Moderately increased risk of urinary stone disease in patients with biopsy-verified coeliac disease

Alimentary Pharmacology and Therapeutics Moderately increased risk of urinary stone disease in patients with biopsy-verified coeliac disease J. F. Lud...
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Alimentary Pharmacology and Therapeutics

Moderately increased risk of urinary stone disease in patients with biopsy-verified coeliac disease J. F. Ludvigsson*,†, F. Zingone‡, M. Fored†, C. Ciacci§ & M. Cirillo¶

*Department of Paediatrics, Örebro University Hospital, Örebro, Sweden. † Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. ‡ Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, Italy. § Department of Gastroenterology, University of Salerno, Salerno, Italy. ¶ Inter-Departmental Centre of Clinical Research, Federico II University, and the Unit of Nephrology, Second University of Naples, Naples, Italy.

Correspondence to: Dr J. F. Ludvigsson, Department of Paediatrics, Örebro University Hospital, Örebro, Sweden. E-mail: [email protected]

Publication data Submitted 21 October 2011 First decision 13 November 2011 Resubmitted 9 December 2011 Accepted 10 December 2011 EV Pub Online 4 January 2012

SUMMARY Background Urinary stone disease is a mal-absorptive disorder that is a significant health problem because of its high prevalence and incidence. However, there are few population-based studies on the risk of urinary stone disease in patients with coeliac disease (CD). Aim To examine the risk of urinary stone disease in CD. Methods Population-based cohort study. Using small intestinal biopsy report data from 1969 to 2008 obtained from all Swedish pathology departments (n = 28), we identified 28 735 patients with CD (equal to Marsh 3: villous atrophy). Patients were then matched for gender, age, county and calendar year to 142 177 reference individuals from the Swedish general population. We used Cox regression to estimate hazard ratios (HRs) for future urinary stone disease and conditional logistic regression to calculate odds ratios (ORs) for urinary stone disease before diagnosis of CD. Individuals with urinary stone disease were identified through the Swedish National Patient Register that contains data on inpatient care, outpatient care and day surgery. Results During follow-up, 314 individuals with CD and 1142 reference individuals developed urinary stone disease. This corresponded to a 27% increased risk of urinary stone disease in CD [95% confidence interval (CI) = 1.12–1.44]. CD patients had an absolute risk of urinary stone disease of 107/100 000 personyears (excess risk of 23/100 000). Risk estimates were similar in men and women, and did not differ according to age at CD diagnosis. Conditional logistic regression found that patients with CD were at a slightly increased risk also of prior urinary stone disease (OR = 1.19; 95% CI = 1.06–1.33). Conclusion In this study, coeliac disease was associated with a moderately increased risk of urinary stone disease both before and after coeliac disease diagnosis. Aliment Pharmacol Ther 2012; 35: 477–484

ª 2012 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2011.04968.x

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J. F. Ludvigsson et al. INTRODUCTION Urinary stone disease (USD) is a concretion or calculi (crystal aggregations) formed by dietary minerals in the urine. The lifetime risk is estimated at about 10%1 and potentially increasing.2 The total cost of USD treatment in America has been estimated to more than 2 billion US dollars per year.3 Urinary stone disease is more common in men and especially prevalent in middle age. Symptoms range from no symptoms at all to severe pain, vomiting, fever and haematuria when the stone obstructs the urinary tract. USD is not only associated with end-stage renal disease4 but also with other comorbidities.5 Coeliac disease (CD) is a lifelong immune-mediated enteropathy.6 It is triggered by gluten exposure in genetically sensitive individuals and affects 1–2% of the Western population.7 CD has been linked to a large number of disorders,8–11 including end-stage renal disease,12 and our research group recently showed that the disease also carries 30–40% excess mortality.13 Many patients with CD suffer from malabsorption (often silent),14 partly demonstrated by the lower weight of patients15 and the high prevalence of CD in patients with iron-deficiency anaemia.16 Research has shown that USD is more common in undiagnosed CD [adjusted odds ratio (OR) 4.0, 95% confidence interval (CI) 2.7–5.9],17 but less is known about the risk of future USD in patients with diagnosed CD. A recent study reported that 3/32 (9%) patients with refractory CD had USD,18 but the design of that study did not allow the authors to calculate a relative risk of USD. The main objective of the current study was therefore to estimate the relative risk of future USD in a population-based cohort of CD patients without a prior history of USD. METHODS Using the personal identity number,19 we matched nationwide data on small intestinal biopsies with the Swedish National Patient Register (containing both inpatient care and hospital outpatient care)20 to examine the risk of USD. Collection of biopsy data The exposure of this cohort study was CD based on villous atrophy (VA) according to small intestinal biopsy. We originally collected data on 351 403 biopsy reports representing 287 586 unique individuals. Details on biopsy data collection are given below. Villous atrophy (VA). We collected data on CD through computerised biopsy reports from all Swedish pathology 478

departments (n = 28). Data collection took place between October 2006 and February 2008, while the biopsies had been performed between 1969 and 2008 (Table 1). In total, we identified 29 148 individuals with CD. We defined CD as VA according to relevant SnoMed pathology codes (see Table S1 for a list of Swedish SnoMed codes translated into the international histopathology grading system by Marsh). For this study, we did not request positive CD serology for the diagnosis of CD, but earlier validation has shown that 88% of individuals with VA also had positive CD serology at the time of biopsy.21 Small intestinal biopsy has been standard procedure for the diagnosis of CD in Sweden for the past 40 years,22 and 96–100% of all Swedish gastroenterologists and paediatricians report that they perform a biopsy in >90% of persons with suspected CD. Patient chart reviews have found that for CD, the positive predictive value of a biopsy with VA is actually higher than having a CD diagnosis in the Swedish National Patient Register.23 When collecting data on VA, we also identified biopsies without villous VA [inflammation without VA (Marsh 1–2; n = 13,446) and normal mucosa (Marsh 0; n = 244 992)]. For the purpose of an earlier mortality study, only those individuals with normal mucosa, but positive CD serology at time of biopsy (N = 3736) were retained in the data set.13

Reference individuals (controls). Records of all patients undergoing biopsy (n = 46 330 of which 29 148 had CD) were then sent to Statistics Sweden for matching with controls using the Total Population Register.24 Each index individual was matched with up to five controls on age, gender, county and calendar period. To protect the integrity of individuals, the government agency Statistics Sweden replaced the personal identity numbers of all biopsied individuals and their reference individuals with serial numbers. Data were also linked to the National Patient Register based on the personal identity number. Exclusion of study participants. After matching, we excluded 174 individuals whose biopsy may have originated from the ileum. We also excluded individuals with no matched control or those who lacked a serial number from Statistics Sweden (total n = 35). In addition, 247 reference individuals were excluded because of data irregularities and another 921 reference individuals who could not be matched. The remaining individuals are identical to those in our study on mortality in CD.13 Aliment Pharmacol Ther 2012; 35: 477-484 ª 2012 Blackwell Publishing Ltd

Urinary stone disease in coeliac disease Additional exclusions are shown in Figure 1. For the purpose of our initial analyses, we excluded anyone with a diagnosis of USD prior to study entry (date of first biopsy). As each stratum consisting of one individual with CD and his or her reference individuals was analysed separately, a number of reference individuals were excluded in that their index individual with CD had been excluded. In all, this study was based on 28 735 individuals with CD and 142 177 reference individuals from the general population.

Outcome measure We defined USD according to relevant ICD (international classification of disease) codes in the Swedish National Patient Register (ICD-7: 602, ICD-8 and ICD-9: 592, ICD-10: N20-22) and the following surgery codes: 6008, 6094-96, 6245, 6263, 6267, 6270, 6291, 6292, 6360,

Table 1 | Characteristics of study participants in the main analysis of celiac disease and risk of future urinary stone disease

KAE, KAT, KBE, KBT, KCE, KCT (see Table S1 for a description of individual ICD codes).

Other covariates Type 1 diabetes mellitus. Using the National Patient Register, we identified study participants with type 1 diabetes. As the Swedish ICD 7, 8 and 9 codes made no distinction between type 1 and type 2 diabetes, in this study, we defined type 1 diabetes as having an inpatient diagnosis of diabetes before age 30 years (Table 1). Relevant ICD codes for type 1 diabetes and for autoimmune thyroid disease are listed in the Appendix. Education. We adjusted for education using seven predefined levels (from 1500 biopsy reports, they found that other diseases than CD seldom occurred in VA (0.3% of patients with VA suffered from IBD and 0.2% from Helicobacter pylori).21 Individuals with USD were identified through data from inpatients, outpatients and day-surgery patients. This procedure yields higher sensitivity than if only relying on the inpatient part of the National Patient Register.

Mechanisms In some respects, our findings are surprising. Patients with CD are often underweight,15 whereas incident USD is more common in obese individuals.28 That said, many individuals with CD gain weight just after diagnosis,17 and we found the highest risk estimates in the first year after diagnosis (HR = 1.46). In a post hoc analysis, we adjusted for BMI and smoking (another USD risk factor) in a subset of women with data from the Medical Birth Register.29 This adjustment did not affect our risk estimate. The microbial flora differs between CD patients and individuals without CD.30, 31 It is possible that the abnormal flora influences urinary oxalate excretion with negative effects on the USD risk.32 We have previously explained the positive association between untreated CD and USD through malabsorption and hyperoxaluria. That explanation may actually be valid for treated CD as well. A large proportion of individuals with CD have persistent inflammation, villous atrophy or both, not only after the first year of treatment but even 8–10 years later.33, 34 Unfortunately, we did not have data on hyperoxaluria or any other data on persistent malabsorption in our patients. Finally, we cannot rule out that the increased risk of USD seen in this study is due to surveillance bias and that patients with CD have been urged by their physicians to seek health care even for minor symptoms, whereas controls with mild USD might have failed to contact their physician. Limitations This study has some limitations that need to be addressed. We were unable to characterise our patients by degree of malabsorption, other clinical characteristics or laboratory measures (e.g. we neither had data on urinary levels of calcium, oxalate, urate, nor did we have data on the prevalence of iron and calcium deficiency). Aliment Pharmacol Ther 2012; 35: 477-484 ª 2012 Blackwell Publishing Ltd

Urinary stone disease in coeliac disease However, in a randomly selected sample of individuals with CD,21 36% suffered from diarrhoea, 35% from anaemia and 29% from weight loss/growth failure. This finding is consistent with international data on CD.35, 36 Hence, we could not estimate the risk of USD based on clinical characteristics of the patients. We were not able to examine the risk of USD in mild vs. severe CD, or in patients with refractory CD as Swedish biopsy registers do not make these distinctions . However, the lack of such data may not be a major drawback, because our previous study that included clinical data found no association between clinical signs of CD and USD.17 Only in a subset of individuals did we have data on dietary adherence (indicating low compliance in about 17% of patients with CD).21 A gluten-free diet may correct hyperoxaluria and hypocalciuria (both are associated with USD risk).17 We did not have data on stone composition or USD severity . This means that we cannot rule out that CD is a strong risk factor for certain subtypes of USDs, but not for others. Finally, the current study was based only on USD and CD necessitating health care contact (USD identified using Swedish national registers; and CD through biopsy databases). The prevalence of earlier USD in our study was 1.4% in controls aged 18–64 years. This percentage is lower than that reported in previous Swedish population-based studies, where researchers actively tried to establish the existence of USD (e.g. 5% in a study of women aged 38–60 years).37 Hence, we cannot rule out that our study may underestimate the absolute risk and the excess risk of USD in CD. We had no data on CD

that remained undiagnosed during follow-up. If these patients had a milder disease than the average patients with a diagnosed CD, our study may have overestimated the association between CD and USD.

CONCLUSION In conclusion, this study found a positive association between CD and USD before and after diagnosis of CD. On the basis of the current study, we recommend increased awareness of USD in patients with CD and vice versa, but do not encourage screening for CD in all patients with USD. ACKNOWLEDGEMENT Declaration of personal and funding interests: None. SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. A comparison of small intestinal histopathology classifications. Table S2. Risk of earlier USD according to patient characteristics. Figure S1. Log-minus-log curves show that the proportional hazards assumption is fulfilled (Green line, CD; Blue line, controls). Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

REFERENCES 1. Sakhaee K. Recent advances in the pathophysiology of nephrolithiasis. Kidney Int 2009; 75: 585–95. 2. Johnson CM, Wilson DM, O’Fallon WM, Malek RS, Kurland LT. Renal stone epidemiology: a 25-year study in Rochester, Minnesota. Kidney Int 1979; 16: 624–31. 3. Pearle MS, Calhoun EA, Curhan GC. Urologic diseases in America project: urolithiasis. J Urol 2005; 173: 848–57. 4. Rule AD, Bergstralh EJ, Melton LJ 3rd, Li X, Weaver AL, Lieske JC. Kidney stones and the risk for chronic kidney disease. Clin J Am Soc Nephrol 2009; 4: 804–11. 5. Rule AD, Roger VL, Melton LJ 3rd, et al. Kidney stones associate with increased risk for myocardial infarction. J Am Soc Nephrol 2010; 21: 1641–4. Aliment Pharmacol Ther 2012; 35: 477-484 ª 2012 Blackwell Publishing Ltd

6. Di Sabatino A, Corazza GR. Coeliac disease. Lancet 2009; 373: 1480–93. 7. Walker MM, Murray JA, Ronkainen J, et al. Detection of celiac disease and lymphocytic enteropathy by parallel serology and histopathology in a population-based study. Gastroenterology 2010; 139: 112–9. 8. Olmos M, Antelo M, Vazquez H, Smecuol E, Maurino E, Bai JC. Systematic review and meta-analysis of observational studies on the prevalence of fractures in coeliac disease. Dig Liver Dis 2008; 40: 46–53. 9. West J, Logan RF, Smith CJ, Hubbard RB, Card TR. Malignancy and mortality in people with coeliac disease: population based cohort study. BMJ 2004; 329: 716–9.

10. Elfstrom P, Granath F, Ekstrom Smedby K, et al. Risk of lymphoproliferative malignancy in relation to small intestinal histopathology among patients with celiac disease. J Natl Cancer Inst 2011; 103: 436–44. 11. Elfstrom P, Montgomery SM, Kampe O, Ekbom A, Ludvigsson JF. Risk of thyroid disease in individuals with celiac disease. J Clin Endocrinol Metab 2008; 93: 3915–21. 12. Welander A, Prutz KG, Fored M, Ludvigsson JF. Increased risk of endstage renal disease in individuals with coeliac disease. Gut 2012; 61: 64–8. 13. Ludvigsson JF, Montgomery SM, Ekbom A, Brandt L, Granath F. Smallintestinal histopathology and mortality

483

J. F. Ludvigsson et al.

14.

15.

16.

17.

18.

19.

20.

21.

484

risk in celiac disease. JAMA 2009; 302: 1171–8. Bode S, Gudmand-Hoyer E. Symptoms and haematologic features in consecutive adult coeliac patients. Scand J Gastroenterol 1996; 31: 54–60. Olen O, Montgomery SM, Marcus C, Ekbom A, Ludvigsson JF. Coeliac disease and body mass index: a study of two Swedish general population-based registers. Scand J Gastroenterol 2009; 44: 1198–206. Hin H, Bird G, Fisher P, Mahy N, Jewell D. Coeliac disease in primary care: case finding study. BMJ 1999; 318: 164–7. Ciacci C, Spagnuolo G, Tortora R, et al. Urinary stone disease in adults with celiac disease: prevalence, incidence and urinary determinants. J Urol 2008; 180: 974–9. Daum S, Ipczynski R, Schumann M, Wahnschaffe U, Zeitz M, Ullrich R. High rates of complications and substantial mortality in both types of refractory sprue. Eur J Gastroenterol Hepatol 2009; 21: 66–70. Ludvigsson JF, Otterblad-Olausson P, Pettersson BU, Ekbom A. The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research. Eur J Epidemiol 2009; 24: 659 –67. Ludvigsson JF, Andersson E, Ekbom A, et al. External review and validation of the Swedish national inpatient register. BMC Public Health 2011; 11: 450. Ludvigsson JF, Brandt L, Montgomery SM, Granath F, Ekbom A. Validation

22.

23.

24.

25.

26.

27.

28.

study of villous atrophy and small intestinal inflammation in Swedish biopsy registers. BMC Gastroenterol 2009; 9: 19. Stenhammar L, Hogberg L, Danielsson L, et al. How do Swedish paediatric clinics diagnose coeliac disease? Results of a nationwide questionnaire study. Acta Paediatr 2006; 95: 1495–7. Smedby KE, Akerman M, Hildebrand H, Glimelius B, Ekbom A, Askling J. Malignant lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma. Gut 2005; 54: 54–9. Johannesson I. The Total Population Register of Statistics Sweden. New Possibilities and Better Quality. Örebro: Statistics Sweden, 2002; 1–18. Stamatelou KK, Francis ME, Jones CA, Nyberg LM, Curhan GC. Time trends in reported prevalence of kidney stones in the United States: 1976–1994. Kidney Int 2003; 63: 1817–23. Ludvigsson JF, Brandt L, Montgomery SM. Symptoms and signs in individuals with serology positive for celiac disease but normal mucosa. BMC Gastroenterol 2009; 9: 57. Pais WP, Duerksen DR, Pettigrew NM, Bernstein CN. How many duodenal biopsy specimens are required to make a diagnosis of celiac disease? Gastrointest Endosc 2008; 67: 1082–7. Asplin JR. Obesity and urolithiasis. Adv Chronic Kidney Dis 2009; 16: 11–20.

29. Cnattingius S, Ericson A, Gunnarskog J, Kallen B. A quality study of a medical birth registry. Scand J Soc Med 1990; 18: 143–8. 30. Tjellstrom B, Stenhammar L, Hogberg L, et al. Gut microflora associated characteristics in children with celiac disease. Am J Gastroenterol 2005; 100: 2784–8. 31. Ou G, Hedberg M, Horstedt P, et al. Proximal small intestinal microbiota and identification of rod-shaped bacteria associated with childhood celiac disease. Am J Gastroenterol 2009; 104: 3058–67. 32. Lieske JC, Goldfarb DS, De Simone C, Regnier C. Use of a probiotic to decrease enteric hyperoxaluria. Kidney Int 2005; 68: 1244–9. 33. Hopper AD, Hadjivassiliou M, Hurlstone DP, et al. What is the role of serologic testing in celiac disease? A prospective, biopsy-confirmed study with economic analysis. Clin Gastroenterol Hepatol 2008; 6: 314–20. 34. Lee SK, Lo W, Memeo L, Rotterdam H, Green PH. Duodenal histology in patients with celiac disease after treatment with a gluten-free diet. Gastrointest Endosc 2003; 57: 187–91. 35. Green PH, Cellier C. Celiac disease. N Engl J Med 2007; 357: 1731–43. 36. Ciacci C, Cirillo M, Sollazzo R, Savino G, Sabbatini F, Mazzacca G. Gender and clinical presentation in adult celiac disease. Scand J Gastroenterol 1995; 30: 1077–81.

Aliment Pharmacol Ther 2012; 35: 477-484 ª 2012 Blackwell Publishing Ltd

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