Risk of HCC in Chronic HBV Patients With New Onset Diabetes
Risk of HCC in Chronic HBV Patients With New Onset Diabetes
The procedures followed were in accordance with the ethical standards of the Institutional Review Board of the Cathay General Hospital (CGH-P101056) and with the Helsinki Declaration (1964, amended most recently in 2008) of the World Medical Association. Informed consent was not obtained as the data were analysed anonymously.
National Health Insurance (NHI) program was launched in Taiwan in March, 1995. The database comprises over 99% of the 24 million residents in Taiwan. Huge amount of research papers using NHIRD have been published and the number of papers increases every year (http://w3.nhri.org.tw/nhird/talk_07.htm). NHIRD includes information on ambulatory and in-patient care, prescription drugs and medical institutions. Diagnoses are coded according to the 9th International Classification of Diseases (ICD-9; Table S1 http://onlinelibrary.wiley.com/store/10.1111/apt.13191/asset/supinfo/apt13191-sup-0003-TabS1-S2-FigLegends.doc?v=1&s=fa8351f6f6ea4748fe47c09475f4356d02e87be0). For the precision of the claim data, the Bureau of National Health Insurance (BNHI) performs expert reviews on a random sample of every 50–100 ambulatory and in-patient claims in each hospital and clinic quarterly. False reports of diagnosis yield a severe penalty from BNHI.
One million enrollees were randomly sampled by BNHI from the original claim data of NHIRD. There was no significant difference in gender (P = 0.613; http://w3.nhri.org.tw/nhird/en/Data_Subsets.html#S2) and age distribution (http://nhird.nhri.org.tw/date_cohort.htm) between the patients in the randomly sampled data and the original NHIRD. Figure 1 represents flow chart of enrolment. Chronic hepatitis B patients were identified by ICD-9 codes from 1997 to 2009. New onset diabetes was defined as a diagnosis of diabetes in the years 1999–2009 but not in the year 1997–1998. Chronic hepatitis B patients who did not have any diagnosis of diabetes from 1997 to 2009 were enrolled in the nondiabetes cohort.
(Enlarge Image)
Figure 1.
Flow chart of enrolment of chronic hepatitis B patients in new onset diabetes and nondiabetes cohort.
Hepatocellular carcinoma was defined as a diagnosis of HCC and inclusion in the Registry for Catastrophic Illness Patient Database (RCIPD), a subpart of the NHIRD. To be registered in the RCIPD, a patient should provide certificate of diagnosis from his or her physician and pathological or radiological report confirming the diagnosis of HCC, which are verified by an expert review committee.
To capture new HCC cases during the follow-up time, patients with the diagnosis of HCC before the inception point were excluded. We also excluded patients with the diagnosis of cirrhosis, either alcoholic or biliary origin. To increase the homogeneity of the study population, we excluded patients with alcoholic liver disease or hepatitis C infection. The new onset diabetes cohort and 1:1 ratio age-, gender- and inception point (onset date of diabetes)- matched nondiabetes cohort were followed up from the inception point until the development of HCC, withdrawal from insurance or December 2009.
We identified drug treatments of chronic hepatitis B patients (interferons, lamivudine, adefovir dipivoxil, telbivudine and entecavir) and drugs for diabetes by the Anatomical Therapeutic Chemical Classification System (Table S1 http://onlinelibrary.wiley.com/store/10.1111/apt.13191/asset/supinfo/apt13191-sup-0003-TabS1-S2-FigLegends.doc?v=1&s=fa8351f6f6ea4748fe47c09475f4356d02e87be0). To adjust for the effect of comorbidities, we searched co-morbid illnesses in the NHIRD to calculate the Deyo comorbidity index as a modification of the Charlson disease severity index. The index comprises 12 diagnostic categories: myocardial infarction; congestive heart failure; peripheral vascular disease; cerebrovascular disease; dementia; chronic pulmonary disease; rheumatic disease; peptic ulcer disease; hemiplegia or paraplegia; renal disease; any malignancy, including lymphoma and leukaemia, except malignant neoplasm of skin; metastatic solid tumour; and human immunodeficiency virus/AIDS. In constructing the index, we did not include mild liver disease, moderate or severe liver disease, diabetes with or without chronic complication, or malignant neoplasm of liver. The summed score for the modified Deyo comorbidity index was compared between the cohorts of chronic hepatitis B patients with new onset diabetes and those without diabetes, which was also included as a covariate in the Cox regression analysis.
The comparison of demographics and clinical characteristics between chronic hepatitis B patients with new onset diabetes and those without diabetes were analysed by χ test for dichotomous variables, and Student t-tests for continuous variables. All tests of significance were two-tailed, and a P value of less than 0.05 was considered statistically significant. The cumulative incidence of the study outcome was estimated by modified Kaplan–Meier method and Gray method, after adjusting for competing mortality, and the modified log-rank test was used to test the statistically significant different in the incidence rates of HCC between patients with new onset diabetes and those without diabetes. The risk of HCC was modelled in a Cox proportional hazards survival analysis that examined the risk associated with diabetes after adjustment for age in each incremental year, gender, hyperlipidaemia, chronic hepatitis B treatment, statins therapy, cirrhosis, comorbidity index and obesity. The sas and spss software were used for the modified Kaplan–Meier survival analysis and the Cox proportional hazards model. All analyses and graphs were performed using sas software version 9.2 (SAS Institute, Cary, NC, USA) and spss program for Windows 10.0 (SPSS Inc., Chicago, IL, USA).
Methods
Ethics Statement
The procedures followed were in accordance with the ethical standards of the Institutional Review Board of the Cathay General Hospital (CGH-P101056) and with the Helsinki Declaration (1964, amended most recently in 2008) of the World Medical Association. Informed consent was not obtained as the data were analysed anonymously.
Databases
National Health Insurance (NHI) program was launched in Taiwan in March, 1995. The database comprises over 99% of the 24 million residents in Taiwan. Huge amount of research papers using NHIRD have been published and the number of papers increases every year (http://w3.nhri.org.tw/nhird/talk_07.htm). NHIRD includes information on ambulatory and in-patient care, prescription drugs and medical institutions. Diagnoses are coded according to the 9th International Classification of Diseases (ICD-9; Table S1 http://onlinelibrary.wiley.com/store/10.1111/apt.13191/asset/supinfo/apt13191-sup-0003-TabS1-S2-FigLegends.doc?v=1&s=fa8351f6f6ea4748fe47c09475f4356d02e87be0). For the precision of the claim data, the Bureau of National Health Insurance (BNHI) performs expert reviews on a random sample of every 50–100 ambulatory and in-patient claims in each hospital and clinic quarterly. False reports of diagnosis yield a severe penalty from BNHI.
Study Population
One million enrollees were randomly sampled by BNHI from the original claim data of NHIRD. There was no significant difference in gender (P = 0.613; http://w3.nhri.org.tw/nhird/en/Data_Subsets.html#S2) and age distribution (http://nhird.nhri.org.tw/date_cohort.htm) between the patients in the randomly sampled data and the original NHIRD. Figure 1 represents flow chart of enrolment. Chronic hepatitis B patients were identified by ICD-9 codes from 1997 to 2009. New onset diabetes was defined as a diagnosis of diabetes in the years 1999–2009 but not in the year 1997–1998. Chronic hepatitis B patients who did not have any diagnosis of diabetes from 1997 to 2009 were enrolled in the nondiabetes cohort.
(Enlarge Image)
Figure 1.
Flow chart of enrolment of chronic hepatitis B patients in new onset diabetes and nondiabetes cohort.
Hepatocellular carcinoma was defined as a diagnosis of HCC and inclusion in the Registry for Catastrophic Illness Patient Database (RCIPD), a subpart of the NHIRD. To be registered in the RCIPD, a patient should provide certificate of diagnosis from his or her physician and pathological or radiological report confirming the diagnosis of HCC, which are verified by an expert review committee.
To capture new HCC cases during the follow-up time, patients with the diagnosis of HCC before the inception point were excluded. We also excluded patients with the diagnosis of cirrhosis, either alcoholic or biliary origin. To increase the homogeneity of the study population, we excluded patients with alcoholic liver disease or hepatitis C infection. The new onset diabetes cohort and 1:1 ratio age-, gender- and inception point (onset date of diabetes)- matched nondiabetes cohort were followed up from the inception point until the development of HCC, withdrawal from insurance or December 2009.
We identified drug treatments of chronic hepatitis B patients (interferons, lamivudine, adefovir dipivoxil, telbivudine and entecavir) and drugs for diabetes by the Anatomical Therapeutic Chemical Classification System (Table S1 http://onlinelibrary.wiley.com/store/10.1111/apt.13191/asset/supinfo/apt13191-sup-0003-TabS1-S2-FigLegends.doc?v=1&s=fa8351f6f6ea4748fe47c09475f4356d02e87be0). To adjust for the effect of comorbidities, we searched co-morbid illnesses in the NHIRD to calculate the Deyo comorbidity index as a modification of the Charlson disease severity index. The index comprises 12 diagnostic categories: myocardial infarction; congestive heart failure; peripheral vascular disease; cerebrovascular disease; dementia; chronic pulmonary disease; rheumatic disease; peptic ulcer disease; hemiplegia or paraplegia; renal disease; any malignancy, including lymphoma and leukaemia, except malignant neoplasm of skin; metastatic solid tumour; and human immunodeficiency virus/AIDS. In constructing the index, we did not include mild liver disease, moderate or severe liver disease, diabetes with or without chronic complication, or malignant neoplasm of liver. The summed score for the modified Deyo comorbidity index was compared between the cohorts of chronic hepatitis B patients with new onset diabetes and those without diabetes, which was also included as a covariate in the Cox regression analysis.
Statistical Analyses
The comparison of demographics and clinical characteristics between chronic hepatitis B patients with new onset diabetes and those without diabetes were analysed by χ test for dichotomous variables, and Student t-tests for continuous variables. All tests of significance were two-tailed, and a P value of less than 0.05 was considered statistically significant. The cumulative incidence of the study outcome was estimated by modified Kaplan–Meier method and Gray method, after adjusting for competing mortality, and the modified log-rank test was used to test the statistically significant different in the incidence rates of HCC between patients with new onset diabetes and those without diabetes. The risk of HCC was modelled in a Cox proportional hazards survival analysis that examined the risk associated with diabetes after adjustment for age in each incremental year, gender, hyperlipidaemia, chronic hepatitis B treatment, statins therapy, cirrhosis, comorbidity index and obesity. The sas and spss software were used for the modified Kaplan–Meier survival analysis and the Cox proportional hazards model. All analyses and graphs were performed using sas software version 9.2 (SAS Institute, Cary, NC, USA) and spss program for Windows 10.0 (SPSS Inc., Chicago, IL, USA).
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