ORIGINAL PAPERS

 

Celiac disease and alcohol use disorders: Increased length of hospital stay, overexpenditures and attributable mortality

Enfermedad celiaca y trastornos por consumo de alcohol: prolongación de estancias, exceso de costes y mortalidad atribuible

 

 

Miguel Gili^1,2, Luis Béjar², Gloria Ramírez^1,2, Julio López^1,2, Juan Luis Cabanillas^2,3 and Brett Sharp⁴

¹Unit of Preventive Medicine, Surveillance and Health Promotion. Hospital Universitario Virgen Macarena. Sevilla, Spain.
²Department of Preventive Medicine and Public Health. School of Medicine. Universidad de Sevilla. Sevilla, Spain.
³Consejería de Salud de la Junta de Andalucía. Sevilla, Spain.
⁴Clinical Unit of Diagnostic Image. Hospital Universitario Virgen de Rocío. Sevilla, Spain

This study was funded by the Delegación del Gobierno, Plan Nacional Sobre Drogas. Ministerio de Sanidad, Servicios Sociales e Igualdad (Ayuda N^o 2009I017, Proyecto G41825811).

Correspondence

 

 

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ABSTRACT

Background and objectives: alcohol use disorders are associated with a greater incidence of certain comorbidities in patients with celiac disease. Currently there is no available information about the impact that these disorders may have on length of hospital stays, overexpenditures during hospital stays, and excess mortality in these patients.
Methods: a case-control study was conducted with a selection of patients 18 years and older hospitalized during 2008-2010 in 87 hospitals in Spain. Estimations of excess length of stays, costs, and attributable mortality were calculated using a multivariate analysis of covariance, which included age, gender, hospital group, alcohol use disorders, tobacco related disease and 30 other comorbidities.
Results: patients who had both celiac disease and alcohol use disorders had an increased length of hospital stay, an average of 3.1 days longer in women, and 1.7 days longer in men. Excess costs per stay ranged from 838.7 euros in female patients, to 389.1 euros in male patients. Excess attributable mortality was 15.1% in women, 12.2% in men.
Conclusions: apart from a gluten-free diet and other medical measures, the prevention of alcohol abuse is indicated in these patients. Patients hospitalized who present these disorders should receive specialized attention after leaving the hospital. Early detection and treatment should be used to prevent the appearance of organic lesions and should not be solely focused on male patients.

Key words: Celiac disease. Alcohol. Hospital stay. Costs. Mortality.

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RESUMEN

Antecedentes y objetivos: los trastornos por consumo de alcohol se han asociado a una mayor incidencia de ciertas comorbilidades entre los pacientes con enfermedad celiaca. En la actualidad no disponemos de información sobre si estos trastornos tienen un impacto en la prolongación de las estancias hospitalarias, mayores costes por estancia y un exceso de mortalidad entre estos pacientes.
Métodos: Se hizo un estudio de casos y controles a partir de una muestra de pacientes de 18 o más años de edad hospitalizados durante 2008-2010 en 87 hospitales de España. Las estimaciones de prolongación de estancias, exceso de costes y mortalidad atribuible se calcularon mediante un modelo de análisis multivariante de la covarianza que incluyó edad, género, grupo hospitalario, trastornos por alcohol, trastornos por tabaco y 30 comorbilidades.
Resultados: los pacientes de enfermedad celiaca con trastornos por alcohol presentaron una prolongación de estancias de 3,1 días en las mujeres y de 1,7 días en los varones, un exceso de costes por estancia de 838,7 euros en las mujeres y de 389,1 euros en los varones, y un exceso de mortalidad atribuible de 15,1% en las mujeres y de 12,2% en los varones.
Conclusiones: además de una dieta sin gluten y otras medidas asistenciales, en estos pacientes está indicada la prevención del abuso de alcohol, y los hospitalizados que presentan estos trastornos deberían recibir asistencia especializada tras el alta hospitalaria. La detección e intervención precoz debería intentar prevenir el desarrollo de lesiones orgánicas y no centrarse exclusivamente en varones.

Palabras clave: Enfermedad celiaca. Alcohol. Estancias hospitalarias. Costes. Mortalidad.

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Introduction

Celiac disease has a variable prevalence, with an average that varies between 0.5% and 1% according to studies performed in Europe and North America (1-6). In Europe, different countries register great discrepancies (0.3% in Germany versus 2.4% in Finland in people between 30 and 64 years of age), for reasons still unclear (6). Prevalence of celiac disease is between 1.5 and 2 times greater in women than in men (7-9), and some studies suggest that it is increasing (8-12).

Celiacs usually present with problems related to malabsorption of iron and folic acid, made worse by the consumption of large quantities of alcohol (13). Among the complications related to celiac disease, many are worsened if the patient consumes in excess alcoholic beverages, for example, peripheral neuropathy (14,15) and epilepsy (16). Abnormal levels of aminotransferases (17) can be found in patients with celiac disease, as well as an association with several autoimmune chronic liver diseases such as primary biliary cirrhosis (18,19). There is also an increased risk of autoimmune cardiomyopathy (20,21).

When these patients have alcohol use disorders, such problems can be seriously aggravated. In fact, any pathology associated with celiac disease, such as metabolic alterations (diabetes type I), neoplasia (tumors of the small intestine and lymphomas), among others, can favor the apparition of complications that worsen the vital prognosis of these patients and increase the length of their hospital stays (22).

For these reasons, the objective of this study is to evaluate the impact that alcohol use disorders have among hospitalized patients already diagnosed with celiac disease, through the analysis of factors such as increased length of hospital stay, excess costs and attributable mortality. In order to do so, this problem was studied in hospitalized patients aged 18 and older in a sample of 87 Spanish hospitals during the period of 2008-2010, while controlling confounding and interacting factors such as age, gender, type of hospital, tobacco related disorders and a considerable number of comorbidities.

 

Methods

Participants

Data for hospital admissions and readmissions were captured in the administrative minimal basic data set (MBDS) of 87 Spanish hospitals during the period of 2008-2010. The study was designed as a case-control study. Sample size for this study, which analyzes problems related to the consumption of alcohol, tobacco, and other substances of abuse, was calculated admitting a 5% alpha error rate, a two tailed test, had a power of 90%, a relationship of non-case:case of at least 4:1, and the least favorable proportion of cases in which the cases are exposed and the non-cases are not exposed according to available scientific evidence was used. In order for the sample to be representative both on a national and regional scale, and keeping in mind the stratification of hospitals according to their size and complexity in the classification set forth by the Ministry of Health, sampling was done in various stages in which 87 Spanish hospitals were selected from all of the autonomous regions of Spain.

From written or digitalized information that was provided by the hospital physician who signs the clinical record, each patient's diagnosis, external causes and procedures were codified according to International Classification of Diseases, 9th review (ICD-9-CM) codes. Codification and data entry in the electronic database are performed by dedicated administrative personnel who have completed in-depth training on medical data registration. This administrative database has demographic data, admission and discharge dates, type of admission and type of discharge, diagnostic codes for principal cause and secondary diagnoses, external causes and procedures using the ICD-9-CM. Also included in these databases are diagnosis-related groups (DRG) and a classification of each hospital into five categories based on size and complexity of services, varying from those with a smaller size and lesser complexity to larger hospitals that offer a broader range of services (23). Analysis was restricted to patients who at the moment of hospital discharge were 18 and older.

Variables

Cases of celiac disease were defined as those which fit the codes specified in the ICD-9-CM as a primary or secondary diagnosis (code 579.0). Alcohol related disorders were defined as alcohol dependence (303.00-303.93), alcohol abuse (305.00-305.03), alcohol-induced mental disorders (291.0-291.9), alcoholic polyneuropathy (357.5), alcoholic cardiomyopathy (425.5), alcoholic gastritis (535.30-535.31), alcoholic liver disorders (571.0-571.3), excessive blood alcohol level (790.3), alcohol toxicity and alcohol poisoning (980.0-980.9 and E860.0-E860.9). The ICD-9-CM code for disorders associated with tobacco dependence was used (305.1).

Age was measured in years. The following comorbidities were identified: Obesity, uncomplicated hypertension, complicated hypertension, cardiac arrhythmias, pulmonary circulation disorders, valvular disease, deficiency anemia, blood loss anemia, fluid and electrolyte disorders, weight loss, hypothyroidism, coagulopathy, myocardial infarction, congestive heart failure, peripheral vascular disorders, cerebrovascular disease, dementia, chronic pulmonary disease, rheumatic disease, peptic ulcer disease, mild liver disease, diabetes without chronic complications, diabetes with chronic complications, hemiplegia or paraplegia, renal disease, moderate or severe liver disease, cancer, leukemia or lymphoma, metastatic cancer, AIDS and depression. We used the ICD-9-CM codes proposed for these comorbidities by Quan et al. (24). Charlson Comorbidity Index was also calculated for every patient (25).

Data analysis

The primary outcome of interest was to determine the length of hospital stays, costs and mortality in patients with celiac disease with or without alcohol use disorders. Costs were calculated using specific hospital spending data organized according to DRG and stratified by hospital group, using estimates published by the Ministry of Health during 2008, 2009, and 2010 (23).

Univariate analysis was used to examine the association between celiac disease and alcohol use disorders, as well as tobacco related disorders, age, gender, and comorbidities. In order to compare continuous variables a Student's t-test or a parametric equivalent was used. For qualitative variables a Chi-squared test was used.

Multivariate analysis of covariance was performed to determine the effect of alcohol use disorders on hospital length of stay (in days), costs and mortality in patients with celiac disease. Data were adjusted for age, gender, tobacco related disorders, group of hospitals and severity of disease using the 30 comorbidities before mentioned. Analysis was performed in STATA version MP 12.1.

 

Results

Patient characteristics

Patient characteristics with celiac disease and without celiac disease are detailed in table I. A total of 5,475,315 patients were identified, of which 3,327 were admitted with celiac disease, while 344,429 had alcohol use disorders. The prevalence of alcohol use disorders was lower among patients with celiac disease (4.9%) than in the rest of patients (6.3%), but with extraordinary differences according to age group and gender, as seen in figure 1. Male celiac patients between the ages of 55-64 years had the highest prevalence of alcohol use disorders (19.3%) while in female celiac patients it was highest in those of 35-44 years of age (3.6%). The prevalence of tobacco related disorders was lower in patients with celiac disease than in the rest of patients (17.8% versus 20.3%).

 

 

 

Patients diagnosed with celiac disease were significantly younger (average age: 48.7 years versus 57.6) and mostly female (70.2% of the cases).

Patients with celiac disease had fewer comorbidities than the rest of the patients, as shown by the average Charlson Comorbidity Index (0.89) compared to the rest of hospitalized patients (1.19). However, there are a series of comorbidities classically associated with celiac disease, which in this study also demonstrated higher prevalence: Anemia, electrolyte disorders, weight-loss, hypothyroidism, autoimmune rheumatic diseases, depression, liver disorders and associated disorders such as coagulopathies.

Prolongation of hospital stays, excess costs and attributable mortality

A differential analysis was performed for female and male patients. In-hospital mortality in patients with celiac disease was greater in males than in females (3.9% versus 2.2%, p = 0.0046). In-hospital mortality in males with celiac disease and alcohol use disorders was inferior than in female patients with celiac disease and alcohol use disorders (3.4% versus 4.3%), though the difference was not found to be statistically significant (p = 0.8042).

Adjusted estimates of excess length of hospital stays, costs per stay and attributable mortality due to alcohol use disorders, which resulted from multivariate analysis of covariance are detailed in table II. One can see that the prolongation of hospital stays (in days) in female patients with celiac disease and alcohol use disorders in comparison to females with celiac disease and without alcohol use disorders is almost double that of male patients (3.1 days versus 1.7 days). Due to this difference, the excess costs per stay in euros in female patients with celiac disease and alcohol use disorders compared to female celiac disease patients without these disorders more than doubled that of male patients (838.7 euros versus 389.1 euros).

 

 

In contrast to the greater in-hospital mortality in male patients with celiac disease, the excess mortality attributable to alcohol use disorders among female patients with celiac disease in comparison with those without alcohol use disorders was greater than in male patients (15.1% versus 12.2%).

 

Discussion

This study shows that patients with celiac disease and alcohol use disorders have increased lengths of hospital stays, incur greater costs during their stay, and have higher mortality rates. These effects are increased in women.

The relationship between alcohol use disorders and celiac disease is complex and influenced by many factors. As mentioned earlier, alcohol abuse and disorders associated with excess consumption worsen the evolution and prognosis of celiac disease and associated autoimmune disorders.

Not only that, there are other relationships that exist involving the immune system. In the gut, there are abundant enzymes that metabolize ethanol into acetaldehyde, a very reactive compound that is thought to have an important role in the pathogenesis of various alcohol use disorders of the digestive tract (26-28). Some studies show that patients with increased consumption of ethanol may produce IgA-mediated immune responses to proteins containing epitopes modified by the action of acetaldehyde (29-31). It has also been shown that the reactions catalyzed by transglutaminases are involved in the pathogenesis of celiac disease (32). In a study in which IgA antibodies active against tissue transglutaminases and proteins modified by acetaldehyde were measured, levels of both these antibodies were significantly higher in patients with alcoholic liver disease and in heavy drinkers without liver disease, showing a direct correlation with levels of biomarkers of ethanol consumption, pro-inflammatory cytokines, and markers of fibrogenesis (33). These findings support the hypothesis that elevated and persistent consumption of alcohol can generate other sources of antigen production and abnormal activation of tissue transglutaminases. Finally, other studies have found that increased levels of antibodies active against transglutaminases may be associated with a greater risk of mortality in the general population, which increases the potential impact that alcohol abuse and its interactions have on mortality in patients with celiac disease (34).

Our study has several limitations. The data used were only those found in the MBDS and were not complemented with additional data from patients. We used clinical definitions of celiac disease, alcohol and tobacco related disorders and comorbidities as assigned by physicians and entered by codifiers. Another limitation is potential underreporting if all of the information required to complete such codes is not available in the clinical record, or due to variations in the codifiers interpretation of data. The ICD-9-CM does not include codes specific to the motive for hospitalizing patients, and in some cases, this would make an interesting variable to study.

Databases such as the MBDS also have clear advantages (35). The data collected are usually completed in most hospital admissions and, as they include virtually all cases, provide reasonably accurate estimates of the incidence, prevalence, comorbidity, and mortality of diseases treated in the hospital setting (36). The data can be analyzed retrospectively, unlike other designs that require prospective data collection, and data from long periods or from large numbers of patients can be gathered quickly and easily. Since the data are collected systematically, costs are considerably reduced. In studies using these databases, there may be less selection bias due to the refusal of patients or their legal representatives to sign consent forms, which would allow the patient to participate in the study.

Because of our large sample size and diversity of hospitals, our data are generalizable and not limited to patients admitted to a small number of centers. The availability of costs of hospitalization for each DRG, stratified by hospital group and specific to each year, facilitates the calculation of excess costs due to prolonged stays attributed to alcohol use disorders. As far as we know, this is the first study of it's kind in which excess length of stays, costs, and mortality attributed to alcohol use disorders among patients with celiac disease have been examined.

There are various possible explanations for the greater impact seen in women rather than men. Mortality was discretely increased in women with celiac disease and alcohol use disorders (4.3% versus 3.4%), despite the fact that the average age of men was greater (Fig. 1), and could be explained by cases among women included that had worse prognosis and increased length of stays and costs (massive cerebral hemorrhage and irreversible hepatic coma). The results for attributable mortality among women have ample margins of confidence (13.0-18.2) and overlap in part with those of men (7.9-16.5), for this reason these differences should be analyzed with caution. On the other hand, the relative percentage of impact is greater in women than in men, because among women in general, there are not as many competing variables of exposition that prolonged hospital stays and increased costs (tobacco dependence, drug use, diet and many other dangerous behaviors more prevalent in males). In the analysis, the increased relative weight of alcohol use disorders controlling the rest of these problems could have influenced the estimations made in the multivariable models. We have no information as to the social class and marital status of these patients, nor the distribution according to gender, factors that could also have influenced the length of hospital stays. Finally, we cannot rule out that complications not reflected in the MBDS may have influenced these outcomes in female patients.

Some studies demonstrate that the prevalence of autoimmune diseases in patients with celiac disease is intimately linked with the duration of the exposure to gluten (37). It has been demonstrated that the antibodies responsible for autoimmunity in diabetes mellitus I and autoimmune thyroiditis can disappear when children with celiac disease consume a gluten-free diet (38), and the scientific evidence indicates that various autoimmune diseases can improve if these patients are prescribed a gluten-free diet (39,40). These authors suggest that many autoimmune diseases could be prevented through the early diagnosis and treatment of celiac disease and, even in patients with an established disorder, a gluten-free diet could decrease symptoms, improve prognosis, and decrease the risk of hospital readmissions. It is plausible that adherence to a gluten-free diet may be worse among patients with alcohol use disorders, who often do not comply with medical advice. According to the results of this study, it is safe to suggest that the diagnosis and treatment of alcohol abuse should be, together with a gluten-free diet and other treatments, one of the principal therapeutic objectives after these patients are discharged. A brief intervention detailing the risks of alcohol and tobacco consumption, and if necessary, referral to a treatment center have been demonstrated to be effective measures (41), and can prevent complications and readmissions in patients with celiac disease. These problems should also be carefully watched for in women, with a focus on early detection and prevention, as there is a greater relative impact than in men. It would also be very interesting to study the influence that alcohol abuse and dependence have in patients in which irreversible organic lesions have not yet appeared. Reducing the number of hospital admissions and readmissions attributed to alcohol use disorders in these patients would help to reduce costs and increase treatment availability in hospitals. Early intervention and prevention of readmissions of patients suffering from pathology associated with celiac disease and alcohol use disorders can also help reduce the burden on patients and family members.

 

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Correspondence:
Miguel Gili.
Unit of Preventive Medicine, Surveillance and Health Promotion.
Hospital Universitario Virgen Macarena.
Avda. del Dr. Fedriani, s/n.
41070 Sevilla. Spain
e-mail: mgili@us.es

Received: 19-07-2013
Accepted: 25-09-2013