Manuscript ID: CAS-OA-1045-2013
Old title: Increased Risk of a Cancer Diagnosis After Early-Onset Cataract: A Nationwide Population-Based Study
New title: Increased Risk of Cancer in Patients with Early-Onset Cataract: A Nationwide Population-Based Study
Chiang Chun Chi, MD,1,2 Cheng-Li Lin, MS,3,4 Chiao-Ling Peng, MS,3,4 Fung-Chang Sung, PhD, MPH,3,4,** Yi-Yu Tsai, MD, PhD1,2,*
1Division of Ophthalmology, China Medical University Hospital, Taichung 404, Taiwan 2School of Medicine, China Medical University College of Medicine, Taichung 404, Taiwan
3Management Office for Health Data, China Medical University Hospital, Taichung 404, Taiwan
4Department of Public Health, China Medical University College of Public Health, Taichung 404, Taiwan
*Corresponding author: Yi-Yu Tsai, MD, PhD; Division of Ophthalmology, China Medical University Hospital, 2 Yuh-Der Road, Taichung 404, Taiwan. Tel.: +886 4 22052121x1141; E-mail: [email protected]
**Co-corresponding author: Fung-Chang Sung, PhD, MPH; Department of Public Health, China Medical University College of Public Health, 91 Hsueh Shih Road, Taichung 404, Taiwan. Tel.: +886 4 2206-2295; E-mail: [email protected] Running Title: Cancer and Early-Onset Cataract
Abstract
Early-onset cataract has been associated with insufficient antioxidative activity, with a potential risk of cancer. This study was to investigate the risk of cancer after being diagnosed with early-onset cataract. Retrospective claims data from the Taiwan National Health Insurance Research Database (NHIRD) were analyzed. Study subjects were comprised of patients with early-onset cataract, aged 20-55 years [International
Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code 366.00, 366.01, 366.02, 366.03, 366.04, 366.09, 366.17, and 366.18] newly diagnosed from 1997 to 2010 (N = 1281), and a comparison cohort without the disorder (N = 5124). Both cohorts were followed up until 2010 to estimate the incidences of cancer. We used the Poisson regression model to compare incidence rate ratios and the 95% confidence interval (CI). Cox proportional hazards regression was used to assess the hazard ratio (HR) of cancer associated with early-onset cataract The overall incidence rate of all cancers was 2.19-fold higher in the early-onset cataract cohort than in the comparison cohort (8.06 vs 3.68 per 1000 person-years) with an adjusted HR of 2.13 (95% CI = 1.48, 3.07). The site specific analysis also showed strong relationship with adjusted HRs of 3.24 ((95% CI = 1.30, 8.10) for head and neck cancer, 3.29 (95% CI 1.16, 9.31) for hepatoma, and 3.19 (95% CI 1.34, 7.58) for breast cancer. This study suggests that patients with early-onset cataract are at an increased risk of being diagnosed with cancer in subsequent years.
Introduction
Cataract is a common cause of reduced visual transparency in elderly patients, associated with decreased metabolic transport of antioxidants in the aging lens.1 The oxidation of nuclear components is increasing in the lens during normal aging and the lens continues to grow lens fibers, reducing transparency. The activities of antioxidant enzymes, such as glutathione
peroxidase, may be reduced in older adults for metabolizing oxidants, such as hydrogen peroxide (H2O2).2 The oxidative damage may start in the nucleus of the lens because of the lowest
metabolic activities; the modified proteins susceptible to oxidation are accumulate with age.3 Changes in other parts of the lens may occur to varying degrees, including the cortical and posterior subcapsular parts.1
Age-related cataract usually occurs in patients older than 60 years,4 some patients experience cataracts under the age of 55. One of the causes of early-onset cataract might relate to an insufficient antioxidative function. Cancer is another disease associated with oxidative stress. The production of reactive oxygen species (ROS) plays important roles in genomic instability and uncontrolled cell proliferation. 5. The overproduction of ROS and faulty antioxidant and DNA repair lead to oxidative damage to cellular
macromolecules and contribute to carcinogenesis. Because the 2 diseases have a similar mechanism, this study investigated whether patients with early-onset cataract are at the risk of subsequent cancer diagnosis in the following years, using a nationwide
Methods Data Sources
This study was designed as a population-based retrospective cohort study to investigate the relationship between having been prescribed early-onset cataract and the occurrence of cancer. All datasets were obtained from the reimbursement database of the Taiwan National Health Insurance (NHI), a single-payer universal insurance system. This insurance system has covered more than 99% of 23.74 million citizens in Taiwan. (Bureau of National Health Insurance. Department of Health, Executive Yuan, Taiwan.
http://www.nhi.gov.tw/english/index.aspx.) In this study, we used the claims data of the Longitudinal Health Insurance Database 2000 (LHID2000) established by the National Health Research Institutes (NHRI), Department of Health, Taiwan. There were no statistically significant differences in the distribution of sex, age or health care costs between cohorts in LHID2000 and all insurance enrollees, as reported by the NHRI in Taiwan. Data files were linked with the identifications of patients that had been anonymized, with identification numbers encrypted, and maintained in the NHI
reimbursement data, to protect the privacy of the individuals. The comprehensive claim files provided information on the registry of medical facilities, details of inpatient orders, types of ambulatory care, socio-demographic status of each insured, and health-care services each patient received, including all payments. The data for each outpatient visit or hospitalization contained up to 5 diagnoses that were coded according to the
International Classification of Diseases, Ninth 9th Revision Clinical Modification (ICD-9-CM) classification.
Ethics Statement
Using retrospective cohort study design, this study was approved by the ethics review committee at the China Medical University and Hospital. The consent was not obtained, which was waived by the approving ethical review.
Study participants
We identified 1281 patients aged 20 to 55 years with newly diagnosed early-onset cataract (ICD-9-CM codes 366.00, 366.01, 366.02, 366.03, 366.04, 366.09, 366.17, and 366.18) from 1997 to 2010 with at least 3 claims for outpatient and/or hospitalization visits as the study cohort by using the diagnosed date as the index date. The juvenile infantile cataract and traumatic cataract were excluded. The index date for the patient was the date of the first outpatient visit for early-onset cataract. We used a systematic random sampling method to select a comparison cohort from the rest of the insured population that was free from early-onset cataract and cancer; the frequency was randomly matched by age (every 5 years), sex, and the year of the index date.
Outcome definition
To identify subjects with cancer outcome for this study, we obtained the Registry of Catastrophic Illness Patient Database (RCIPD) for all patients who were diagnosed with cancer from January 1, 1997 to December 31, 2010. Any of the diagnoses of cancer except metastatic (ICD-9-CM codes 140-195 and 200-208) made by doctors and officials of the NHI system was considered an acceptable code. We then excluded patients aged less than 20 years and who were diagnosed with any type of cancer (ICD-9-CM codes 140-208) before the index date. Nine groups of cancer were evaluated, including head
and neck cancer (ICD-9-CM codes 140-149), colon cancer (codes 153-154), hepatoma (codes 155), breast cancer (code 174), uterus cancer (codes 180-184), bladder cancer (codes 188), kidney cancer (codes 189), thyroid cancer (codes 193) and others.
Comorbidities of interest
In addition, we measured patients with at least 3 claims for outpatient visits or hospitalization visits at the baseline by the principal and secondary diagnoses for diseases considered possible co-morbidities associated with cancer. Based on ICD-9-CM codes, diseases included were hypertension (codes 401 to 405), diabetes mellitus (code 250), and hyperlipidemia (code 272), stroke (codes 430 to 438), ischemic heart disease (codes 410 to 414), asthma (code 493) and chronic obstructive pulmonary disease (COPD) (codes 490 to 496) and alcohol-related illness (including alcoholic psychoses (code 291), alcohol dependence syndrome (code 303), alcohol abuse (code 305), alcoholic fatty liver (code 571.0), acute alcoholic hepatitis (code 571.1), alcoholic cirrhosis (code 571.2) and alcoholic liver damage (code 571.3).
Statistical Analysis
The distributions of the categorical socio-demographic characteristics and comorbidities were compared between the study cohort and the comparison cohort, and the differences were examined using the Chi-square test. Subjects with stratified age groups between 20-35 years, 36-45 years, and 46-55 years at the index date of early-onset cataract were analyzed. The person-years of follow-up time were calculated for each patient until cancer was diagnosed or censored. The follow-up person-years were calculated to assess the incidence density rates. We used the Poisson regression model to
assess the study cohort to compare cohort incidence rate ratios (IRR) and the 95% confidence interval (CI). Cox proportional hazards regression analysis was used to assess the cancer risk associated with early-onset cataract by adjusting for cofactors significantly related to early-onset cataract. All analyses were performed using the SAS statistical package (version 9.1 for Windows; SAS institute, Inc., Cary, NC, USA). A two-tailed P value of less than 0.05 indicated the statistical significance level.
Results
Socio-demographic characteristics data are shown in Table 1. No significant differences in distributions of age and sex were found between the early-onset cataract cohort and the comparison cohort. There were more women than men and near two-thirds of the patients aged 46 years to 55 years in both cohort (mean age approximately 46.2 ± 7.4 y). The early-onset cataract cohort had higher prevalences of hypertension, diabetes mellitus, hyperlipidemia, stroke, ischemic heart disease, asthma, chronic obstructive pulmonary disease and alcohol-related illnesses (P < 0.05).
The incidence rate and adjusted hazard ratio (HR) among the early-onset cataract cohort and the comparison cohort is shown in Table 2. The overall incidence rate of all cancer was 2.19-fold higher in the early-onset cataract cohort than in the comparison cohort (8.06 vs 3.68 per 1000 person-years) with an adjusted HR of 2.13 (95% CI = 1.48-3.07). In the early-onset cataract cohort, the incidence of cancer was higher in women than in men. Compared with comparison cohort, the adjusted HR of cancer in the early-onset cataract cohort was also higher for women than men. The incidence increased with
age, with the age-specific adjusted HR of cancer significant only for the early-onset cataract cohort aged 46-55 years (adjusted HR = 2.14, 95% CI = 1.41–3.25). Patients with comorbidities of diabetes, hyperlipidemia, stroke, ischemic heart disease, COPD or alcohol-related illnesses had an increased cancer incidence. However, the early-onset cataract patients without comorbidities were more likely to have significant adjusted HR of cancer.
Furthermore, Table 3 presents the site-specific analysis of cancer risks between the study and comparison cohorts. Compared to the comparison group, half (25 cases) of all cancer occurrence events were higher for head and neck cancer, hepatoma, and breast cancer, with adjusted HRs of 3.24 (95% CI = 1.30–8.10), 3.29 (95% CI = 1.16-9.31) and 3.19 (95% CI = 1.34-7.58), respectively, for patients with early-onset cataract.
Kaplan-Meier analysis showed that patients with early-onset cataract had significantly higher cumulative incidence rate for all cancers than the comparisons did (8.13 vs. 3.90) by the end of 12-year follow-up, especially for head and neck cancer (1.07 vs. 0.39%), hepatoma (1.25 vs. 0.36%), and breast cancer (1.59 vs. 0.39%) (Figure 1).
Discussion
Cataract is a common disorder in older population, while the early-onset cataract is rare for younger population. No previous study has reported the relationship between early-onset cataract and the risk of cancer. The present retrospective cohort study found the cancer risk was more than 2-fold greater for patients with early-onset cataract than for general population, particularly for neck cancer, hepatoma, and breast cancer. This finding is important for patients with early-onset cataract, although the mechanism of
developing cancer deserves explore.
The association with comorbidities revealed that subjects with diabetes and hyperlipidemia had a higher risk of developing cancer compared to the comparison group, with adjusted HR of 2.71 (95% CI = 1.09–6.75) and 2.51 (95% CI = 1.12–5.64), respectively. This finding is consistent with other epidemiological study findings.6,7 Forte et al. found that diabetes and obesity are inextricably linked, associating with an
increased incidence of solid tissue cancers.6 Chen et al. found a 2-fold to 3-fold increase in the risk of hepatoma in patients with diabetes. Diabetes and obesity have synergistic effects with hepatitis B or C, leading the risk to more than100-fold.7
Patients with metabolic syndrome have a constellation of problems, including obesity, dyslipidemia, diabetes, and insulin resistance.8 Among Western studies, the Australians Blue Mountain Eye Study has shown that the metabolic syndrome is associated with all 3 types of cataracts (nuclear, cortical, and posterior subcapsular cataracts) in a cohort of the elderly.9 An European study also reported an increased odds of cataracts for middle-aged women with arterial pressure, central obesity, and higher trigl.10 may advance the
formation of glycation of lens proteins and the hyperosmotic effects of sorbitol on lens fibers formed through the aldose reductase pathway.11 Although the mechanism linking hyperlipidemia and cataract is unclear, certain pathophysiological mechanisms have been proposed. Leptin, secreted mainly by adipocytes, is a cytokine also has been involved in the cataract formation.12 People with hyperlipidemia are likely to have hyperleptinemia and leptin resistance.13 Thus, hyperlipidemia may promote cataract formation.
metabolic syndrome components and their combination could increase risk of cataract extraction.14 Consequently, controlling metabolic syndrome and its components, is considered vital for preventing early-onset cataract.
In addition to metabolic syndrome, several possible mechanisms exist for the
association between early-onset cataract and cancer, including inflammation, ROS, and genetic factors. ROS alters gene expression patterns and contributes to the carcinogenesis process through oxidative stress in cancer-associated fibroblasts.5,15-19 The ROS effect on the oxidative damage to lens proteins may result in lens opacification.3 Although, oxidative stress associated with UV light has been constantly considered with a central role to the pathogenesis of cataracts.20-22 Therefore, if the antioxidative function is
deficient at younger ages, early-onset cataract may occur because of oxidatively damaged DNA unrepaired, leading to a higher cancer susceptibility for younger adults.
Another possible link between early-onset cataract and cancer is genetic factors, relating to genetic polymorphisms, occurring in the general population for genes involved in a predisposition to carcinogenesis or cataractogenesis.23-26 Among the several cancer related polymorphic genes encoding for enzymes involved in free radical metabolism, the glutathione S-transferase (GST) gene system is one of the most well-known.27,28 Saadat et al. has found an odds ratio of 1.51 (p = 0.045) for cataract in subjects with the null genotype of GSTM1.26 GSTs are the family of phase II isoenzymes that protect against endogenous oxidative stress and exogenous potential toxins. They detoxify a variety of electrophilic compounds, generated by ROS damage to intracellular molecules.29 UV light, chronic inflammation, hepatitis B, and hepatitis C are all sources of ROS.30 The polymorphisms of GSTM1, GSTT1, GSTP1, and GSTO2 have been associated with the
risk of various cancers such as breast cancer, hepatoma, and skin carcinoma.30-32 This may explain our results that the early-onset cataract cohort had significantly higher risk in all cancers, especially head and neck cancer, hepatoma, and breast cancer, than the
comparison cohort. Hence, the polymorphism of GST may be a possible link between early-onset cataract and carcinogenesis.
Our study has a few limitations. First, diagnoses of early-onset cataract, cancer, and other comorbid medical conditions are identified completely dependent on ICD codes. However, the NHI Bureau of Taiwan has established a mechanism to interview patients and reviews medical charts to verify the diagnosis validity and quality of care. The hospital received heavy penalties by the NHI Bureau when discrepancies, overcharges, and malpractice are discovered. To ensure the validity of the early-onset cataract diagnosis in this study, we ensured that all of the study cohort patients had at least 3 consensus diagnoses of early-onset cataract. Second, a small number of patients may have undetected early-onset cataract and would have been categorized as non-early-onset cataract, and consequently, might have had a small chance of being selected as part of the comparison cohort. However, the sample sizes of both groups are large to contain the selection bias. In our study, patients with early-onset cataract showed a significantly higher risk of cancer development. Further studies are deserved to confirm this
association and the mechanism involved. Third, the early-onset cataract cohort is more prevalent with a history of hypertension, diabetes mellitus, and hyperlipidemia. They were more likely to see a doctor and this might cause detection bias due to frequent examinations. Fourth, information on established risk factors of cancer, such as cigarette smoking, alcohol consumption, dietary habits and family history are not available in the
claims data. To minimize confounding from these factors, we have included in the data analysis with smoking related disorders such as stroke, ischemic heart disease COPD and asthma, and alcohol related illnesses for adjustment. The over all measured adjusted cancer risk associated with changed little from the crude risk. In addition less than 5% women are smoker in Taiwan, the cancer risk associated with early onset cataract was greater for women than for men.
In conclusion, this population-based study has demonstrated that early-onset cataract is a significant predictor for subsequent cancer diagnosis after adjusting for possible confounding factors. Further studies should be conducted to see if our data can be replicated and help clarify the underlying pathophysiological mechanisms of early-onset cataract and their associations with cancer development.
Acknowledgements
Support was provided in part by the National Sciences Council, Executive Yuan (grant numbers SC99-2621-M-039-001), China Medical University Hospital (grant number 1MS1, DMR-103-065 and DMR-103-067), Taiwan Department of Health Clinical Trial and Research Center for Excellence (grant number DOH101-TD-B-111-004), and Cancer Research Center of Excellence (DOH101-TD-C-111-005).
Disclosure statement Financial Support None
There is no conflicting relationship exists for any author
Conflicts of interest
References
1. Truscott RJ. Age-related nuclear cataract: a lens transport problem. Ophthalmic Res. 2000;32:185-94.
2. Spector A. Oxidation and aspects of ocular pathology. J CLAO 1990;16:S8-10 3. Augusteyn RC. Protein modification in cataract: possible oxidative mechanisms. In:
Duncan G, editor. Mechanisms of cataract formation in the human lens. London: Academic Press; 1981, p.72-111
4. Tsai SY, Hsu WM, Cheng CY, et al. Epidemiologic study of age-related cataracts among an elderly Chinese population in Shih-Pai, Taiwan. Ophthalmology. 2003;110:1089-95.
5. Klaunig JE, Kamendulis LM, Hocevar BA. Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol. 2010;38:96-109.
6. Forte V, Pandey A, Abdelmessih R, et al. Obesity, Diabetes, the Cardiorenal Syndrome, and Risk for Cancer. Cardiorenal Med. 2012;2:143-162.
7. Chen CL, Yang HI, Yang WS, et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology. 2008; 135: 111-121.
8. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006; 43: S99-S112
9. Tan JS, Wang JJ, Mitchell P. Influence of diabetes and cardiovascular disease on the long term incidence of cataract: The Blue Mountains eye study. Ophthalmic Epidemiol
10. Paunksnis A, Bojarskiene F, Cimbalas A, et al. Relationship between cataract and metabolic syndrome and its components. Eur J Ophthalmol 2007;17:605-14. 11. Stitt AW. Advanced glycation: An important pathological event in diabetic and
age related ocular disease. Br J Ophthalmol 2001;85:746-53.
12. Gomez-Ambrosi J, Salvador J, Fruhbeck G. Is hyperleptinemia involved in the development of age related lens opacities? Am J Clin Nutr 2004;79:888-9.
13. Narin F, Atabek ME, Karakukcu M, et al. The association of plasma homocysteine levels with serum leptin and apolipoprotein B levels in childhood obesity. Ann Saudi Med 2005;25:209-14.
14. Lindblad BE, Hakansson N, Philipson B, Wolk A. Metabolic syndrome
components in relation to risk of cataract extraction: A prospective cohort study of women. Ophthalmology 2008;115:1687-92.
15. Balliet RM, Capparelli C, Guido C, et al. Mitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth: understanding the aging and cancer connection. Cell Cycle. 2011;10:4065-73.
16. Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, et al. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle. 2010;9:3256-76.
17. Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, et al.
in situ: visualizing the therapeutic effects of metformin in tumor tissue. Cell Cycle. 2011;10:4047-64
18. Pavlides S, Tsirigos A, Vera I, et al. Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the "reverse Warburg effect": a transcriptional informatics analysis with validation. Cell Cycle. 2010;9:2201-19.
19. Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, et al. Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle. 2011;10:1772-83. 20. Ayala MN, Michael R, Soderberg PG. In vivo cataract after repeated exposure to
ultraviolet radiation. Exp Eye Res 2000;70:451–6.
21. Ayala MN, Michael R, Soderberg PG. Influence of exposure time for UV radiation-induced cataract. Invest Ophthalmol Vis Sci 2000;41: 3539–43. 22. West SK, Longstreth JD, Munoz BE, et al. Model of risk of cortical cataract in
theUSpopulation with exposure to increased ultraviolet radiation due to stratospheric ozone depletion. Am J Epidemiol 2005;162:1080–8. 23. Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev
Pharmacol Toxicol 2005;45:51-88.
24. Landi S. Mammalian class theta GST and differential susceptibility to carcinogens: a review. Mutat Res 2000;463:247-83.
25. Salama SA, Abdel-Rahman SZ, Sierra-Torres CH, et al. Role of polymorphic GSTM1 and GSTT1 genotypes on NNK-induced genotoxicity. Pharmacogenetics 1999;9:735-43.
26. Saadat I, Ahmadi Z, Farvardin-Jahromi M, Saadat M. Association between cataract and genetic polymorphisms of GSTM1, GSTT1, and GSTO2 with respect of work place. Mol Vis. 2012;18:1996-2000
27. Mannervik B. The isozymes of glutathione S-transferase. Adv Enzymol 1985; 57: 357-417.
28. Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000; 343: 78-85.
29. Vineis P. Cancer as an evolutionary process at the cell level: an epidemiological perspective. Carcinogenesis 2003; 24: 1-6.
30. White DL, Li D, Nurgalieva Z, El-Serag HB. Genetic variants of glutathione S-transferase as possible risk factors for hepatocellular carcinoma: a HuGE systematic review and meta-analysis. Am J Epidemiol. 2008;167:377-89. 31. Sohail A, Kanwal N, Ali M, et al. Effects of glutathione-S-transferase
polymorphisms on the risk of breast cancer: A population-based case-control study in Pakistan. Environ Toxicol Pharmacol. 2013;35:143-53.
32. Leite JL, Morari EC, Granja F, et al. Influence of the glutathione s-transferase gene polymorphisms on the susceptibility to basal cell skin carcinoma. Rev Med Chil. 2007;135:301-6.
Figure legend:
Figure 1. Cumulative incidences of compared between early-onset cataract cohort and comparison cohort for (A) all cancers, (B) head and neck cancer, (C) hepatoma, and (D) breast cancer.
