Celiac Disease Diagnosis: Simple Rules Are Better Than Complicated Algorithms

Celiac disease is the only treatable autoimmune disease, provided that a correct diagnosis is achieved and a strict, lifelong gluten-free diet is implemented. The current diagnostic algorithm for celiac disease includes initial screening serological tests, followed by a confirmatory small intestinal biopsy showing the autoimmune insult typical of celiac disease. The biopsy, considered the diagnostic gold standard, has been recently questioned as a reliable and conclusive test for every case. Indeed, the wide variability of celiac disease-related findings suggests that it is difficult to conceptualize the diagnostic process into rigid algorithms that do not always cover the clinical complexity of this disease. Instead we find clinically useful the shifting to a quantitative approach that can be defined as the “4 out of 5” rule: the diagnosis of celiac disease is confirmed if at least 4 of the following 5 criteria are satisfied: typical symptoms of celiac disease; positivity of serum celiac disease immunoglobulin, A class autoantibodies at high titer; human leukocyte antigen (HLA)-DQ2 or DQ8 genotypes; celiac enteropathy at the small bowel biopsy; and response to the gluten-free diet.     

The importance of and options available for screening of celiac disease

Even though guidelines for diagnosing celiac disease have been compiled and accepted by a number of expert associations, this disease continues to be under-diagnosed in children and, particularly, in adults. This is even though numerous scientific papers, short case studies and review papers have been published highlighting this issue and consensually supporting screening methods. In addition, research results by reputable Czech and Slovak authors suggest that, at present, only a small proportion of all cases of celiac disease are correctly diagnosed. Considering this, methods to diagnose the disease in its initial stage are continuously being sought. Biopsy of the mucosa of the small intestine remains the gold standard when diagnosing celiac disease. Within the targeted diagnostic algorithm, less invasive techniques should precede biopsy. These are applied mainly in cases of atypical forms of the disease and are based on an examination of serum autoantibodies. Their application and use is advantageous from many perspectives. However, practical clinical experience showed that they are not always sufficiently specific and sensitive. Using their own experience and published literature, the authors discuss the issues of screening and diagnosing celiac disease. It is obvious that targeted screening will undoubtedly uncover new, mainly atypical forms of celiac disease, while some cases shall remain undiagnosed. The diagnosis of celiac disease can be made on the basis of clinical, laboratory and histopathological correlation, respecting possible difficulties.     

Diagnostic approach to suspected irritable bowel syndrome

Diagnostic activity in patients with suspected irritable bowel syndrome (IBS) should be brief and focussed, limited to investigations that are likely to exclude serious alternative diagnoses and when negative support a positive diagnosis of IBS. The diagnosis of IBS is clinical, and is robust over time, although other symptoms may add to the clinical picture and other symptoms of functional disorders are common. The most important differential diagnoses are celiac disease, colorectal carcinoma and colitis. 'Red Flag' symptoms and signs should be considered indications for full colonoscopy, which should be performed with a low threshold in patients above 50 years of age. Serologic markers are useful to exclude celiac disease, but positive tests must be confirmed with duodenal biopsies.     

Depression in adult untreated celiac subjects: diagnosis by the pediatrician

Untreated celiac disease can lead to serious behavioral disorders. We describe three adult patients with undiagnosed or untreated celiac disease without particular intestinal signs, causing persistent depressive symptoms in three of the parents of our pediatric patients. In two of the three cases, the pediatrician suspected the diagnosis when taking the family history of the children. In fact, a diagnosis of celiac disease was made during childhood, when they had intestinal symptoms, but the gluten-free diet was spontaneously interrupted during the teenage period because of the disappearance of the typical intestinal signs. In the third case the mother was tested for antiendomysium antibodies (EmA), as she had a diagnosed celiac child. In all three patients, the depressive symptoms improved quickly with a gluten-free diet. In conclusion, celiac disease should be taken into consideration in the presence of behavioral and depressive disorders, particularly if they are not responsive to the usual antidepressive therapy.     

Silent Celiac Disease Activated by Pancreaticoduodenectomy

Diarrhea and weight loss are common after pancreaticoduodenectomy, and arise from varying etiologies. An uncommon but important cause for these symptoms is the postoperative activation of silent celiac disease. We sought to describe the clinical presentation, diagnosis, treatment, and follow-up of a series of patients with silent celiac disease unmasked after pancreaticoduodenectomy, and to summarize the existing case reports on this association. A search of the electronic medical record at our institution was performed cross-referencing terms associated with celiac disease and pancreaticoduodenectomy for the years 1976–2004. Cases were then reviewed to ensure that no signs or symptoms attributable to celiac disease were present preoperatively. Seven patients were identified; five were male, and the median age was 56. All patients underwent surgery for a presumed pancreatic or ampullary malignancy. Six patients developed symptoms ultimately attributable to celiac disease immediately after pancreaticoduodenectomy, most commonly diarrhea and weight loss. A single patient had silent celiac disease incidentally diagnosed at pancreaticoduodenectomy that remained silent postoperatively on an unrestricted diet. Symptoms completely resolved in 4 of 6 patients after initiation of a gluten-free diet, with partial improvement in the remaining 2 patients. The median delay from pancreaticoduodenectomy to diagnosis of celiac disease in the 6 symptomatic patients was 6 months. Clinicians should consider celiac disease as a potential diagnosis in patients with failure to thrive and diarrhea after pancreaticoduodenectomy. This entity is uncommon, but may be underrecognized. The underlying mechanism may relate to an increased antigenic load secondary to postsurgical changes in intestinal physiology.     

Current epidemiology and accessibility to diet compliance in adult celiac disease.

BACKGROUND: The widespread of serologic diagnosis for celiac disease has brought about an epidemiologic shift. Little up-to-date information is available on relevant epidemiologic issues regarding diagnosis, information, and therapy. OBJECTIVE: To examine forms of presentation, diagnostic difficulties, follow-up, information sources, and treatment-related issues regarding celiac disease. METHOD: A cross-sectional observational study using a self-completed questionnaire. RESULTS: Seventy-three adult patients were included; 15.0% of cases were diagnosed over 60 years of age. Most were non-smokers (91.8%). The rate of first-degree relatives with celiac sprue was 10.9%. The disease had a classic presentation in only 54.7% of cases. A functional gastrointestinal disorder was initially suspected in 42.4% of patients. Diet adherence is adequate, with unintentional lack of compliance in 15.5% of patients. Diet results in absent or improved symptoms in virtually all patients, but most of them consider compliance a challenge. Forty percent had difficulty finding gluten-free food, and 50.8% had problems in labelling recognition. CONCLUSIONS: Celiac disease presents at any age, has a great variety of manifestations, and responds very well to gluten-free diet. It is crucial that patients be highly motivated and informed, and that they know for certain which foods and manufactured products are to be to used. Therefore, adequate control will result from coordination and cooperation regarding all resources involved, including medical care, and information provided by associations and other sources such as the Web.     

Celiac disease in older people

In recent years, there has been increasing recognition that the classical textbook presentation of celiac disease with a malabsorption syndrome and a flat jejunal mucosa is only part of a broad spectrum of clinical and histological features associated with gluten sensitivity. Diagnosis of this treatable condition is often delayed or missed because of a failure to appreciate that celiac disease can present at any age and that symptoms are often subtle and not clearly related to gastrointestinal disease. Nonspecific symptoms and nutritional deficiencies are especially common in older patients and may not always be investigated thoroughly. Use of serological screening tests has improved ease of detection of celiac disease in patients without classical symptoms.     

Intolerance of gluten--a new disease or undiagnosed celiac disease

The prevalence of celiac disease is about 1% in the population and is growing due to the wide use of immunological methods of diagnosis. In recent years, in-depth research of the celiac disease has led not only to an increase in the number of patients with celiac disease, but also to the emergence of a broad spectrum of diseases associated with the ingestion of gluten. In this regard, a new pathology, known as "gluten intolerance or gluten sensitivity", attracted special attention of researchers. Studies in recent years have established that patients with this pathology may have both gastrointestinal symptoms and extraintestinal manifestations. Examinations of such patients usually do not find histological changes of the mucous membrane of the small intestine and autoimmune antibodies (to tissue transglutaminase (tTG) and endomysial (EMA)); however an increased level of gliadin antibodies (AGA) is often observed. Allergy to gluten is also absent. A gluten-free diet for such patients, like in case of the celiac disease, leads to the disappearance of clinical symptoms. Exact criteria for the diagnosis of this nosology have not been identified so far, but most researchers believe that prevalence of "gluten intolerance" is much higher than that of celiac disease.     

Non-celiac gluten sensitivity: Time for sifting the grain

In the last few years, a new nomenclature has been proposed for the disease induced by the ingestion of gluten, a protein present in wheat, rice, barley and oats. Besides celiac disease and wheat allergy, the most studied forms of gluten-related disorders characterized by an evident immune mechanism (autoimmune in celiac disease and IgE-mediated in wheat allergy), a new entity has been included, apparently not driven by an aberrant immune response: the non-celiac gluten sensitivity (NCGS). NCGS is characterized by a heterogeneous clinical picture with intestinal and extraintestinal symptoms arising after gluten ingestion and rapidly improving after its withdrawal from the diet. The pathogenesis of NCGS is largely unknown, but a mixture of factors such as the stimulation of the innate immune system, the direct cytotoxic effects of gluten, and probably the synergy with other wheat molecules, are clues for the complicated puzzle. In addition, the diagnostic procedures still remain problematic due to the absence of efficient diagnostic markers; thus, diagnosis is based upon the symptomatic response to a gluten-free diet and the recurrence of symptoms after gluten reintroduction with the possibility of an important involvement of a placebo effect. The temporary withdrawal of gluten seems a reasonable therapy, but the timing of gluten reintroduction and the correct patient management approach are have not yet been determined.     

Celiac disease: From pathophysiology to treatment

Celiac disease, also known as "celiac sprue", is a chronic inflammatory disorder of the small intestine, produced by the ingestion of dietary gluten products in susceptible people. It is a multifactorial disease, including genetic and environmental factors. Environmental trigger is represented by gluten while the genetic predisposition has been identified in the major histocompatibility complex region. Celiac disease is not a rare disorder like previously thought, with a global prevalence around 1%. The reason of its under-recognition is mainly referable to the fact that about half of affected people do not have the classic gastrointestinal symptoms, but they present nonspecific manifestations of nutritional deficiency or have no symptoms at all. Here we review the most recent data concerning epidemiology, pathogenesis, clinical presentation, available diagnostic tests and therapeutic management of celiac disease.     

Celiac disease in a rheumatology unit: a case study

The objective of the study is to present a series of 20 patients who have been attending a rheumatology unit and were diagnosed with celiac disease in adult life. The record-charts of 20 Italian not consanguineous patients affected by celiac disease (1 man and 19 women, mean age of 46.7), diagnosed at >16 years of age, followed by a rheumatology unit were reviewed (group 1). Any other autoimmune disease diagnosed in the patients were given was recorded; moreover, the reason for rheumatologist evaluation was registered as well as the presence of symptoms suggestive of celiac disease and the obstetric history. The clinical features were compared with those of a group of 40 celiac patients (8 men and 32 women, mean age of 43.1) followed by a medicine department (group 2); even in these cases the diagnosis of celiac disease was performed in adult life. Sixteen out of 20 patients in Group 1 were diagnosed as suffering from celiac disease by the rheumatologist. Seventeen concomitant autoimmune disorders among which nine were connective tissue diseases were found in 15 patients. The main reason for rheumatologist evaluation was arthromyalgias. Ten patients showed one or more clinical features suggestive of celiac disease; moreover, eight patients had a history of sideropenic anemia. After the adoption of a gluten-free diet there were three pregnancies that all ended with alive newborns, differently from the obstetric history before celiac disease diagnosis, characterized by a relevant number of miscarriages and foetus deaths. In Group 2, a total of ten autoimmune diseases concomitant with celiac disease were found in eight patients; autoimmune thyroid disorders represented the most frequent cases. No connective tissue diseases were recognized. Celiac disease may coexist with connective tissue diseases; the recognition of this association is difficult because celiac disease may present with atypical or even symptomless forms or in some cases may resemble a multisystem disorder or may mimic a rheumatologic condition; on the other hand, the variety of symptoms of rheumatic disorders may make difficult the diagnosis of celiac disease in association with a systemic autoimmune disease. These confounding factors often lead to a delay in performing the right diagnostic formulation.     

Diarrhea in a patient with Down syndrome and endemic sprue

BACKGROUND: Down syndrome is associated with disorders such as celiac disease, hypothyroidism, and insulin-dependent diabetes mellitus. In patients with mono- or oligosymptomatic celiac disease the time interval between the onset of symptoms and diagnosis often is unacceptably long. CASE REPORT: A female patient with Down syndrome is presented who had acute watery diarrhea, which spontaneously ceased but recurred after a few days. After endoscopic and histologic evaluation and measurement of gliadin, endomysium, and reticulin antibodies celiac sprue was diagnosed. Further investigation showed findings of autoimmune hypothyroidism and secondary hyperparathyreoidism. After the patient was put on a gluten-free diet her state quickly improved. CONCLUSION: Associations between Down syndrome and autoimmune diseases exist. Patients with acute gastrointestinal symptoms should be evaluated as to celiac disease. The time interval between the onset of symptoms and diagnosis of celiac disease can be shortened, if all diagnostic tools are used at the appropriate time.     

Celiac sprue (the great modern-day imposter)

PURPOSE OF REVIEW: To review the current epidemiological information on celiac disease and the various presentations and associated. RECENT FINDINGS: Epidemiologic studies reveal celiac disease to be common, occurring in approx. 1% of the population. It is being diagnosed worldwide, even in developing countries. The classic mode of presentation has become less common, with diarrhea or a malabsorption syndrome as the mode of presentation in fewer than 50% of individuals. The other major modes of presentation are iron-deficiency anemia, osteoporosis, screening of family members, or incidentally at endoscopy done for dyspepsia or reflux. Neurological presentations may include peripheral neuropathy or ataxia. Arthritis is commonly found in patients with celiac disease when systematically sought. Patients often have a previous diagnosis of irritable bowel syndrome. Autoimmune diseases occur more frequently (three to ten times more) in those with celiac disease than the general population. However, this increased incidence of autoimmune diseases is not prevented by early diagnosis of celiac disease. SUMMARY: We will review the various associated diseases/presentations of celiac disease. The heterogeneity of the symptoms can make the diagnosis challenging and certainly the great modern-day imposter.     

Malabsorption work-up: utility of small bowel biopsy.

A wide variety of small intestinal mucosal diseases lead to malabsorption. Although stool studies, especially stool for excess fat, and functional tests for deficiency states are important clues to malabsorption, small intestinal biopsies are probably the most crucial part of the diagnostic process. Many mucosal disorders have distinctive histologic features that allow for precise diagnosis. However, these histologic changes might be subtle. The role of the gastroenterologist is to provide the pathologist with adequate clinical information and tissue material to ensure a complete examination pathologically. Celiac disease is the most common mucosal cause of chronic malabsorption in the western world. Celiac disease can present classically as large volume fatty diarrhea, but it more commonly presents with subtle clinical symptoms or iron deficiency anemia. Although the histologic hallmark of celiac disease is increased intraepithelial lymphocytosis along with villous atrophy, increased intraepithelial lymphocytosis alone in an appropriate clinical context might suggest the diagnosis of celiac disease. The aim of this review is to highlight the importance of close cooperation and communication between the gastroenterologist and the pathologist to optimize the diagnosis of mucosal diseases that result in malabsorption.     

Undiagnosed celiac disease in childhood

AIMS: This study was designed to assess the proportion of adult patients with celiac disease who had had undiagnosed symptoms during childhood and to determine the consequences of such diagnostic delay. PATIENTS AND METHODS: One hundred eighty-four patients with celiac disease (56 males, 128 females, age range 17-88 years) were classified according to diagnosis and symptoms of celiac disease during childhood. Prevalence of short stature, low fertility, clinical osteoporosis, cancer, and autoimmune disease were assessed in each celiac group and compared with a control group matched for gender and age. RESULTS: Compared with the control group, patients with celiac disease were shorter (men 171.4 +/- 9.0 cm vs 176.4 +/- 6.9 cm, P<0.01; women 159.7 + 7.3 cm vs 162.7 +/- 6.2 cm, P<0.01) and had a higher prevalence of symptomatic osteoporosis (5%) cancer (10%), and autoimmune disease (25%). Compared with matched controls and with patients whose celiac disease had been diagnosed during childhood (n=36), or who had remained symptom-free (n=95), patients who had undiagnosed symptomatic celiac disease during childhood exhibited higher prevalence of short stature (26%), low female fertility or low birth weight (36%). Multivariate analysis showed that short stature and low fertility correlated with duration of symptoms before diagnosis; osteoporosis and cancer correlated with age. The prevalence of autoimmune disease was unrelated to early onset of symptoms or delay to diagnosis. CONCLUSIONS: Missing the diagnosis of celiac disease in a symptomatic child may lead to short stature and low female fertility.     

Celiac disease presenting as resistant hypothyroidism.

The high prevalence of celiac disease in patients with autoimmune hypothyroidism, compared to the general population, has been well documented but screening for celiac disease is not recommended as yet in otherwise asymptomatic hypothyroid patients. In recent years the high prevalence of undiagnosed celiac disease in the general population, largely as a result of the many atypical manifestations of the disease, has become apparent. We report the case of a 58-year-old woman with autoimmune hypothyroidism who was initially suspected of having celiac disease on the basis of apparent resistance to levothyroxine therapy, and who had no other clinical or laboratory clues to suggest the diagnosis. Cases of undiagnosed celiac disease causing levothyroxine malabsorbtion have previously been described, but all previous cases had other obvious manifestations of the disease. We believe that this atypical presentation of celiac disease warrants further attention, and that the diagnosis of celiac disease should always be considered in patients requiring higher than expected doses of thyroid hormone replacement, even in patients with normal bowel habit, and no other apparent manifestations of the disease.     

Celiac disease genetics: current concepts and practical applications.

Celiac disease is a multifactorial disease with complex genetics. Both HLA and non-HLA genes contribute to the genetic component, but recent findings suggest that the importance of non-HLA genes might have been overestimated. No susceptibility genes other than HLA-DQ have yet been identified in celiac disease. In contrast to the meager knowledge regarding non-HLA genes, we have acquired a detailed understanding about which HLA genes are predisposing for disease, and how they are involved in the pathogenesis. This knowledge might pave the road for novel treatments for the disease. The role of HLA as a necessary, but not sufficient, genetic factor can moreover be used for diagnostic purposes to exclude a celiac disease diagnosis. The applicability of HLA genotyping is particularly useful for excluding celiac disease in family members or risk groups with fairly unbiased distribution of HLA alleles (ie, patients with Turner syndrome and patients with Down syndrome) and in patients with a clinical suspicion of celiac disease.     

Relation between cigarette smoking and celiac disease: evidence from a case-control study

OBJECTIVES: It has been suggested that environmental factors other than gliadin might play a role in pathogenesis of celiac disease. Cigarette smoking was reported to exert a protective effect against the development of symptomatic celiac disease; however, this relationship was not confirmed. The aim of this study was to determine the effect of cigarette smoking on celiac disease. METHODS: A cohort of 87 consecutive celiac disease patients attending the clinic of Malabsorption and 174 age- and sex-matched individuals diagnosed with functional GI disorder were included in the study. Clinical information was obtained both at the time of diagnosis and at follow-up by reviewing the clinical history. Smoking information was obtained through an in-person interview using a questionnaire. RESULTS: Although 33% of controls were current smokers at the time of the study, only 16% of celiac patients were smokers at diagnosis (odds ratio, 0.39; 95% confidence interval 0.19-0.79; p < 0.006). The proportion of nonsmokers among patients (84%) was significantly greater than that among controls (67%; odds ratio, 2.54; 95% confidence interval 1.27-5.16; p < 0.007). Current smoker patients had a lower baseline BMI (p < 0.05) and body weight (p < 0.05) compared to former smokers. Compared with nonsmokers, control individuals who were active smokers at entry in the study were younger (p < 0.02) and had lower body weight (p < 0.03) and BMI (p < 0.03). Interestingly, positive lineal correlation was observed between age at diagnosis and daily cigarette consumption (r = 0.72; p < 0.004) in active smokers. We did not detect any relationship either between causes for cessation of smoking and clinical symptoms or between differences in the proportions of smoking habits when patients were stratified according to their clinical status at diagnosis (symptomatic vs subclinical/asymptomatic cases). CONCLUSIONS: This study provides evidence that, compared with control subjects, a significantly lower proportion of patients with celiac disease were current smokers at the time of diagnosis, and that cigarette smoking delayed diagnosis of celiac disease. Our study suggests that the nutritional compromise of patients with celiac disease who smoked resulted from the summation of the effect of celiac disease per se and that produced by the smoking habit. Further studies are necessary to identify whether the relationship between smoking and celiac disease is causal or incidental.     

Endocrinological disorders and celiac disease

Celiac disease is a permanent intolerance to dietary gluten. Its well known features are abdominal symptoms, malabsorption of nutrients, and small-bowel mucosal inflammation with villous atrophy, which recover on a gluten-free diet. Diagnosis is challenging in that patients often suffer from subtle, if any, symptoms. The risk of clinically silent celiac disease is increased in various autoimmune conditions. The endocrinologist, especially, should maintain high suspicion and alertness to celiac disease, which is to be found in 2-5% of patients with insulin-dependent diabetes mellitus or autoimmune thyroid disease. Patients with multiple endocrine disorders, Addison's disease, alopecia, or hypophysitis may also have concomitant celiac disease. Similar heredity and proneness to autoimmune conditions are considered to be explanations for these associations. A gluten-free diet is essential to prevent celiac complications such as anemia, osteoporosis, and infertility. The diet may also be beneficial in the treatment of the underlying endocrinological disease; prolonged gluten exposure may even contribute to the development of autoimmune diseases. The diagnosis of celiac disease requires endoscopic biopsy, but serological screening with antiendomysial and antitissue transglutaminase antibody assays is an easy method for preliminary case finding. Celiac disease will be increasingly detected provided the close association with autoimmune endocrinological diseases is recognized.     

Silent celiac disease in chronic hepatitis C: impact of interferon treatment on the disease onset and clinical outcome

GOALS: To assess the impact of interferon treatment on celiac disease onset in hepatitis C patients and to clarify its clinical relevance and outcome. BACKGROUND: Hepatitis C is associated with autoimmunity, which can be exacerbated by interferon treatment. Cases of celiac disease activation during interferon treatment have been reported. STUDY: Retrospective evaluation of 534 hepatitis C patients with or without symptoms compatible with celiac disease onset during interferon treatment and 225 controls. Anti-transglutaminase antibodies were assayed. HLA-DQA1 and -B1 loci were typed. Upper gastrointestinal endoscopy was applied to confirm the diagnosis in antibody-positive patients. RESULTS: Anti-transglutaminase antibodies were detected before treatment in 1.3% of hepatitis C patients and in 0.4% of controls (not significant). Eighty-six percent of patients with anti-transglutaminase antibodies showed activation of celiac disease while on interferon. Symptoms ranged from mild to severe, and interferon had to be discontinued in 2 of 7 (29%) patients. Symptoms disappeared in 6 of 7 patients after interferon withdrawal. Onset of symptoms compatible with celiac disease during interferon therapy was significantly associated with the presence of anti-transglutaminase antibodies (OR 53). CONCLUSIONS: In hepatitis C patients, the activation of silent celiac disease during interferon treatment is almost universal and should be suspected, but it uncommonly requires interferon treatment discontinuation. Symptoms subside after interferon withdrawal.