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Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the most frequent forms of chronic liver disease in developed countries1. It is closely related to insulin resistance, the clinical and biological manifestations of which are included in the metabolic syndrome. NAFLD encompasses a wide spectrum of diseases ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), and can progress to cirrhosis. Any of these pathological conditions may predispose to the development of hepatocellular carcinoma (HCC)2–6. In particular, recent evidence suggests that 30–60 per cent of patients with metabolic syndrome develop HCC without severe underlying fibrosis2–6. In the absence of symptomatic liver disease it appears that many of these patients present at a more advanced age with large tumours at the time of diagnosis than patients with chronic liver disease of other aetiology4. As a consequence, few therapeutic options other than liver resection are left in this context.
Operative risk according to the severity of chronic liver disease and prognostic factors for longer survival, such as tumour size, differentiation and vascular invasion, have been studied extensively in the context of liver resection for HCC7, 8. These issues are still largely unclear in the setting of patients with HCC developed in a background of metabolic syndrome. Both impaired performance status of these patients as a consequence of advanced age, central obesity, diabetes and cardiovascular co-morbidities, as well as the impact of the underlying liver status, could adversely affect the postoperative course. The frequent absence of severe underlying fibrosis may result in these patients being considered as having a ‘normal’ liver. This, in turn, may result in inadequate preparation for liver resection9–11.
Only one small series has focused on the outcomes of surgical treatment of HCC in patients with NAFLD6, but that study did not specifically address the presence of an associated metabolic syndrome. Thus, the aim of the present study was to characterize the outcomes of liver resection in patients who developed HCC in a background of metabolic syndrome (MS-HCC) in order to determine the influence of the underlying liver on both the postoperative course and long-term outcome.
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The metabolic syndrome encompasses clinical and biological manifestations of insulin resistance. NAFLD, which defines hepatic manifestations of insulin resistance, ranges from simple steatosis to NASH1, 2 and can progress to cirrhosis. The metabolic syndrome is increasingly recognized as a co-risk factor for HCC20. In the present series of 62 patients with metabolic syndrome who underwent liver resection for HCC, only about 30 per cent of the patients developed HCC in underlying severely fibrotic livers. Thus, the present series confirms that HCC might arise in a context of insulin resistance even in the absence of severe underlying fibrosis1, 3–6, 21.
In the present study, the gradual increase over the years in the proportion of metabolic syndrome-associated HCCs, amongst other aetiologies, probably accounts for both better classification and rising incidence of this disease. Almost 40 per cent of the patients presented with minimal parenchymal lesions and would probably have been classified as having ‘HCC developed on normal liver’, even as recently as 10 years ago. The rising incidence of the metabolic syndrome in the general population—up to 24 per cent in the USA, especially in elderly patients12—suggests that surgeons can expect increasing numbers of patients to be referred to hepatopancreatobiliary units for HCC in this context.
As for other causes of HCC22, it is likely that patients with metabolic syndrome may benefit from earlier diagnosis of the tumour. In fact, HCC was diagnosed incidentally in nearly 60 per cent of patients, mostly at an advanced stage, and with more than 90 per cent of patients showing abnormal liver function. This suggests that liver imaging in the presence of unusual liver test results could aid earlier tumour diagnosis in patients with metabolic syndrome.
Over recent years, continuing refinements in surgical technique, patient selection and perioperative care have led to increasingly safer liver resection23. However, these advances have not translated wholly into improved care for the specific population of patients with MS-HCC and underlying liver disease. In this subgroup, the high mortality rate observed in the present study might be explained by the underestimation of patients' co-morbidity. Advanced age, obesity and diabetes, which are all known to affect the postoperative course negatively24, were found in more than 80 per cent of patients. Furthermore, the observed concordance between the higher incidence of major postoperative cardiorespiratory events and the presence of a fatty underlying liver confirms the independent association of NAFLD, an intense proinflammatory state secondary to advanced insulin resistance, and increased vulnerability following impaired cardiorespiratory status25. This finding suggests that specific preoperative cardiorespiratory and anaesthetic evaluation should probably be undertaken in these patients.
The most striking finding in this series was the relationship between the operative risk and the presence of an abnormal underlying parenchyma, especially in patients without severe fibrosis. Similar to major hepatectomy for colorectal liver metastases in patients after prolonged chemotherapy26, and in line with other studies27–29, the present results underline the influence of significant steatosis on operative outcome. Moreover, the increased morbidity and mortality rates observed in patients with a NAS of 2 or more suggest that the operative risk is further enhanced in the presence of associated inflammatory processes.
Based on these results, it would seem reasonable to suggest that improvements in perioperative management should be undertaken, especially for patients with stage F0–F2 fibrosis and a NAS of 2 or above. In fact, when major resection was planned, these patients had preoperative PVE less frequently than those with stage F3–F4. This may indicate that there was an underestimation of the operative risk, especially for patients without severe underlying fibrosis, and therefore inadequate preoperative and operative management. It is thus likely that these patients would benefit from preoperative assessment of the underlying parenchyma using percutaneous biopsy or magnetic resonance imaging30 and parenchyma-sparing resection31, as well as careful use of hepatic inflow clamping, as in patients with cirrhosis32.
The final interesting result of this study was the good long-term prognosis of patients with MS-HCC. Indeed, both 1- and 3-year overall and disease-free survival rates (83 and 75 per cent, and 83 and 70 per cent, respectively) compare favourably with data reported recently on resection of HCC in chronic liver disease of other aetiology5. Interestingly, patients with normal underlying parenchyma had more advanced disease, including larger tumours, more frequent satellite nodules and higher microvascular invasion rates. This is most likely a consequence of the delayed diagnosis in the absence of specific symptoms. Accordingly, the trend towards better survival observed in patients with normal underlying liver cannot be attributed to more favourable biology, but should rather be related to increased mortality rates in patients with abnormal underlying liver. Nevertheless, the good long-term results in this group of patients support a radical treatment, provided that surgeons are aware of the particular hazards of liver resection and thus offer optimal perioperative care to these patients.
The present study has several limitations owing to both its retrospective nature and the small number of patients included over a long period. The retrieved factors for the metabolic syndrome did not all fulfil the consensus definition19, and the assumption that all patients taking a statin or fenofibrate had dyslipidaemia might have led to the inclusion of some patients who were receiving such medication for primary cardiovascular prevention. Similarly, given the higher enrolment of patients with metabolic syndrome during the later years of the study, it is likely that earlier in the study some patients with metabolic syndrome with incomplete diagnostic workup may have been misclassified. Finally, considering the high mortality rate, one could legitimately wonder whether liver transplantation might be the appropriate treatment for these patients5, 33. However, as only a small number of patients had lesions within the Milan criteria, it appears that liver resection is presently the only curative option for the majority of these patients.