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Obesity and diabetes as a risk factor for hepatocellular carcinoma
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Liver Transplantation
Volume 10, Issue S2, February 2004
Jean M. Regimbeau 1, Magali Colombat 2, Philippe Mognol 1, François Durand 3, Eddie Abdalla 1, Claude Degott 2, Françoise Degos 3, Olivier Farges 1, Jacques Belghiti 1 *1Fédération Médico-Chirurgicale d'Hépato-Gastro-Entérologie, Department of Surgery, Hospital Beaujon, Assistance Publique-Hôpitaux de Paris and Faculty of Medicine Xavier Bichat, University Paris VII, Paris, France 2Fédération Médico-Chirurgicale d'Hépato-Gastro-Entérologie, Department of Pathology, Hospital Beaujon, Assistance Publique-Hôpitaux de Paris and Faculty of Medicine Xavier Bichat, University Paris VII, Paris, France 3Fédération Médico-Chirurgicale d'Hépato-Gastro-Entérologie, Department of Hepatology, Hospital Beaujon, Assistance Publique-Hôpitaux de Paris and Faculty of Medicine Xavier Bichat, University Paris VII, Paris, France
ABSTRACT
Ten percent of patients who undergo resection for hepatocellular carcinoma (HCC) associated with chronic liver disease have no detectable cause for this underlying liver disease. Recent studies have shown that patients with cryptogenic chronic liver disease frequently have risk factors for nonalcoholic fatty liver disease (NAFLD).
This study examines the incidence of risk factors for NAFLD in patients with chronic liver disease who underwent resection for HCC. Among 210 patients with chronic liver disease who underwent resection for HCC, 18 (8.6%) had no identifiable cause for the underlying liver disease. These patients were assessed for obesity, diabetes mellitus, and histological features of the tumor and the adjacent liver parenchyma.
Comparisons were made with matched patients with alcohol- and chronic-viral-hepatitis-related HCC. The prevalence of obesity (50% vs. 17% vs. 14%), diabetes (56% vs. 17% vs. 11%), aspartate aminotransferase / alanine aminotransferase ratio < 1 (50% vs. 19% vs. 17%), and steatosis > 20% (61% vs. 17% vs. 19%) was significantly higher in patients with cryptogenic liver disease than in patients with alcohol abuse and chronic viral hepatitis (P < 0.0001 for each). Well-differentiated tumors were significantly more common in patients with cryptogenic liver disease (89% vs. 64% in patients with alcohol-related HCC vs. 55% in patients with chronic viral hepatitis-related HCC, P < 0.0001).
In conclusion, the hypothesis that obesity and diabetes mellitus may be important risk factors for cryptogenic chronic liver disease in patients with HCC is supported by the analysis of surgically treated patients. Whether HCC is primarily related to obesity and diabetes mellitus or secondarily to a NAFLD-like parenchymal lesions remains to be clarified.
Discussion
The results of this study confirm that patients with HCC and an underlying liver disease of unknown origin frequently have some of the characteristic features of NAFLD as well as significant risk factors for this condition.
In our series, the low proportion of patients who are categorized as having cryptogenic liver disease among those who undergo resection for HCC (9%) was comparable to or lower than that reported by others in patients who did[3] or did not undergo surgical resection. This low proportion is likely to reflect an intensive preoperative viral screening and a thorough evaluation of alcohol use or abuse (including oriented reevaluation of all living patients) in this analysis. Thus, it is unlikely that patients categorized in the cryptogenic liver disease group in the present series had in fact an unrecognized cause, given currents information regarding risk factors for liver diseases and HCC.
Further strengthening the hypothesis that NAFLD is a risk factor for HCC is the high incidence of diabetes and obesity in the cryptogenic liver disease group as compared with the alcohol-related liver disease patients, patients who may otherwise share most of the features of NAFLD. To avoid the anticipated difficulties for differentiating the diagnosis of NAFLD from alcohol-related disorders in the present series, we included reevaluation of clinical and pathologic features in these specific groups. When possible, reinterview concerning present and past alcohol consumption was also performed.
Interestingly, patients in the cryptogenic liver disease group had a high prevalence of risk factors for NAFLD. In this group, 89% had steatosis, 56% had type II diabetes, 50% were obese, and 50% had an AST/ALT ratio < 1, suggesting that even if they did not meet all the pathological criteria for NAFLD, at the time they had end-stage liver disease, it seems likely that most of them could have a past history of NAFLD. The impact of obesity and diabetes, present in 50% and 56%, respectively, of the patients in the cryptogenic disease group, might be underestimated, since these conditions could also have been significant risk factors for the development of HCC in patients with other causes of cirrhosis. For example, 14% of our patients with chronic viral hepatitis were obese, and 11% had type II diabetes, proportions that are twice as high as those in the general French population (8% and 5%, respectively). The incidence of diabetes and obesity in alcohol-related HCC patients this study is even more striking:17% and 17%, respectively. Moreover, it must be kept in mind that only BMI at the time of resection was considered and that a past history of overweight was not taken into account, which could also contribute to an underestimation of the true impact of obesity on chronic liver disease and HCC. The finding that HCCs associated with cryptogenic liver diseases were larger and more frequently multiple raises the concern that patients in this group could have been referred later to specialized centers.
Some of the characteristic features of NAFLD, such as the presence of parenchymal inflammation, hepatocyte necrosis or ballooning degeneration, were absent in the majority of the patients with cryptogenic liver disease. This discrepancy could be anticipated in the present series in which all patients had extensive fibrosis or cirrhosis. Indeed, the development of fibrosis tends to make these pathological manifestation in patients with NAFLD disappear.
Whether the development of HCC is related to obesity and diabetes or to underlying NAFLD- related changes remains unclear. Obesity and diabetes have been shown to increase the risk of uterus, breast, colon, and pancreas malignancies.[22-26] Until recently, only three cases of HCC have been reported in NAFLD patients. Since then, four papers have specifically analyzed the occurrence of HCC in NAFLD. In these series of patients with well-documented NAFLD-related cirrhosis, the risk of HCC was estimated to be 7% to 27%. A predominance of males and well-differentiated HCC were common findings in these series.
In conclusion, this series of patients with surgical resection for cryptogenic-liver-disease-related HCC shows that these patients frequently exhibit the same risk factors as those for NAFLD. These results support the hypothesis that NAFLD is a significant risk factor for HCC. Therefore, the diagnosis of HCC might be considered in obese and/or diabetic patients with liver nodules, even if they do not have overt manifestations of chronic liver disease. Finally, features of past or present NAFLD should always be accurately assessed before labeling as occult alcohol abusers those patients who have HCC and who deny alcohol consumption.
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