Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease

Leung, Christopher; Yeoh, Sern Wei; Patrick, Desmond; Ket, Shara; Marion, Kaye; Gow, Paul J; Angus, Peter W

doi:10.3748/wjg.v21.i4.1189

Cited by 110 publications

(91 citation statements)

References 47 publications

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“…Furthermore, because HCC is associated with systemic metabolic disease, including type 2 diabetes, metabolic syndrome, and NAFLD (Leung et al 2015), and because changes in PK isoform expression can impact glucose fate (Lunt et al 2015), we asked whether Pkm2 −/− mice might likewise be more susceptible to age-induced whole-body metabolic changes. We measured fasting blood glucose and insulin levels in young and old Pkm2 −/− mice or wild-type littermates.…”

Section: Pkm2-null Mice Display Increased Age-induced Metabolic Distrmentioning

confidence: 99%

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

et al. 2016

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Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase (PK), and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2-null mice (Pkm2). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2 −/− mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism.

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Section: Pkm2-null Mice Display Increased Age-induced Metabolic Distrmentioning

confidence: 99%

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

et al. 2016

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“…Once cirrhosis develops, the rate of HCC in cirrhotic patients was reported to be about 11.3 % in Japanese in 5 years [7], or 12.8% in 5 years in the US [11]. Special attention must be paid to NASH patients without advanced fibrosis or cirrhosis because HCC does occur at this stage, and once it occurs, the malignancy often presents with a larger tumor size than in cirrhotic patients [12], although the rate is thought to be relatively low (0.5-2.4% over 7 years in different ethnic groups and regions) [2, 7, 11] (Figure 1). From limited clinical data, it appears that histopathologic features, risk factors and prognosis of HCC occurring in NASH-associated cirrhosis are significantly different from the features of other etiologies of liver disease, such as hepatitis B or C viral infection [13].…”

Section: Introductionmentioning

confidence: 99%

Utilization of animal models to investigate nonalcoholic steatohepatitis-associated hepatocellular carcinoma

2016

Oncotarget

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Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of liver disorders with fat accumulation from simple fatty liver, nonalcoholic steatohepatitis (NASH), fibrosis/cirrhosis and NAFLD/NASH-associated hepatocellular carcinoma (HCC). NASH is a progressive form of NAFLD and requires medical attention. One of 5-10 NASH patients may progress to end-state liver disease (ESLD or cirrhosis) in 5-10 years; meanwhile, life-threatening complications of ESLD and HCC account for major mortality. An increasing burden of NAFLD in clinics, elucidation of its pathogenesis and progression, and assessment of the efficacy of potential therapeutics demand reliable animal models. Most NASH-associated HCC occurs in cirrhotic subjects; however, HCC does appear in NASH patients without cirrhosis. Lipotoxicity, oxidant stress, insulin resistance, endoplasmic reticulum stress, altered adipokine and lymphokine profiles and gut microbiome changes affect NAFLD progression and constitute key pathobiologic interplays. How these factors promote malignant transformation in a microenvironment of steatotic inflammation and fibrosis/cirrhosis, and lead to development of neoplasms is one of critical questions faced in the hepatology field. The present review summarizes the characteristics of emerging rodent NASH-HCC models, and discusses the challenges in utilizing these models to unveil the mysteries of NASH-associated HCC development.

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“…Hepatocellular carcinoma (HCC) accounts for about 82% of primary liver cancer in Australia 1 . HCC is most frequently identified in patients with cirrhosis, typically caused by chronic hepatitis B (HBV) or C virus (HCV) infections, alcohol‐related liver disease, or non‐alcoholic fatty liver disease 3 . ‐ 5 A variety of treatments are available, including curative therapies (liver transplantation, surgical resection, percutaneous and laparoscopy‐assisted ablation) and palliative measures, such as trans‐arterial chemo‐embolisation, a kinase inhibitor (sorafenib), selective internal radiation therapy, and best supportive care.…”

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confidence: 99%

Surveillance improves survival of patients with hepatocellular carcinoma: a prospective population‐based study

Hong

Gow

Fink

et al. 2018

Medical Journal of Australia

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Objectives: To determine the factors associated with survival of patients with hepatocellular carcinoma (HCC) and the effect of HCC surveillance on survival. Design, setting and participants: Prospective population‐based cohort study of patients newly diagnosed with HCC in seven tertiary hospitals in Melbourne, 1 July 2012 – 30 June 2013. Main outcome measures: Overall survival (maximum follow‐up, 24 months); factors associated with HCC surveillance participation and survival. Results: 272 people were diagnosed with incident HCC during the study period; the most common risk factors were hepatitis C virus infection (41%), alcohol‐related liver disease (39%), and hepatitis B virus infection (22%). Only 40% of patients participated in HCC surveillance at the time of diagnosis; participation was significantly higher among patients with smaller median tumour size (participants, 2.8 cm; non‐participants, 6.0 cm; P < 0.001) and earlier Barcelona Clinic Liver Cancer (BCLC) stage disease (A/B, 59%; C/D, 25%; P < 0.001). Participation was higher among patients with compensated cirrhosis or hepatitis C infections; it was lower among those with alcohol‐related liver disease or decompensated liver disease. Median overall survival time was 20.8 months; mean survival time was 18.1 months (95% CI, 16.6–19.6 months). Participation in HCC surveillance was associated with significantly lower mortality (adjusted hazard ratio [aHR], 0.60; 95% CI, 0.38–0.93; P = 0.021), as were curative therapies (aHR, 0.33; 95% CI, 0.19–0.58). Conversely, higher Child–Pugh class, alpha‐fetoprotein levels over 400 kU/L, and later BCLC disease stages were each associated with higher mortality. Conclusions: Survival for patients with HCC is poor, but may be improved by surveillance, associated with the identification of earlier stage tumours, enabling curative therapies to be initiated.

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Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease

Abstract: HCC can develop in NAFLD without cirrhosis. At diagnosis such tumours are larger than those in cirrhotics, conferring a poorer prognosis.

Cited by 110 publications

References 47 publications

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

Utilization of animal models to investigate nonalcoholic steatohepatitis-associated hepatocellular carcinoma

Surveillance improves survival of patients with hepatocellular carcinoma: a prospective population‐based study

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