Published online Aug 24, 2024. doi: 10.5306/wjco.v15.i8.1048
Revised: June 10, 2024
Accepted: June 27, 2024
Published online: August 24, 2024
Processing time: 146 Days and 19.1 Hours
Celiac disease (CeD) is an autoimmune disorder triggered by the immune res
To investigate the prevalence of MN in hospitalized CeD patients in the United States.
Using data from the National Inpatient Sample spanning two decades, from January 2000 to December 2019, we identified 529842 CeD patients, of which 78128 (14.75%) had MN. Propensity score matching, based on age, sex, race, and calendar year, was employed to compare CeD patients with the general non-CeD population at a 1:1 ratio.
Positive associations were observed for several malignancies, including small intestine, lymphoma, nonmelanoma skin, liver, melanoma skin, pancreas myelodysplastic syndrome, biliary, stomach, and other neuroendocrine tumors (excluding small and large intestine malignant carcinoid), leukemia, uterus, and testis. Conversely, CeD patients exhibited a reduced risk of respiratory and secondary malignancies. Moreover, certain malignancies showed null associations with CeD, including head and neck, nervous system, esophagus, colorectal, anus, breast, malignant carcinoids, bone and connective tissues, myeloma, cervix, and ovary cancers.
Our study is unique in highlighting the detailed results of positive, negative, or null associations between different hematologic and solid malignancies and CeD. Furthermore, it offers insights into evolving trends in CeD hospital outcomes, shedding light on advancements in its management over the past two decades. These findings contribute valuable information to the understanding of CeD’s impact on health and healthcare utilization.
Core Tip: This study from National Inpatient Sample database presents one of the largest studied cohort of celiac disease (CeD) and present significant insights into the association between CeD and various malignancies, including gastrointestinal, genitourinary, hematologic, and gynecologic cancers. Interestingly, CeD patients exhibit a reduced risk of respiratory malignancies. Variations in hospital outcomes, such as length of stay, cost of care, and inpatient mortality, highlight the complex relationship between CeD and malignancies. The study underscores the importance of recognizing this relationship, emphasizing the need for vigilant screening in CeD patients, particularly for specific malignancies like small intestine, lymphoma, and skin cancers. These findings contribute to refining CeD management and understanding broader healthcare trends over two decades.
- Citation: Haider MB, Al Sbihi A, Reddy SN, Green P. Prevalence of malignant neoplasms in celiac disease patients - a nationwide United States population-based study. World J Clin Oncol 2024; 15(8): 1048-1060
- URL: https://www.wjgnet.com/2218-4333/full/v15/i8/1048.htm
- DOI: https://dx.doi.org/10.5306/wjco.v15.i8.1048
Celiac disease (CeD) is an autoimmune, inflammatory condition developed in genetically predisposed individuals due to the immune response to the gluten component of wheat[1]. The most recent global prevalence of CeD is 1.4% based on serological markers and 0.7% confirmed through histological examination[2]. This disease is characterized by the presence of specific autoantibodies in the bloodstream and distinct pathological changes in the small intestine, including villous atrophy, crypt hypertrophy, and an increase in intraepithelial lymphocytes[3]. What sets CeD apart is that by avoiding gluten, its progression can be halted, and mucosal damage can even be reversed[4].
Individuals with CeD are at an elevated risk of developing other autoimmune conditions, such as autoimmune thyroiditis, type 1 diabetes mellitus, Addison’s disease, and various other disorders[5]. Furthermore, there is a well-established heightened risk of malignancies among CeD patients. Recent research has shown that CeD increases the likelihood of developing specific cancers, including gastrointestinal, lymphomas, skin cancers, and others[6,7]. Studies have indicated that the risk of cancer is most pronounced within the first year after diagnosis and subsequently decreases, likely due to better adherence to a gluten-free diet. Therefore, early diagnosis and gluten avoidance may reduce the risk of such complications[8,9].
Geographic differences in the occurrence of malignancies among individuals with CeD have been observed[10]. However, there is a lack of population-based studies on the connection between CeD and cancer in the United States. In this study, we investigate the prevalence of malignant neoplasms (MN) in CeD patients admitted to hospitals in the United States. We analyze the significance of the association between MN and CeD, categorized by the type of cancer, using a national inpatient database comprising 529842 CeD patients. The second part of our research explores hospital outcomes, including detailed mortality data, length of hospital stays, and the cost of care in CeD patients both with and without MN.
We employed data from the National (Nationwide) Inpatient Sample (NIS) database spanning a two-decade period from January 2000 to December 2019. The NIS is an integral component of the Healthcare Cost and Utilization Project (HCUP), a collaborative initiative established through a Federal-State partnership and financially supported by the Agency for Healthcare Research and Quality (AHRQ). This database stands as the most extensive publicly accessible repository of inpatient care information, encompassing over seven million hospital admissions and representing a 20% stratified sample of all hospital discharges across the United States[11].
Within this dataset, a comprehensive array of patient demographic details, clinical information (including diagnoses and procedure codes), and data pertaining to hospital utilization and outcomes are included. The diagnostic coding system employed in the dataset adhered to the International Classification of Diseases, 9th Edition (ICD-9) until the third quarter of 2015, after which it transitioned to the ICD-10 system in September 2015[12]. Importantly, it is noteworthy that HCUP databases align with the definition of limited datasets, and in accordance with the Health Insurance Portability and Accountability Act, no International Review Board review is necessitated for limited datasets[13].
Patient and hospital characteristics, along with outcomes and resource utilization data, were retrieved from the NIS database using ICD codes (see Supplementary Table 1). Individuals who were admitted with either the primary or secondary diagnosis of CeD, as indicated by ICD-9 code 579.0 or ICD-10 code K90.0, were included in the case group. The case group underwent matching, aligning with individuals from the non-CeD general population in a 1:1 ratio based on age, sex, race, and calendar year, utilizing the nearest neighbor propensity score method. Detailed information about the progression of cases and controls to compare the prevalence of MN is shown in Figure 1.
Additionally, we conducted a comparison of hospital outcomes between individuals with MN who had CeD and those without it. The group without CeD but with MN was carefully chosen from the general population, employing a 1:1 nearest neighbor propensity score matching technique based on age, sex, race, calendar year, and precise matching regarding the type of malignant neoplasm. Figure 2 provides a visual representation of the process outlining the development of cohorts with and without CeD in the context of MN.
We conducted a comparison of the occurrence of MN in individuals with CeD, referred to as cases, against a matched group without CeD, referred to as controls. We examined the demographic characteristics of CeD patients, including age, sex, race, and socioeconomic status, in the context of the presence or absence of MN. The NIS dataset included socioeconomic status information, which was categorized by dividing the median household income in the patient’s zip code into quartiles for each year.
Furthermore, we conducted a comparison of hospital-related outcomes among individuals with CeD who had MN and matched them against those without CeD. The matching process was based on age, sex, race, year, and the specific profile of MN. We assessed various aspects of hospital outcomes, which encompassed inpatient mortality, the length of hospital stays, and the overall charges incurred. To ensure accuracy, the total cost of care was adjusted using the Consumer Price Index from the United States Bureau of Labor Statistics[14].
Data processing was conducted using R (Studio 1.4), and statistical analyses were performed using SAS (SAS Institute, Cary, NC, United States). We executed one-to-one propensity score matching employing the “Matchit” package in R, employing nearest neighbor and exact matching techniques. Nominal variables were presented using frequency distributions, while continuous variables were summarized with means and standard deviations.
To compare the prevalence of MN in CeD patients with and without CeD, we utilized the χ2 test. Group comparisons of continuous variables were carried out using the Student t-test and the Rao-Scott χ2 test, accounting for the weighted sample in the analysis. We adhered to the year-specific AHRQ recommendations and adjusted the weights for years up to 2012[15]. Age was categorized into five groups for group-level comparisons: < 18; 18-49; 49-59; 59-69; and ≥ 70 years. In instances where race and socioeconomic status data were missing, they were categorized as “other”.
For assessing temporal trends, we employed the Cochran-Armitage trend test for nominal variables and Poisson regression with a log link for continuous variables. Outliers and missing values in the length of stay (LOS) and total charges were excluded from the hospital outcomes analysis. Hypothesis testing was conducted with a two-tailed approach, and statistical significance was established at a P value < 0.05.
The baseline characteristics of the CeD patients with and without MN are shown in Table 1. We found 529842 CeD patients from January 2000 to December 2019 in weighted NIS, of which 78128 (14.75%) had MN. Among the CeD patients, those who had MN were older, with a mean age of 68 (± 16) years as compared to a mean age of 53 (± 22) years in CeD without MN with P value < 0.0001, more males (36% among CeD with MN vs 28% among CeD without MN) than females (64% among CeD with MN vs 72% among CeD without MN) with P value < 0.0001, frequent in the Caucasian race (84% among CeD with MN vs 79% among CeD without MN) than African American race (1.90% among CeD with MN vs 2.96% among CeD without MN) with P value < 0.0001.
| Overall CeD patients | CeD without MN, weighted, n (%) | CeD with MN, weighted, n (%) | P value | |
| Weighted total | 529842 | 451714 (85.25) | 78128 (14.75) | |
| Sex | < 0.00012 | |||
| Female | 374102 (70.61) | 323904 (71.70) | 50199 (64.25) | |
| Male | 155739 (29.39) | 127810 (28.30) | 27929 (35.75) | |
| Age (year), mean ± SD | 55.34 ± 22.17 | 53.08 ± 22.40 | 67.66 ± 15.94 | < 0.00011 |
| Age groups (year) | < 0.00013 | |||
| < 18 | 30807 (5.82) | 29910 (6.62) | 898 (1.15) | |
| 18-49 | 168411 (31.79) | 159531 (35.31) | 8880 (11.35) | |
| 49-59 | 75661 (14.28) | 65080 (14.42) | 10581 (13.54) | |
| 59-69 | 85753 (16.18) | 68589 (15.18) | 17164 (21.96) | |
| ≥ 70 | 169209 (31.93) | 128604 (28.47) | 40605 (51.97) | |
| Race/ethnicity | < 0.00013 | |||
| White | 421882 (79.64) | 356333 (78.88) | 65549 (83.90) | |
| Black | 14876 (2.81) | 13386 (2.96) | 1490 (1.90) | |
| Hispanic | 20834 (3.93) | 18657 (4.13) | 2177 (2.78) | |
| Asian or Pacific Islander | 2746 (0.51) | 2462 (0.55) | 284 (0.36) | |
| Native American | 1698 (0.32) | 1501 (0.33) | 197 (0.25) | |
| Other | 67806 (12.79) | 59375 (13.14) | 8431 (10.79) | |
| Median household income for patient’s zip code | < 0.00013 | |||
| 0-25th percentile | 91079 (17.19) | 79152 (17.52) | 11927 (15.26) | |
| 26th to 50th percentile (median) | 125043 (23.60) | 107046 (23.70) | 17997 (23.05) | |
| 51st to 75th percentile | 143974 (27.17) | 122501 (27.12) | 21472 (27.48) | |
| 76th to 100th percentile | 160727 (30.34) | 135206 (29.93) | 25521 (32.66) | |
| Other | 9019 (1.70) | 7807 (1.73) | 1211 (1.55) |
Table 2 compared the prevalence of MN in CeD (cases) and matched (age, sex, and race) non-CeD patients in NIS from 2000 to 2019. As compared to non-CeD patients, CeD patients are at heightened risk of small intestine [odds ratio (OR) = 7.71; 95% confidence interval (CI): 5.0-11.9; P < 0.0001], lymphoma (OR = 2.06; 95%CI: 1.90-2.23; P < 0.0001), other gastrointestinal (GI) organs (OR = 2.02; 95%CI: 1.41-2.92; P < 0.0001), nonmelanoma skin (OR = 1.97; 95%CI: 1.81-2.16; P < 0.0001), thyroid (OR = 1.84; 95%CI: 1.58-2.13; P < 0.0001), liver (OR = 1.83; 95%CI: 1.49-2.24; P < 0.0001), melanoma skin (OR = 1.54; 95%CI: 1.35-1.76; P < 0.0001), pancreas (OR = 1.53; 95%CI: 1.29-1.80; P < 0.0001), myelodysplastic syndrome (OR = 1.84; 95%CI: 1.55-2.17; P < 0.0001), biliary (OR = 1.39; 95%CI: 1.01-1.91; P = 0.045), stomach (OR = 1.35; 95%CI: 1.08-1.69; P < 0.0.005), other neuroendocrine tumors (excluding small and large intestine malignant carcinoid) (OR = 1.48; 95%CI: 1.03-2.12; P = 0.031), leukemia (OR = 1.13; 95%CI: 1.02-1.25; P = 0.02), uterus (OR = 1.17; 95%CI: 1.03-1.32; P = 0.013), prostate (OR = 1.14; 95%CI: 1.06-1.23; P < 0.001), and testis (OR = 1.50; 95%CI: 1.07-2.10; P = 0.018). The bar chart in Supplementary Figure 1 also showed the prevalence comparison of MN positively associated with CeD.
| Neoplasm type | CeD cases | CeD controls | OR (95%CI) | P value |
| Unweighted (n = 108052), 50%, n (%) | Unweighted (n = 108052), 50%, n (%) | |||
| All malignant neoplasm | 15884 (14.70) | 14125 (13.07) | 1.15 (1.12-1.18) | < 0.0001 |
| Positive association | ||||
| Stomach | 179 (0.17) | 133 (0.12) | 1.35 (1.08-1.69) | 0.0092 |
| Small intestine | 177 (0.16) | 23 (0.02) | 7.71 (5.0-11.9) | < 0.0001 |
| Liver | 261 (0.24) | 143 (0.13) | 1.83 (1.49-2.24) | < 0.0001 |
| Biliary | 90 (0.08) | 65 (0.06) | 1.39 (1.01-1.91) | 0.0446 |
| Other GI organs | 87 (0.08) | 43 (0.04) | 2.02 (1.41-2.92) | < 0.0001 |
| Thyroid | 474 (0.44) | 259 (0.24) | 1.84 (1.58-2.13) | < 0.0001 |
| Pancreas | 358 (0.33) | 235 (0.22) | 1.53 (1.29-1.80) | < 0.0001 |
| Melanoma skin | 552 (0.51) | 359 (0.33) | 1.54 (1.35-1.76) | < 0.0001 |
| Nonmelanoma skin (all other skin excluding melanoma) | 1441 (1.33) | 735 (0.68) | 1.97 (1.81-2.16) | < 0.0001 |
| Other neuroendocrine tumors | 74 (0.07) | 50 (0.05) | 1.48 (1.03-2.12) | 0.0311 |
| Lymphoma | 1861 (1.72) | 912 (0.84) | 2.06 (1.90-2.23) | < 0.0001 |
| Leukemia | 835 (0.77) | 742 (0.69) | 1.13 (1.02-1.25) | 0.0187 |
| Myelodysplastic syndrome | 397 (0.37) | 216 (0.20) | 1.84 (1.55-2.17) | < 0.0001 |
| Uterus | 562 (0.52) | 482 (0.45) | 1.17 (1.03-1.32) | 0.0131 |
| Prostate | 1421 (1.32) | 1247 (1.15) | 1.14 (1.06-1.23) | 0.0007 |
| Testis | 84 (0.08) | 56 (0.05) | 1.50 (1.07-2.10) | 0.0179 |
| Negative association | ||||
| Respiratory | 1244 (1.15) | 1813 (1.68) | 0.68 (0.63-0.73) | < 0.0001 |
| Secondary malignancies | 2199 (2.04) | 2846 (2.63) | 0.76 (0.73-0.81) | < 0.0001 |
| Urinary | 952 (0.88) | 1053 (0.97) | 0.90 (0.83-0.99) | 0.0234 |
| Null association | ||||
| Head and neck | 272 (0.25) | 314 (0.29) | 0.87 (0.74-1.02) | 0.0823 |
| Nervous system | 227 (0.21) | 257 (0.24) | 0.88 (0.74-1.06) | 0.1722 |
| Esophagus | 152 (0.14) | 125 (0.12) | 1.22 (0.96-1.54) | 0.1045 |
| Colorectal | 1752 (1.62) | 1774 (1.64) | 0.99 (0.93-1.06) | 0.7087 |
| Anus | 21 (0.02) | 26 (0.02) | 0.81 (0.45-1.44) | 0.4658 |
| Breast | 2844 (2.63) | 2919 (2.70) | 0.98 (0.92-1.03) | 0.3166 |
| Other endocrine (excluding thyroid and pancreas) | 25 (0.02) | 30 (0.03) | 0.83 (0.49-1.41) | 0.5001 |
| Malignant carcinoid tumor - small intestine | 14 (0.01) | 13 (0.01) | 1.08 (0.51-2.29) | 0.8474 |
| Malignant carcinoid tumor - large intestine | 5 (0.005) | 6 (0.005) | 0.83 (0.25-2.73) | 0.7630 |
| Bone and connective tissues | 134 (0.12) | 161 (0.15) | 0.83 (0.66-1.04) | 0.1157 |
| Myeloma | 313 (0.29) | 274 (0.25) | 1.14 (0.97-1.34) | 0.1070 |
| Cervix | 448 (0.41) | 418 (0.39) | 1.07 (0.94-1.22) | 0.3070 |
| Ovary | 472 (0.44) | 430 (0.40) | 1.10 (0.96-1.25) | 0.1611 |
| Other female genital organs | 126 (0.12) | 139 (0.13) | 0.91 (0.71-1.15) | 0.4242 |
| Other male genital organs | 11 (0.01) | 4 (0.004) | 2.75 (0.88-8.63) | 0.0707 |
Conversely, individuals with CeD exhibit a notably reduced risk of developing respiratory malignancies (OR = 0.68; 95%CI: 0.63-0.73; P < 0.0001) and secondary malignancies (OR = 0.76; 95%CI: 0.73-0.81; P < 0.0001). Furthermore, our analysis did not reveal any significant association between CeD and the occurrence of malignancies affecting the head and neck, nervous system, esophagus, colorectal, anus, breast, malignant carcinoids, bone and connective tissues, myeloma, cervix, or ovary.
Figure 3 and Table 3, provide a comparative analysis of hospital outcomes and resource utilization. This assessment includes mortality rates, length of hospitalization, and the overall cost of care, and it contrasts patients with CeD who have MN with a matched group of patients without CeD but with MN. The matching process is based on age, sex, race, and the specific type of malignant neoplasm. The mean differences in length of the stay and total cost of care are found to be higher in CeD cohort (0.21 days; 99%CI: 0.05-0.38; P < 0.001) and ($3172; 99%CI: $1467-$4878; P < 0.001), respectively. However, the inpatient mortality is lower in CeD with MN than non-CeD with MN (0.72; 99%CI: 0.61-0.86; P < 0.001). Supplementary Figure 2 illustrated the trend in the total cost of care for hospitalized CeD patients with MN, compared to non-CeD patients with MN.
Utilizing the NIS dataset, which offers a representative sample of the United States population, our investigation revealed that individuals with CeD exhibited a notably heightened incidence of at least sixteen distinct MN. The most significant increase was observed in cases of small intestinal adenocarcinomas, with an OR of 7.7, followed by lymphomas (OR = 2.06) and other malignancies affecting the GI organs (OR = 2.01). Conversely, a reduced risk was identified for respiratory MNs. This study aligns with some findings from previous research while also highlighting notable disparities.
The initial documentation of malignancy in individuals with CeD dates back to 1965 when a case of small intestinal adenocarcinoma was reported in France[16]. Subsequently, during the late 1960s, research investigating the connection between CeD and the development of malignancies began to emerge[17,18]. Over the ensuing decades, a series of research studies conducted in Europe provided substantial evidence supporting the association between CeD and MN[19-22]. Likewise, a study conducted in the United States observed a heightened risk of MNs in a limited cohort of CeD patients compared to the general American population[23]. Various investigations have highlighted that the risk of MN development is notably higher in the early stages following the diagnosis of CeD. However, as time progresses, the Standardized Incidence Ratio (SIR) for MNs tends to decrease and may even become statistically nonsignificant after the initial year of diagnosis or in subsequent years[24-26]. Additionally, some studies have demonstrated that individuals with CeD experience elevated mortality rates in the initial years following diagnosis, potentially linked to malignancies[27-30]. Notably, adherence to a gluten-free diet emerges as a robust protective factor against the development of malignancies[8,31]. A study underscores that mortality rates are significantly higher among patients with delayed diagnoses or severe symptoms at the time of diagnosis[29].
The precise pathogenic mechanism underlying malignancy development in CeD remains an enigma[32]. Several factors, including but not limited to persistent inflammation, the release of proinflammatory cytokines, continual antigen stimulation, cytokine surges, heightened susceptibility to carcinogens, and nutritional deficiencies induced by the disease or the adoption of a gluten-free diet, have all been proposed as potential contributors to the onset of malignancies[23,33].
Among the malignancies exhibiting a positive association with CeD, our findings indicate that lymphomas have the highest prevalence and the second-highest OR within the CeD sample. The connection between CeD and the deve
Two Swedish studies, one involving roughly 11000 CeD patients and the other with approximately 11650 CeD patients, reported SIR of 6.3 (95%CI: 4.2-125)[31] and 6.6 (95%CI: 5.0-8.6) for NHL[38]. Furthermore, Elfström et al[39] research suggested that the risk of lymphoproliferative malignancies was similar between CeD patients with only positive serology and those without documented inflammation, compared to the general population. Additionally, earlier investigations have identified relative risks (RR) ranging from 3 to 100 for various lymphoma subtypes in the context of CeD[8,31,38,40,41]. The prevalence of enteropathy-associated T-cell lymphoma (EATL), a rare tumor, has attracted research attention alongside the increasing incidence of CeD in recent decades[42-44]. Typically, EATL has been linked to refractory CeD, which is characterized by the persistent or recurrent pathological manifestations of CeD despite stringent adherence to a gluten-free diet[45,46]. Notably, in regions of Northern Europe where CeD is more widespread, EATL type 1 (pleomorphic and anaplastic, typically CD56 negative, with gains in chromosomes 1q and 5q) prevails over EATL type 2 (medium-sized cancer cells, typically CD56 positive, with oncogene MYC gain), which is more commonly observed in Asian countries[47-50]. It is notable that there is no clear causality on the exact mechanism of how CeD patients develop lymphoma, the main hypothesis is that as an autoimmune disease with immunity overactivation, persistent inflammation, villous atrophy, and intestinal mucosal healing resulting in aberrant lymphocytes’ hyperproliferation can result in a possibility of malignant transformation of intraepithelial lymphocytes causing lymphomas[51-53]. Numerous studies have reported the occurrence of both T and B cell lymphomas in individuals with CeD[39,54-56]. In terms of prognosis, research has indicated that CeD patients face a roughly 0.15% elevated risk of NHL-related mortality in the decade following diagnosis[57]. It is also notable that T-cell lymphomas tend to exhibit a poorer prognosis in comparison to B-cell lymphomas[58,59].
Our findings indicate that small bowel carcinomas (SBC) exhibit the highest OR of 7.71 (95%CI: 5.0-11.9) among MN, demonstrating a positive correlation with CeD. SBC is a rare malignancy in the general population, and its association with CeD is firmly established. This connection was initially documented by Swinson et al[22], revealing a RR of 82.6 for SBC development in individuals with CeD. Over subsequent decades, several significant studies have reaffirmed this association. Elfström et al[60] in a prospective analysis encompassing more than 45000 CeD patients, reported an average hazard ratio (HR) for SBC development ranging from 2.22 to 4.67, stratified based on CeD marsh classification or positive serology. In 2014, Ilus et al[61] conducted a retrospective investigation involving 32439 CeD patients in Finland, unveiling a positive link between CeD and SBC development. The study reported an SIR of 5 in females, 3.47 in males, and 4.29 in all combined cases. Another substantial retrospective Swedish study led by Emilsson et al[62], encompassing more than 48000 CeD patients, reported an HR of 3.05, underscoring the affirmative association between CeD and SBC. Additionally, a sequential progression from adenoma to carcinoma has been suggested as a potential pathway for SBC development in CeD[63]. Notably, the survival rates for SBC in CeD patients are comparatively higher than those in individuals without CeD[64]. As prostate cancer is the most common cancer in males in general[65], our study shows a positive association between prostate cancer and CeD with an HR of 1.14 (95%CI: 1.06-1.23). Surprisingly, other studies that addressed this association did not show any significantly heightened risk of prostate cancer in CeD[25,31,61,66].
To our knowledge, this study stands as one of the most extensive investigations underscoring the positive link between nonmelanoma skin cancers and CeD. In contrast, the association between melanoma and CeD has been examined in three studies, with one study, also conducted in the United States, reporting a notably elevated SIR[23]. Conversely, two studies from Sweden failed to establish any significant connection between these two conditions[31,67]. Notably, the latter study, which involved 29028 patients, did not identify a significant association.
Our study reveals a positive correlation between pancreatic malignancies and CeD. However, it’s essential to note the divergence in findings across various studies concerning the association between CeD and pancreatic malignancies. For instance, Elfström et al[60] reported a substantially higher HR of 10.7 within the first year of follow-up, which subsequently decreased to 1.4. Lebwohl et al[26] conducted another large Swedish study, documented analogous outcomes with distinct HR. In contrast, a study utilizing a United States Veterans Affairs database reported an elevated RR for pancreatic cancer in individuals with CeD[68], while two separate European studies failed to identify any significant risk association[31,69].
Our results indicate an elevated incidence and a positive correlation between thyroid malignancies and CeD. It is worth mentioning that the existing literature has yielded conflicting outcomes in this regard. Specifically, two studies conducted in the United States and Italy have reported a positive association[70,71], whereas two other population-based studies in Sweden have reported a lack of significant association[31,72].
It is noteworthy that our study’s findings align with those of other research regarding the risk of lung cancer in CeD patients. Our study reveals a statistically significant negative correlation between respiratory malignancies and CeD. Similarly, the two largest studies conducted in Finland[61] and Sweden[26] also report a negative association. Conversely, several other studies have failed to identify a heightened risk of lung malignancies in individuals with CeD[23-25,31,69,73,74]. This lack of association could potentially be attributed to a lower prevalence of smoking among individuals with CeD[75,76]. Regarding colorectal cancer, our study demonstrates no significant association with CeD. This finding is consistent with a study by Lebwohl et al[77], which also reported no elevated risk of colorectal cancer. However, results from the study by Ilus et al[61], indicated an increased risk of colon cancer but not rectal cancer.
In the context of breast cancer risk in CeD, most available studies have reported a significantly decreased risk, including large-scale investigations by Lebwohl et al[26], Ilus et al[61], and Ludvigsson et al[78], as well as other relatively smaller studies with similar findings[31,25,69,79]. Our study supports this trend, reporting no increased risk of breast cancer in individuals with CeD, which aligns with several previous studies on this association[23,24,73,74,80].
Our study exhibits several notable strengths. First and foremost, it leverages an extensive database, including more than 108000 individuals diagnosed with CeD, which, when weighted, expands to encompass over 500000 individuals. This dataset stands as the most substantial cohort among comparable studies within the existing body of research, as far as our knowledge extends. Secondly, we investigated hospital outcomes, encompassing a variety of factors associated with mortality, LOS, and the burden on the healthcare system, spanning a substantial two-decade period. However, it is important to acknowledge several limitations in our study. Firstly, it is confined to inpatient populations, potentially limiting the generalizability of our findings to outpatient settings. Secondly, the NIS dataset lacks essential clinical details such as laboratory values, treatment modalities, and diagnostic procedures like histology and endoscopy findings that definitively confirm CeD. Thirdly, the NIS, as an administrative database, may be susceptible to selection bias and coding errors, which can occur without external validation. Lastly, it’s worth noting that the NIS does not track individual patients, meaning that if a patient is admitted multiple times, they may contribute to multiple entries in the database. Furthermore, we lack information about the level of adherence to a gluten-free diet among the patients and the degree to which their CeD is controlled. These limitations should be considered when interpreting our results.
Our study is unique in highlighting the detailed results of positive, negative, or null associations between different hematologic and solid malignancies and CeD. It also sheds light on data on hospitalized CeD patients with and without MN in terms of mortality, LOS, and related costs with trends shown over the last two decades, which have been understudied in this disease.
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