Is diabetes a risk factor for hepatocellular carcinoma?

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GASTROENTEROLOGY Vol. 127, No. 1

endoscopic therapy might be added only in pharmacological treatment failures. GENNARO D’AMICO GIADA PIETROSI ILARIA TARANTINO Department of Medicine Ospedale V Cervello Palermo, Italy LUIGI PAGLIARO Institute of Medicina Generale e Pneumologia University of Palermo Palermo, Italy

Figure 1. Overall mortality. Cumulative odds ratio (random effects model) for trials (A) with not adequate and, respectively, (B) with adequate methodological quality. Numbers on the left of the graphs are the cumulative number of patients included in the trials. RCTs, randomized controlled trials.

trials. We showed that this trend toward benefit from sclerotherapy is exaggerated and statistically significant in poor quality trials and is abolished in good quality trials. The cumulative meta-analysis according to quality of trials (Figure 1) shows that the benefit from sclerotherapy in poor quality trials was statistically significant after the inclusion of only 294 patients and that no benefit is shown in good quality trials after the inclusion of 622 patients. These findings strongly suggest that the nonsignificant trend toward a death risk reduction with sclerotherapy found by combining all the 15 studies is more likely a distorted estimate resulting from some potential bias in several “low-quality” studies rather than a falsely negative result due to insufficient power. In accordance with the overestimation of benefit was the underestimation of adverse events associated with sclerotherapy in low quality studies, as opposed to the findings of good quality studies. The other Cochrane meta-analysis6 quoted by Triantos et al. includes 5 studies comparing somatostatin with placebo and 7 in which endoscopic therapy plus somatostatin or somatostatin analogues was compared with endoscopic therapy plus placebo and does not allow to draw conclusions on a single treatment. In this respect, Triantos et al. probably missed another Cochrane metaanalysis showing that terlipressin significantly reduces mortality when compared with placebo.7 Finally, in the trial of sclerotherapy8 quoted by Triantos et al., which they consider as the methodologically best trial of sclerotherapy, patients actively bleeding from varices at the diagnostic endoscopy, and thereafter randomized to control nonactive therapy, underwent a second endoscopy to receive sham endoscopic therapy. They were left bleeding without any active therapy until when a blinded physician considered that transfusions or vasopressin or tamponade were clinically needed: there were no study criteria for the use of these therapies. After all these considerations, remains the overall conclusion also reached by Triantos et al. (see their cumulative meta-analysis) that there is no scientific evidence supporting sclerotherapy as the first line treatment of variceal bleeding when compared with vasoactive drugs, which control bleeding in more than 80% of patients. Therefore,

1. D’Amico G, Pietrosi G, Tarantino I, Pagliaro L. Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis: a Cochrane meta-analysis. Gastroenterology 2003;124:1277– 1291. 2. Escorsell A, Ruiz del Arbol L, Planas R, Albillos A, Banares R, Cales P, Pateron D, Bernard B, Vinel JP, Bosch J. Multicenter randomized controlled trial of terlipressin versus sclerotherapy in the treatment of acute variceal bleeding: the TEST study. Hepatology 2000; 32:471– 476. 3. Sivri B, Oksuzoglu G, Bayraktar Y, Kayhan B. A prospective randomized trial from Turkey comparing octreotide versus injection sclerotherapy in acute variceal bleeding. Hepato-Gastroenterol 2000;47:166 –173. 4. El-Jackie A, Rowaisha I, Waked I, Saleh S, Abdel Ghaffar Y. Octreotide vs. sclerotherapy in the control of acute variceal bleeding in schistosomal portal hypertension: a randomized trial (abstr). Hepatology 1998;28:533. 5. Jenkins SA, Shields R, Davies M, Elias E, Turnbull AJ, Bassendine MF, James OFW, Iredale JP, Vyas SK, Arthur MJP, Kingsnorth AN, Sutton R. A multicentre randomised trial comparing octreotide and injection sclerotherapy in the management and outcome of acute variceal hemorrhage. Gut 1997;41:526 –533. 6. Gotzsche P. Somatostatin analogues for acute bleeding oesophageal varices (Cochrane Review). In: The Cochrane Library. Chichester, UK: John Willey & Sons, 2003. 7. Ioannau G, Doust J, Rockey D. Terlipressin for acute esophageal variceal hemorrhage. (Cochrane Review). In: The Cochrane Library. Chichester, UK: John Willey & Sons, 2003. 8. Hartigan PM, Gebhard RL, Gregory PB, Veterans Affair Cooperative Variceal Sclerotherapy Group. Sclerotherapy for actively bleeding oesophageal varices in male alcoholics with cirrhosis. Gastrointest Endosc 1997;46:1–7. doi:10.1053/j.gastro.2004.05.044

Is Diabetes a Risk Factor for Hepatocellular Carcinoma? Dear Sir: We have read with interest the paper entitled “Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma” by El-Serag et al. published in a recent issue of GASTROENTEROLOGY.1 It is an elegant study which enrolled a huge patient population and looked at the incidence of chronic liver disease and hepatocellular carcinoma (HCC) between patients with and without diabetes mellitus (DM). The authors demonstrated that diabetes may increase the risk of both chronic liver disease and HCC with a clear durationresponse relationship, and such an effect is independent of viral hepatitis. It is well known that hepatitis B and C virus (HBV, HCV) are major etiologies of HCC worldwide. Although patients with

July 2004

known liver disease including those with HBV or HCV infection had been pre-excluded in the sensitivity analysis, a major flaw in this study is that not all patients had been routinely surveyed for the serological markers of HBV and HCV and the exact number of patients screened for these markers were unknown. Clear information of the status of viral hepatitis is very crucial because either HBV or HCV infection could contribute to the development of subclinical hepatitis or cirrhosis, which subsequently predisposes patients to DM and increases the risk of HCC. An important mechanism that may explain why DM has a causal association with HCC is related to the ability of the analyzed risk factors and their strength in terms of inducing a specific outcome. HCV infection is common in the United States and other Western countries to serve as a major etiology of HCC. Consistent with the current study is that DM has been reported to link with tumor recurrence in HCC patients undergoing resection in a study from Japan, where HCV infection is also endemic.2 By contrast, chronic HBV infection is highly prevalent in Taiwan and is the predominant etiology of HCC. Our previous study indicated that among the Chinese patients with HCC, 75% were seropositive for HBV surface antigen (HBsAg), and 97% were seropositive for antibody to hepatitis B core antigen.3 In a large-scale prospective study from another group in Taiwan, the risk ratio for the development of HCC in HBsAg carriers was estimated to be between 9.6 to 60.2 depending on the status of hepatitis B e antigen, whereas the risk ratio among those with chronic HCV infection was estimated to be 2.7.4 These results suggest that HBV, compared with HCV, might have a higher potential to initiate hepatic malignant transformation. Interestingly, the risk ratio of HCC among diabetic patients was estimated between 2.1 to 2.4 in the current study,1 which is considered a lot lower than the risk induced by HBV but very close to that by HCV. We have shown that DM is not a risk factor for tumor recurrence in HCC patients after resection because the ability of DM to induce HCC may be masked and the predictive power is impaired in the presence of other stronger risk factors.5,6 The same mechanism could also bias the results by El-Serag et al. since a substantial portion of patients could have been infected by either virus and left undetected. Moreover, there have been evidences to indicate a tight link between DM and HCV infection.7–9 These concerns raise the possibility that diabetes is an associated but not independent covariate. Alternatively, if the proportion of infected subjects was small, the impact of viral hepatitis is minimal and DM could become a prevailing risk factor in the multivariate analysis. Collectively, DM may induce various forms of hepatic injury and could indeed predispose to HCC formation. However, the virological factor is likely to compete with DM and confound the results in risk factor analysis. The complex association between these risk factors may not be confidently disentangled unless the status of viral hepatitis is clearly known and their effect has been completely eliminated. TEH–IA HUO SHOU–DONG LEE JAW–CHING WU Department of Medicine Taipei Veterans General Hospital and National Yang-Ming University School of Medicine Taipei, Taiwan 1. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004;126:460 – 468. 2. Ikeda Y, Shimada M, Hasegawa H, Gion T, Kajiyama K, Shirabe K,

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Yanaga K, Takenaka K, Sugimachi K. Prognosis of hepatocellular carcinoma with diabetes mellitus after hepatic resection. Hepatology 1998;27:1567–1571. Lee SD, Lee FY, Wu JC, Hwang SJ, Wang SS, Lo KJ. The prevalence of anti-hepatitis C virus among Chinese patients with hepatocellular carcinoma. Cancer 1992;69:342–345. Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, Hsiao CK, Chen PJ, Chen DS, Chen CJ. Taiwan Community-Based Cancer Screening Project Group. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002;347:168 –174. Huo TI, Wu JC, Lui WY, Lee PC, Huang YH, Chau GY, Tsay SH, Chang FY, Lee SD. Diabetes mellitus is a recurrence-independent risk factor in patients with hepatitis B virus-related hepatocellular carcinoma undergoing resection. Eur J Gastroenterol Hepatol 2003;15:1203–1208. Huo TI, Wu JC, Lui WY, Huang YH, Lee PC, Chiang JH, Chang FY, Lee SD. Differential mechanism and prognostic impact of diabetes mellitus on patients with hepatocellular carcinoma undergoing surgical and non-surgical treatment: the lexical effect. Am J Gastroenterol 2004 (in press). Wang CS, Wang ST, Yao WJ, Chang TT, Chou P. Community-based study of hepatitis C virus infection and type 2 diabetes: an association affected by age and hepatitis severity status. Am J Epidemiol 2003;158:1154 –1160. Mehta SH, Brancati FL, Strathdee SA, Pankow JS, Netski D, Coresh J, Szklo M, Thomas DL. Hepatitis C virus infection and incident type 2 diabetes. Hepatology 2003;38:50 –56. Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000;133:592–599. doi:10.1053/j.gastro.2004.05.045

Reply. We agree with Dr. Huo that the major challenge to a causal association between diabetes and liver disease is that diabetes could be a result of pre-existing severe liver disease. Several case control studies found a statistically significant positive association between diabetes and hepatocellular carcinoma (HCC). However, it remained unclear whether diabetes preceded the development of significant chronic liver disease and HCC. Therefore, we made several important steps to ensure that diabetes has preceded the development of chronic nonalcoholic liver disease (CNLD), or HCC, and therefore increase the probability of capturing only new (incident) cases of chronic liver disease and HCC. In this study, we excluded patients with acute or chronic liver disease due to any cause recorded during the index hospitalization, during any previous hospitalization dating back to 1980, or during the first year that followed their index hospitalization. This lead to excluding approximately 20% of the initial cohort. We also examined the findings after excluding patients with new diagnoses of HCV, hepatitis B, alcohol use, alcoholic liver disease, or fatty liver recorded after the first-year of follow-up. This led to further exclusion of 3.2% of the remaining cohort. It is therefore unlikely that a large number of patients with significant liver disease escaped over the course of at least one hospitalization. Importantly, these exclusions resulted in no effect on the relative risk of diabetes for HCC and a slight increase in the relative risk for CNLD from 1.98 to 2.13. Given that exclusion of known cases of viral hepatitis did not meaningfully affect the results, it seems unlikely that exclusion of a small number of additional cases would have had appreciable effects. Lastly, we examined the risk of CNLD and HCC in a subset of patients in whom these events were recorded after at least 10 years of follow up, and found more than a 2-fold increase in the risk of CNLD or HCC.1 These steps make it

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