Celiac Disease in the Elderly

Abstract

Purpose of review:

This review highlights literature from the past several years and explores the impact on current understanding of celiac disease diagnosis, complications, and management in older adults.

Recent findings:

Celiac disease in the elderly is becoming increasingly prevalent but remains underdiagnosed, with a high potential burden of downstream morbidity and modestly increased risk of mortality. Clinical presentations are often related to extraintestinal symptoms and can be subtle. Duodenal biopsy remains the gold-standard for diagnosis in older adults, along with supporting serologies. Refractory celiac disease is a particular concern in the aging population, and treatment for this rare condition remains unsatisfactory. Older adults exhibit lower rates of mucosal healing, though the reasons for this are poorly understood.

Summary:

Current understanding of celiac disease in the elderly continues to advance, though significant knowledge gaps persist. Large, prospective studies are needed to further characterize celiac disease pathogenesis, complications, and management in older adults.

INTRODUCTION

Celiac disease is a chronic, immune-mediated enteropathy driven by gluten exposure in genetically predisposed individuals.(1) It is characterized by antibodies to transglutaminase and gliadin and villus atrophy of the small intestinal mucosa resulting in malabsorption of nutrients, with adoption of a gluten-free diet leading to clinical and histological improvement. While once traditionally considered a pediatric disorder, celiac disease is often diagnosed in adults and increasingly, in the elderly; in this latter population there are particular considerations and concerns.(2) This review focuses on findings from recent studies of celiac disease in older adults and how they have advanced our current understanding of the clinical manifestations, diagnosis, complications, and management of celiac disease in the aging population.

EPIDEMIOLOGY

Celiac disease affects about 1% of the population worldwide.(3) While the most common age of diagnosis is between the 4^th and 6^th decades of life, approximately 25% of all celiac disease diagnoses are now made in patients over 60 years of age, and 20% in those over 65 years.(4) A recent cohort study of 1,605 newly diagnosed celiac disease patients in the United Kingdom found that 13.0% were diagnosed over 65 years of age between 1990 and 2017; when examining the yearly rate of celiac disease diagnoses in the elderly population, the proportion of diagnoses increased from 0% in 1990–1991 to 18.7% in 2016–2017.(5)** It is unclear whether this increase in diagnoses represents an improved recognition of celiac disease in the adult population, including those with long-standing disease, or a true rise in de novo cases in those who seroconverted at that age. Several studies have shown that compared to the increase in older male diagnoses, there is a paucity of diagnoses in young adult males, suggesting that the rise in diagnoses among the elderly may be partially related to more frequent interactions with the healthcare system.(4, 6)

CLINICAL PRESENTATION

Celiac disease exhibits a wide spectrum of clinical presentations, including both intestinal and extraintestinal symptoms. The classical presentation of celiac disease includes symptoms related to malabsorption, including diarrhea, abdominal pain, and weight loss.(1) However, symptoms have changed over time, with the presenting symptom of diarrhea now occurring in less than half of patients with celiac disease.(7) This is likely due to increasing awareness of celiac disease and its variety of clinical presentations.

The mode of presentation of celiac disease appears to vary by age, with older individuals frequently presenting with symptoms not directly associated with the gastrointestinal tract.(8) When older adults do present with intestinal symptoms, they are usually mild or vague, making the diagnosis difficult. For example, diarrhea may be intermittent or small in volume, or patients may present with abdominal bloating or discomfort rather than frank pain. For those with extraintestinal manifestations, symptoms often arise from nutrient malabsorption and can involve all organ systems.(9) Anemia is one of the most common extraintestinal clinical findings, occurring in up to 60–80% of older adults with celiac disease.(10) Anemia in celiac disease has been mainly attributed to iron deficiency but may be multifactorial due to folate and vitamin B12 deficiencies and chronic inflammation. Neurological symptoms such as peripheral neuropathy or ataxia may in some cases be driven by deficiencies of vitamin B12 and thiamine, along with immune-based neurologic dysfunction. Decreased bone mineral density is largely mediated by calcium and vitamin D malabsorption, along with chronic inflammation. Other extraintestinal manifestations include elevated transaminases, dermatitis herpetiformis, dental enamel defects, follicular hyperkeratosis, edema, atrophy, weakness, fatigue, and arthralgias.

The highly variable, nonspecific, and often subtle nature of these extraintestinal findings may lead clinicians to explore alternative diagnoses or dismiss symptoms. For example, anemia and weight loss may prompt a workup for malignancy prior to considering celiac disease, altered bowel habits may be attributed to a functional etiology such as slowing of bowel transit, and fatigue may be written off as a symptom of normal aging. As a result, older adults tend to experience a delay in the diagnosis of celiac disease. A study from the 1990’s found an average delay of 28 years in those diagnosed over 60 years of age, with a maximum delay of 50 years.(11) In a subsequent study of elderly patients presenting with classical manifestations, the average diagnostic delay was 17 years.(12) A recent report found an average delay of 3.5 years in those without gastrointestinal symptoms, although these individuals encompassed adults of all ages.(13) Despite significant strides overall, the diagnostic delay remains prolonged, and older individuals are still less likely than younger patients to undergo duodenal biopsy during endoscopy for symptoms suggestive of celiac disease.(14) If left unrecognized for an extended period, severe presentations in the elderly, including celiac crisis, may occur.(15, 16)

DIAGNOSTIC TESTNG

Across all age groups, celiac disease is considerably underdiagnosed.(17) Among older adults, the diagnosis of celiac disease requires a high degree of clinical suspicion. While population-based screening for celiac disease is not supported by the current evidence, an active case-finding strategy has been shown to increase the detection of disease.(18, 19) This was observed in a study of serologic screening in older adults, many of whom had at least mild symptoms or other diagnostic clues to suggest the presence of celiac disease.(20, 21)

Older patients tend to have more subtle serologic findings than younger individuals, which can pose diagnostic challenges. This was demonstrated in a recent prospective study of 15,551 adults over 11 years which found that adults who initially tested positive for tissue transglutaminase antibodies and then later tested negative were older and had lower than average initial values than adults who had positive serologic tests at both time points.(22)** Thus, current guidelines still rely on duodenal biopsy to confirm the diagnosis of celiac disease in elderly patients, even in those with positive serologies; notably, this is in contrast to the shift towards a biopsy avoidance strategy in pediatric celiac disease.(23) As an adjunct to duodenal biopsy, there is evidence that lymphogram flow cytometry analysis of duodenal specimens, albeit at a lower TCRγδ+ detection threshold than that used for younger adults, may be of diagnostic value in older patients.(24)

COMPLICATIONS

In addition to the clinical manifestations associated with malabsorption, celiac disease is associated with multiple subsequent morbidities. The risk of complications is associated with the age at diagnosis, with most risk elevations more pronounced among those diagnosed at an older age. This was illustrated in a recent study which found that patients older than 60 years at diagnosis had an 18-fold higher risk of overall complications than those diagnosed at 18–40 years, and a 9-fold higher risk than those diagnosed at 40–60 years.(25) Outlined below are common comorbidities, complications, and other important clinical considerations for older patients with celiac disease (Table 1).

Table 1.

Selected considerations in elderly patients with celiac disease.

Condition	Comments
Osteoporosis and fracture	Osteoporosis is more prevalent in older adults with celiac disease and is likely mediated by calcium and vitamin D malabsorption, and chronic inflammation. Adherence to a gluten-free diet can improve DEXA T scores and restore bone mineral density.
Dementia	Elderly people with celiac disease have a modestly increased risk of vascular dementia, possibly related to longstanding microvascular changes. Persistent neurocognitive deficits despite adherence to a gluten-free diet may be confounded by underlying mood changes.
Malignancy	There is a small excess mortality risk in older adults with celiac disease, particularly in those newly diagnosed with celiac disease. Lymphoproliferative disorders and gastrointestinal cancers are the most commonly observed malignancies and may present at advanced stages.
Persistent villus atrophy	Refractory celiac disease is more prevalent among elderly patients with celiac disease. Older age at diagnosis of refractory celiac disease is a risk factor for mortality. For reasons that are poorly understood, older adults with celiac disease have lower rates of duodenal villus healing compared to younger individuals.

Low Bone Mineral Density and Fractures

With advanced age, low bone mineral density becomes increasingly common. Among patients with celiac disease, the risk of osteopenia and osteoporosis is likely mediated by calcium and vitamin D malabsorption, as well as chronic inflammation. According to a retrospective cohort study, rates of osteoporosis in patients with celiac disease increase substantially with age, affecting 67% and 70% of male and female patients over 65 years, respectively, compared to 9% and 14% of their counterparts under 65 years.(26) Low bone mineral density can be found in individuals with otherwise-silent celiac disease but is generally more common and severe among patients with symptomatic disease.(27) Osteopenia has also been reported in up to one third of symptom-free adults whose celiac disease was diagnosed during childhood and who resumed a normal diet in adulthood.(28) Reassuringly, adoption of a gluten-free diet can significantly improve lumbosacral and femoral T scores and restore bone mineral density, a benefit seen in younger and older adults equally.(26)

Related to the issue of low bone mineral density is the risk of fracture. One meta-analysis quantified this risk to be 8.7% in patients with celiac disease, compared to 6.1% in the general population.(29) Risk factors for fracture include age over 70 years, previous osteoporotic fracture, weight loss greater than 10%, and low body weight.(30) Furthermore, a recent study using data from the US National Health and Nutrition Examination Survey identified celiac disease as an independent risk factor of osteoporotic fractures in men, but not women, over 40 years.(31) Whether this sex difference is related to the baseline increased risk of low bone mineral density in postmenopausal women in the general population, or other undefined risk factors in older men with celiac disease, remains unclear. Nevertheless, these features may potentially help clinicians risk-stratify celiac disease patients when considering the need for screening or surveillance dual-energy x-ray absorptiometry (DEXA).

Autoimmune Disease

Celiac disease is strongly associated with other autoimmune diseases, co-occurring in approximately 20% of adult patients.(32) This association has been attributed, in part, to shared histocompatibility haplotypes, particularly DQ alleles, between groups.(33) Associated conditions include type 1 diabetes mellitus, thyroid disease, inflammatory bowel disease, Sjogren’s disease, and various liver disorders.(9)

Among older adults who are newly diagnosed with celiac disease, the comparative risk of concomitant autoimmune disorders is still debated. Several small retrospective studies have provided evidence for high rates of autoimmune disease in elderly patients with newly diagnosed celiac disease, including one that found autoimmune disease to be nearly ubiquitous in patients diagnosed with celiac disease over 50 years, and another that demonstrated a significantly higher rate of multiple autoimmune syndrome in older patients compared to younger patients.(8, 34) However, others have shown that the occurrence of autoimmune conditions in celiac disease does not differ between those diagnosed with celiac disease at a younger versus older age.(9) It is uncertain whether a gluten-free diet can reduce or prevent the development of autoimmune disease in older adults diagnosed with celiac disease.(35)

Cardiovascular Disease

Although the relationship between celiac disease and cardiovascular risk is not well-defined, it has been reported that individuals with celiac disease are at increased risk of ischemic heart disease.(36) Among those without celiac disease, a low-gluten diet may coincide with reduced consumption of beneficial whole grains, which may increase cardiovascular risk.(37) The effect of celiac disease and dietary changes on other metabolic parameters remains unclear. According to meta-analysis data, while celiac disease patients have consistently been shown to have higher levels of total cholesterol, high density lipoprotein, and fasting glycemia, there are inconsistent reports of low density lipoprotein levels, triglycerides, and blood pressure in this group.(38) Data on the relationship between smoking and celiac disease are also mixed: while several small studies have shown a lower incidence of celiac disease among current smokers, one population-based study found that smoking was more common in women with celiac disease compared to those without celiac disease.(39, 40) Patients with celiac disease have a 3.1-fold lower risk of type 2 diabetes mellitus, a 3.6-fold lower risk of metabolic syndrome, and a lower average body mass index compared to age- and gender-matched controls (24.7 vs. 27.5 kg/m²), potentially mitigating cardiovascular risk.(41) Other cardiovascular risk factors, such as chronic inflammation and age itself, have not been systematically studied in patients with celiac disease.

Neurocognitive Changes

Several studies have indicated an association between celiac disease and neurocognitive changes in the aging population. For example, a recent population-based cohort study of 8,846 older adults over 50 years found a modestly increased risk of dementia in the first year following a diagnosis of celiac disease, which was restricted to vascular dementia and not Alzheimer’s dementia.(42) While the increased risk of dementia may be subject to ascertainment bias, it is postulated that microvascular changes may contribute to the neurocognitive impairments seen in celiac disease, particularly given the known association between celiac disease and both cardiovascular and cerebrovascular disease.(36, 43)

In another study, it was found that elderly patients with celiac disease who were adherent to a gluten-free diet had lower scores on the Mini Mental State Examination (a global cognitive function test), as well as lower performance on a variety of tests assessing speech and attention, compared to age- and sex-matched controls without celiac disease.(44) These deficits were accompanied by selective conservation of almost all types of memory. Here, it is posited that the neurocognitive deficits seen in older patients with celiac disease may perhaps be confounded by underlying depression in some cases. This aligns with our understanding that children with celiac disease have an increased risk of developing mood disorders, and that this effect persists into adulthood.(45) Taken together, these findings indicate that mental health screening may potentially benefit older individuals with celiac disease.

Malignancy

It is well-known that celiac disease confers an increased risk for gastrointestinal neoplasia and lymphoproliferative disorders. While early studies describe up to a 10-fold increased risk of gastrointestinal malignancies and a 40- to 70-fold increased risk of non-Hodgkin lymphoma, more recent studies indicate that the risk of malignancy is much lower than previously observed.(46, 47)

The evolving landscape of malignancy risk in celiac disease has prompted its re-evaluation, particularly given improved disease awareness and better access to gluten-free food. A recent population-based Swedish study of 47,241 patients with biopsy-proven celiac disease found that the overall risk of malignancy was increased 1.11-fold (HR 1.11; 95% CI 1.07–1.15), notably in the first year after celiac disease diagnosis (HR 2.47; 95% CI 2.22–2.74) and not subsequently, although the risks of lymphoproliferative, hematologic, hepatobiliary, and pancreatic cancer persisted.(48)** Notably, the overall risk was highest in those diagnosed with celiac disease after age 60 (HR 1.22, 95% CI 1.16–1.29) and was not increased in those diagnosed before age 40.

The increased risk of malignancy in older adults has been corroborated in other reports. In a retrospective cohort study of patients newly diagnosed with celiac disease, the incidence of non-Hodgkin’s lymphoma was significantly higher in adults over 65 years compared to those under 65 years (5.0% vs. 0.3%, respectively).(26) Additionally, there have been several recent case reports of late-presenting celiac disease in elderly patients found to have advanced T-cell lymphoma, ultimately resulting in death.(49, 50) These findings suggest that, while the risk of malignancy is far lower than prior estimates, there is still a modestly increased risk of malignancy, particularly in the elderly. Currently, there are no consensus guidelines for malignancy screening or surveillance in this population.

MORTALITY RISK

Celiac disease has a good prognosis if it is diagnosed early and if the patient adheres to a lifelong gluten-free diet. However, multiple studies have found an increased overall mortality risk among people diagnosed with celiac disease. Several causes are deemed responsible for the mortality risk; these include malignancy, cardiovascular disease, and recurrent respiratory infections.(27, 51, 52)

While older studies indicate a 1.39- to 2.0-fold increased mortality risk in patients with celiac disease, there is some debate over the mortality risk in recent years.(51) Findings from a retrospective Swedish study of 49,829 patients with celiac disease found a small but statistically significant mortality risk of 9.7 vs. 8.6 deaths per 1000 person-years.(53) The relative increase in mortality risk was present across all age groups but greatest in those diagnosed between 18 and 39 years; while those over 60 years had the highest absolute mortality rate at 54.3 deaths per 1000 person-years, they had the lowest age- and gender-matched relative risk compared to age-matched population controls (HR 1.18; 95% CI 1.14–1.22). This diminished relative risk may be related to the higher baseline mortality risk in the general population in individuals over 60 years.

REFRACTORY CELIAC DISEASE

Refractory celiac disease is defined as the persistence of malabsorptive symptoms and small intestinal villus atrophy despite adherence to a strict gluten-free diet for at least 12 months. The prevalence of refractory celiac disease among celiac disease patients is low.(54) Older age at diagnosis has been noted as a risk factor for refractory celiac disease, which may be due to longstanding untreated disease, although the exact mechanisms have not been well-described.(55)

The implications of refractory celiac disease depend on the type: those without aberrant lymphocytes (type 1) have a better prognosis than those with abnormal lymphocytes (type 2), which confers a high risk for progression to enteropathy-associated T-cell lymphoma.(56) Using age, serum albumin concentration, and the presence of abnormal intraepithelial lymphocytes, a three-factor clinical score was shown to predict 5-year survival in patients with refractory celiac disease.(57) Here, older age at diagnosis of refractory celiac disease served as a negative prognostic factor, suggesting that older patients are not only at higher risk for developing refractory celiac disease, but that they are also at a higher related mortality risk.

MANAGEMENT AND HEALING

The mainstay of celiac disease treatment is lifelong adherence to a strict gluten-free diet. Improvement in symptoms typically occurs within days to weeks, and often precedes normalization of serologic markers and duodenal villus atrophy.(58) Multiple studies have suggested that older patients with celiac disease can adhere to a gluten-free diet at a similar rate relative to their younger counterparts.(7, 11) In the elderly population, adopting a strict gluten-free diet can improve quality of life, even in those who are screen-detected with subtle or no symptoms at diagnosis; this is important given the considerable lifestyle restrictions that are required by a gluten-free diet.(59)

Most studies have found that mucosal healing occurs more slowly in the elderly, and that older age may serve as a risk factor for persistent villus atrophy in patients with symptomatic disease.(60, 61) In a prospective, longitudinal study of symptomatic adult patients with celiac disease on a strict gluten-free diet, persistent villus atrophy was observed in 53% of patients after 2 years, with multivariate analysis demonstrating older age as the only associated independent risk factor.(62)** One possible explanation for these findings is that older patients are inadvertently exposed to ongoing low levels of gluten over time.(63) Patients may also differ in their threshold response to gluten exposure, but this has not been studied in the elderly population specifically.(64)

Overall, while rates of mucosal healing have improved markedly in recent years, this has not been the case for the elderly population. This was illustrated in a retrospective study of 7,648 Swedish patients with celiac disease who underwent follow-up biopsy: 31% of all patients had persistent villus atrophy during the years 2000–2008, whereas this rate was 56% among those at least 70 years of age.(65) The reasons for this phenomenon are not clear but likely due to impaired healing mechanisms with advanced age. It is also possible that lower dietary adherence may be present in older adults; some of these individuals may have more difficulty acquiring the necessary information to adhere to a gluten-free diet, or be unable to perform the necessary adaptations (including changes to grocery shopping or cooking) to maintain a consistently gluten-free diet. These unique cognitive and physical constraints should be considered when providing guidance and counseling to older adults diagnosed with celiac disease to maximize the possibility of mucosal healing.

CONCLUSIONS

Despite its frequently subtle clinical presentations, celiac disease in older adults is becoming increasingly prevalent but likely remains underdiagnosed. In contrast to the shift towards a biopsy avoidance strategy in children, diagnostic algorithms still rely on duodenal biopsy in older adults, reflecting the milder serologic patterns generally observed in the elderly. The importance of an early diagnosis is evidenced by the high potential burden of downstream morbidity and the modestly increased risk of mortality. Refractory celiac disease is a particular concern in the aging population and is associated with increased mortality risk. Lastly, the reason for lower rates of mucosal healing among older adults remains poorly understood and is an area in need of further investigation.