure to dietary toxins such as aflatoxins and aristolochic acid. All these risk factors are potentially preventable, highlighting the considerable potential of risk prevention for decreasing the global burden of HCC. HCC surveillance and early detection increase the chance of potentially curative treatment; however, HCC surveillance is substantially underutilized, even in countries with sufficient medical resources. Early-stage HCC can be treated curatively by local ablation, surgical resection or liver transplantation. Treatment selection depends on tumour characteristics, the severity of underlying liver dysfunction, age, other medical comorbidities, and available medical resources and local expertise. Catheter-based locoregional treatment is used in patients with intermediate-stage cancer. Kinase and immune checkpoint inhibitors have been shown to be effective treatment options in patients with advanced-stage HCC. Together, rational deployment of prevention, attainment of global goals for viral hepatitis eradication, and improvements in HCC surveillance and therapy hold promise for achieving a substantial reduction in the worldwide HCC burden within the next few decades.
Alcohol-related liver disease is a major cause of morbidity and mortality in the United States. Alcoholic liver disease encompasses a clinicohistological spectrum, including fatty liver, alcoholic ...hepatitis, and alcoholic cirrhosis. Fatty liver is a benign and reversible condition, but progression to alcoholic hepatitis and cirrhosis is life-threatening. Alcoholic hepatitis is diagnosed predominantly on clinical history, physical examination, and laboratory testing, although liver biopsy is often necessary to secure the diagnosis. The major focus of management is abstinence from alcohol, supportive care, treatment of complications of infection and portal hypertension, and maintenance of positive nitrogen balance through nutritional support. Corticosteroid therapy is controversial but should be considered in patients with a discriminant function greater than 32 and/or presence of spontaneous hepatic encephalopathy in the absence of infection, gastrointestinal bleeding, and renal failure. The only curative therapy for advanced alcoholic cirrhosis is liver transplantation. Several recent advances in understanding the pathogenesis of alcoholic liver disease may lead to novel future treatment approaches, including inhibition of tumor necrosis factor a, antioxidant therapy, stimulation of liver regeneration, and stimulation of collagen degradation.
Cold ischemia/warm reperfusion (CI/WR) injury remains a problem in liver transplantation. The aim of the current study was to assess the utility of the pan‐caspase inhibitor IDN‐6556 on CI/WR injury ...during human liver transplantation. This report is a post hoc analysis of a Phase II, multi‐center, randomized, placebo‐controlled, double‐blinded, parallel group study. Subjects were assigned to four treatment groups: Group 1 (Organ storage/flush: Placebo—Recipient: Placebo); Group 2 (Organ storage/flush: 15 μg/mL—Recipient: Placebo); Group 3 (Organ storage/flush: 5 μg/mL—Recipient: 0.5 mg/kg); and Group 4 (Organ storage/flush: 15 μg/mL—Recipient: 0.5 mg/kg). Liver cell apoptosis was assessed by serum concentrations of the apoptosis‐associated CK18Asp396 (‘M30’) neo‐epitope, TUNEL assay and caspase 3/7 immunohistochemistry. Liver injury was assessed by serum AST/ALT determinations. Serum markers of liver cell apoptosis were reduced in all groups receiving drug as compared to placebo. However, TUNEL, caspase 3/7 positive cells and serum AST/ALT levels were only consistently reduced in Group 2 (drug exposed to organ only). This reduction in serum transaminases was significant and observed across the study. In conclusion, IDN‐6556 when administered in cold storage and flush solutions during liver transplantation offers local therapeutic protection against CI/WR‐mediated apoptosis and injury. However, larger studies are required to confirm these observations.
The first human trial of a caspase inhibitor in organ preservation suggests the agent offers local therapeutic protection against liver CI/WR‐mediated apoptosis and injury.
Death of hepatocytes and other hepatic cell types is a characteristic feature of liver diseases as diverse as cholestasis, viral hepatitis, ischemia/reperfusion, liver preservation for ...transplantation and drug/toxicant‐induced injury. Cell death typically follows one of two patterns: oncotic necrosis and apoptosis. Necrosis is typically the consequence of acute metabolic perturbation with ATP depletion as occurs in ischemia/reperfusion and acute drug‐induced hepatotoxicity. Apoptosis, in contrast, represents the execution of an ATP‐dependent death program often initiated by death ligand/death receptor interactions, such as Fas ligand with Fas, which leads to a caspase activation cascade. A common event leading to both apoptosis and necrosis is mitochondrial permeabilization and dysfunction, although the mechanistic basis of mitochondrial injury may vary in different settings. Prevention of these modes of cell death is an important target of therapy, but controversies still exist regarding which mode of cell death predominates in various forms of liver disease and injury. Resolution of these controversies may come with the recognition that apoptosis and necrosis frequently represent alternate outcomes of the same cellular pathways to cell death, especially for cell death mediated by mitochondrial permeabilization. An understanding of processes leading to liver cell death will be important for development of effective interventions to prevent hepatocellular death leading to liver failure and to promote cancer and stellate cell death in malignancy and fibrotic disease. (Hepatology 2006;43;S31–S44.)
Lysosomes in cell death Guicciardi, Maria Eugenia; Leist, Marcel; Gores, Gregory J
Oncogene,
04/2004, Letnik:
23, Številka:
16
Journal Article
Recenzirano
Odprti dostop
For many years apoptosis research has focused on caspases and their putative role as sole executioners of programmed cell death. Accumulating information now suggests that lysosomal cathepsins are ...also pivotally involved in this process, especially in pathological conditions. In particular, the role of lysosomes and lysosomal enzymes in initiation and execution of the apoptotic program has become clear in several models, to the point that the existence of a 'lysosomal pathway of apoptosis' is now generally accepted. This pathway of apoptosis can be activated by death receptors, lipid mediators, and photodamage. Lysosomal proteases can be released from the lysosomes into the cytosol, where they contribute to the apoptotic cascade upstream of mitochondria. This review focuses on the players and the molecular mechanisms involved in the lysosomal pathway of apoptosis as well as on the importance of this pathway in development and pathology.
Alcoholic hepatitis is a distinct clinical syndrome among people with chronic and active alcohol abuse, with a potential for 30%–40% mortality at 1 month among those with severe disease. ...Corticosteroids or pentoxifylline are the current pharmacologic treatment options, but they provide only about 50% survival benefit. These agents are recommended for patients with modified discriminant function (mDF) ≥32 or Model for End-Stage Liver Disease score ≥18. The Lille score is used to determine response to steroids. Currently, a minimum of 6 months of abstinence from alcohol use is required for patients to receive a liver transplant, a requirement that cannot be met by patients with severe alcoholic hepatitis nonresponsive to steroids (Lille score ≥0.45). Data are emerging on the benefit of liver transplantation in select patients with first episode of severe alcoholic hepatitis. This review also focuses on recent treatment trials in alcoholic hepatitis including liver transplantation and its associated controversies, as well as possible future targets and pharmacologic treatment options for patients with alcoholic hepatitis that are being pursued through upcoming consortium studies.
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