For Celiac Disease, Diagnosis Is Not Enough
2012; Elsevier BV; Volume: 10; Issue: 8 Linguagem: Inglês
10.1016/j.cgh.2012.03.020
ISSN1542-7714
AutoresPeter R. Gibson, Susan Shepherd, Jason A. Tye‐Din,
Tópico(s)Helicobacter pylori-related gastroenterology studies
ResumoEver since gluten was identified as the causative antigen of celiac disease (CD) in the 1950s, the mainstay of therapy has been life-long gluten elimination. Its success in reversing the severe malabsorption and reducing the sizeable mortality rate not uncommonly seen in young children half a century ago ironically has limited rigorous and systematic evaluation of the gluten-free diet (GFD) as a therapy. Instead, research has focused on improving diagnosis and understanding disease epidemiology. However, with the growing understanding of the clinical burden of untreated or poorly treated CD,1Ludvigsson J.F. Montgomery S.M. Ekbom A. et al.Small-intestinal histopathology and mortality risk in celiac disease.JAMA. 2009; 302: 1171-1178Crossref PubMed Scopus (281) Google Scholar, 2Rubio-Tapia A. Rahim M.W. See J.A. et al.Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet.Am J Gastroenterol. 2010; 105: 1412-1420Crossref PubMed Scopus (265) Google Scholar efforts now should be harnessed toward establishing exactly what constitutes appropriate CD management and follow-up evaluation. Current guidelines are vague and/or not evidence-based. With such a background, it not surprising that the study by Herman et al3Herman M.L. Rubio-Tapia A. Lahr B.D. et al.Patients with celiac disease are not followed up adequately.Clin Gastroenterol Hepatol. 2012; 10: 893-899Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar revealed haphazard and deficient follow-up evaluation of patients in a population-based study.Optimal management of a chronic disease requires definition of therapeutic goals. Adherence to dietary therapy is central to good outcomes. Four main methods to determine dietary adherence have been proposed. First, dietitian-led evaluation is the closest to a gold standard, but is limited by the paucity of trained dietitians with the necessary skills and time to devote to this task, and is dependent on appropriate education and truthfulness to achieve accurate results. Second, the circulating concentrations of celiac antibodies such as antitransglutaminase or antigliadin can reflect disease activity, and, by extension, dietary compliance. Levels of celiac-associated antibodies typically decrease with gluten restriction and stay the same or increase further with nonadherence,4Nachman F. Sugai E. Vázquez H. et al.Serological tests for celiac disease as indicators of long-term compliance with the gluten-free diet.Eur J Gastroenterol Hepatol. 2011; 23: 473-480PubMed Google Scholar and normalization is anticipated in most patients after 1 year of a strict GFD.5Dipper C.R. Maitra S. Thomas R. et al.Anti-tissue transglutaminase antibodies in the follow-up of adult coeliac disease.Aliment Pharmacol Ther. 2009; 30: 236-244Crossref PubMed Scopus (48) Google Scholar, 6Bürgin-Wolff A. Dahlbom I. Hadziselimovic F. et al.Antibodies against human tissue transglutaminase and endomysium in diagnosing and monitoring coeliac disease.Scand J Gastroenterol. 2002; 37: 685-691Crossref PubMed Scopus (86) Google Scholar Unfortunately, celiac-associated antibodies are not always present and their levels provide limited information regarding GFD adherence and mucosal healing.7Dickey W. Hughes D.F. McMillan S.A. Disappearance of endomysial antibodies in treated celiac disease does not indicate histological recovery.Am J Gastroenterol. 2000; 95: 712-714Crossref PubMed Google Scholar The main clinical value of monitoring serology may be as a marker of nonadherence to the diet rather than of adherence. Furthermore, there are substantial differences in the performances of each serologic assay and between commercial kits for each assay,8Reeves G.E. Squance M.L. Duggan A.E. et al.Diagnostic accuracy of coeliac serological tests: a prospective study.Eur J Gastroenterol Hepatol. 2006; 18: 493-501Crossref PubMed Scopus (89) Google Scholar limiting their reproducibility. The third method is the use of simple, validated, gluten-free adherence questionnaires. A 4-item questionnaire correlated significantly with endomysial antibodies and villous atrophy,9Biagi F. Andrealli A. Bianchi P.I. et al.A gluten-free diet score to evaluate dietary compliance in patients with coeliac disease.Br J Nutr. 2009; 102: 882-887Crossref PubMed Scopus (95) Google Scholar and a 7-item questionnaire, the Celiac Dietary Adherence Test, correlated highly with standardized dietitian measures and was superior to tissue transglutaminase serology.10Leffler D.A. Dennis M. Edwards George J.B. et al.A simple validated gluten-free diet adherence survey for adults with celiac disease.Clin Gastroenterol Hepatol. 2009; 7: 530-536Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar Such tools may be useful in research settings, but their clinical usefulness in the individual patient is uncertain. Finally, healing of the intestinal mucosa via duodenal biopsy has been used as the ultimate judge of dietary adherence and is discussed later.The clinical end points that to date have been the cornerstones of treatment efficacy are relief of symptoms, and correction and prevention of nutritional abnormalities. They are readily assessable and symptom avoidance is the main motivation for CD patients to adhere to the GFD.11O'Leary C. Wieneke P. Healy M. et al.Celiac disease and the transition from childhood to adulthood: a 28-year follow-up.Am J Gastroenterol. 2004; 99: 2437-2441Crossref PubMed Scopus (69) Google Scholar However, reliance on symptoms as the key indicator of success or otherwise is not evidence-based. On the contrary, symptoms are a poor guide to mucosal healing12Abrams J.A. Diamond B. Rotterdam H. et al.Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy.Dig Dis Sci. 2004; 49: 546-550Crossref PubMed Scopus (130) Google Scholar, 13Lanzini A. Lanzarotto F. Villanacci V. et al.Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet.Aliment Pharmacol Ther. 2009; 29: 1299-1308Crossref PubMed Scopus (174) Google Scholar and are not applicable to increasing proportions of patients who have few or no symptoms at diagnosis.Therapeutic targets need to be extended to those associated with reduction of long-term complications. One target might be immunologic consequences of disease activity. An emerging concept is that CD more aptly is regarded as a genetically linked, systemic immune disease as opposed to a primary malabsorptive enteropathy. This evolution in perspective is supported by strong genetic and immune data that implicate genes involved in antigen presentation (HLA-DQ2 and -DQ8) and gluten-specific CD4+ T cells,14Abadie V. Sollid L.M. Barreiro L.B. et al.Integration of genetic and immunological insights into a model of celiac disease pathogenesis.Annu Rev Immunol. 2011; 29: 493-525Crossref PubMed Scopus (362) Google Scholar rather than gastrointestinal function. Moreover, compelling clinical evidence supports the existence of a gluten-sensitive state characterized by positive celiac serology but minimal or absent enteropathy with symptoms and end-organ damage, such as impaired bone density, which favorably responds to a GFD.15Kurppa K. Collin P. Sievänen H. et al.Gastrointestinal symptoms, quality of life and bone mineral density in mild enteropathic coeliac disease: a prospective clinical trial.Scand J Gastroenterol. 2010; 45: 305-314Crossref PubMed Scopus (55) Google Scholar These observations have driven much of the changes in the revised diagnostic criteria for CD, which now place greater emphasis on genetics (HLA) and celiac serology, and less on Marsh 3 histologic changes for diagnosis.16Husby S. Koletzko S. Korponay-Szabó I.R. et al.European Society for Pediatric Gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease.J Pediatr Gastroenterol Nutr. 2012; 54: 136-160Crossref PubMed Scopus (1899) Google Scholar Currently, the only practical therapeutic target that can be used to indicate immunologic remission is normalization of celiac serology, but correlation with disease activity is, at best, modest.Despite the conceptual shift, the marker of ongoing celiac activity that is accessible in the vast majority of CD patients is ongoing intestinal injury, which is associated with higher risks of complications and death. The evidence derives from observations of patients with unrecognized CD associated with increased serology, the vast majority of whom are highly likely to have had chronic intestinal inflammation,17Metzger M.H. Heier M. Mäki M. et al.Mortality excess in individuals with elevated IgA anti-transglutaminase antibodies: the KORA/MONICA Augsburg cohort study 1989–1998.Eur J Epidemiol. 2006; 21: 359-365Crossref PubMed Scopus (79) Google Scholar, 18Rubio-Tapia A. Kyle R.A. Kaplan E.L. et al.Increased prevalence and mortality in undiagnosed celiac disease.Gastroenterology. 2009; 137: 88-93Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar and, direct observations in which those failing to heal the intestinal mucosa show increased risk of mortality1Ludvigsson J.F. Montgomery S.M. Ekbom A. et al.Small-intestinal histopathology and mortality risk in celiac disease.JAMA. 2009; 302: 1171-1178Crossref PubMed Scopus (281) Google Scholar, 2Rubio-Tapia A. Rahim M.W. See J.A. et al.Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet.Am J Gastroenterol. 2010; 105: 1412-1420Crossref PubMed Scopus (265) Google Scholar and complications.1Ludvigsson J.F. Montgomery S.M. Ekbom A. et al.Small-intestinal histopathology and mortality risk in celiac disease.JAMA. 2009; 302: 1171-1178Crossref PubMed Scopus (281) Google Scholar, 19Kaukinen K. Peräaho M. Lindfors K. et al.Persistent small bowel mucosal villous atrophy without symptoms in coeliac disease.Aliment Pharmacol Ther. 2007; 25: 1237-1245Crossref PubMed Scopus (122) Google Scholar, 20Haines M.L. Anderson R.P. Gibson P.R. Systematic review: the evidence base for long-term management of coeliac disease.Aliment Pharmacol Ther. 2008; 28: 1042-1066Crossref PubMed Scopus (153) Google Scholar Persistent villous atrophy is associated with a more than 3-fold increased risk of osteoporosis, refractory CD, and malignancy irrespective of symptom resolution on a GFD.19Kaukinen K. Peräaho M. Lindfors K. et al.Persistent small bowel mucosal villous atrophy without symptoms in coeliac disease.Aliment Pharmacol Ther. 2007; 25: 1237-1245Crossref PubMed Scopus (122) Google Scholar It is assumed, therefore, that achieving mucosal healing will prevent morbidity and mortality associated with CD.Histopathologic assessment of duodenal biopsy specimens is the only way of assessing mucosal healing because there are no surrogate markers that are highly predictive of healing.20Haines M.L. Anderson R.P. Gibson P.R. Systematic review: the evidence base for long-term management of coeliac disease.Aliment Pharmacol Ther. 2008; 28: 1042-1066Crossref PubMed Scopus (153) Google Scholar In clinical practice, the reluctance to perform repeated duodenal biopsies in patients with CD has been evident. This may be the legacy of the use of jejunal capsule biopsies or gastroscopy before adequate sedation, both unpleasant and invasive procedures, but modern gastroscopy is simple and safe. Notably, in other conditions in which mucosal healing is becoming a target of therapy such as Crohn's disease, there seems to be very little reluctance to perform repeated colonoscopies, a more hazardous and unpleasant procedure. The lack of tolerable, long-term therapeutic options for CD outside the GFD also has removed the focus on assessing the small bowel, although this may change if pharmacotherapeutics such as budesonide are shown to be effective in controlled trials.If mucosal healing is a primary goal of therapy, when biopsies are to be performed is undefined. It has been well documented that healing is slow (or incomplete) in many patients despite a strict GFD,13Lanzini A. Lanzarotto F. Villanacci V. et al.Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet.Aliment Pharmacol Ther. 2009; 29: 1299-1308Crossref PubMed Scopus (174) Google Scholar but how quickly it is achieved in those who have healed at 1 to 2 years has been the subject of minimal research. If the aim is to perform the biopsy when the majority of patients have healed to confirm dietary compliance, then no earlier than 2 years is the generally recommended interval. If the aim is to determine who has not healed so that remedial interventions (such as dietary education or adjunctive medication) can be instituted, then it seems reasonable that this should be performed earlier. There is currently no case for reviewing healed mucosa unless the clinical situation demands a relook, but even this has not been evaluated. Until the intestinal lesion is followed up more intensively, the understanding of refractory CD will continue to be cloudy. Thus, there is a strong case for a re-evaluation of intestinal biopsy policies to achieve mucosal healing. Currently, follow-up small-bowel biopsy is not recommended by most guidelines in CD patients who achieve a clinical and serologic response to a GFD.An additional aspect of long-term management is the surveillance for diseases and complications associated with CD. Once the diagnosis is made, GFD is instituted and the patients are under ongoing clinical review, the development of associated diseases, such as thyroid disease or diabetes, is likely to be relatively uncommon. The cost effectiveness of surveillance via blood tests, such as thyroid function tests or a random or fasting blood glucose test, has not been assessed. However, most of the associated conditions are insidious in their onset and early recognition would be of clear clinical benefit to the patients. Bone density evaluation within a year of diagnosis is recommended by most guidelines. Monitoring nutritional status via, for example, weight and levels of vitamin D, folate, vitamin B12, zinc, and iron studies on a yearly basis once these levels have been normalized after diagnosis seems reasonable, if not evidence-based.Quality follow-up evaluation and optimal outcomes would be facilitated by clear guidelines, the lack of which might be at least partly responsible for the generally poor follow-up evaluation described in Olmstead County.3Herman M.L. Rubio-Tapia A. Lahr B.D. et al.Patients with celiac disease are not followed up adequately.Clin Gastroenterol Hepatol. 2012; 10: 893-899Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar There is a strong case for a re-evaluation of intestinal biopsy policies to achieve mucosal healing. The report by Herman et al3Herman M.L. Rubio-Tapia A. Lahr B.D. et al.Patients with celiac disease are not followed up adequately.Clin Gastroenterol Hepatol. 2012; 10: 893-899Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar underscores that the time is right for celiac clinicians and researchers to divert some of their enthusiasm for making the diagnosis of CD to establishing clear, evidence-based guidelines for its management. Ever since gluten was identified as the causative antigen of celiac disease (CD) in the 1950s, the mainstay of therapy has been life-long gluten elimination. Its success in reversing the severe malabsorption and reducing the sizeable mortality rate not uncommonly seen in young children half a century ago ironically has limited rigorous and systematic evaluation of the gluten-free diet (GFD) as a therapy. Instead, research has focused on improving diagnosis and understanding disease epidemiology. However, with the growing understanding of the clinical burden of untreated or poorly treated CD,1Ludvigsson J.F. Montgomery S.M. Ekbom A. et al.Small-intestinal histopathology and mortality risk in celiac disease.JAMA. 2009; 302: 1171-1178Crossref PubMed Scopus (281) Google Scholar, 2Rubio-Tapia A. Rahim M.W. See J.A. et al.Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet.Am J Gastroenterol. 2010; 105: 1412-1420Crossref PubMed Scopus (265) Google Scholar efforts now should be harnessed toward establishing exactly what constitutes appropriate CD management and follow-up evaluation. Current guidelines are vague and/or not evidence-based. With such a background, it not surprising that the study by Herman et al3Herman M.L. Rubio-Tapia A. Lahr B.D. et al.Patients with celiac disease are not followed up adequately.Clin Gastroenterol Hepatol. 2012; 10: 893-899Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar revealed haphazard and deficient follow-up evaluation of patients in a population-based study. Optimal management of a chronic disease requires definition of therapeutic goals. Adherence to dietary therapy is central to good outcomes. Four main methods to determine dietary adherence have been proposed. First, dietitian-led evaluation is the closest to a gold standard, but is limited by the paucity of trained dietitians with the necessary skills and time to devote to this task, and is dependent on appropriate education and truthfulness to achieve accurate results. Second, the circulating concentrations of celiac antibodies such as antitransglutaminase or antigliadin can reflect disease activity, and, by extension, dietary compliance. Levels of celiac-associated antibodies typically decrease with gluten restriction and stay the same or increase further with nonadherence,4Nachman F. Sugai E. Vázquez H. et al.Serological tests for celiac disease as indicators of long-term compliance with the gluten-free diet.Eur J Gastroenterol Hepatol. 2011; 23: 473-480PubMed Google Scholar and normalization is anticipated in most patients after 1 year of a strict GFD.5Dipper C.R. Maitra S. Thomas R. et al.Anti-tissue transglutaminase antibodies in the follow-up of adult coeliac disease.Aliment Pharmacol Ther. 2009; 30: 236-244Crossref PubMed Scopus (48) Google Scholar, 6Bürgin-Wolff A. Dahlbom I. Hadziselimovic F. et al.Antibodies against human tissue transglutaminase and endomysium in diagnosing and monitoring coeliac disease.Scand J Gastroenterol. 2002; 37: 685-691Crossref PubMed Scopus (86) Google Scholar Unfortunately, celiac-associated antibodies are not always present and their levels provide limited information regarding GFD adherence and mucosal healing.7Dickey W. Hughes D.F. McMillan S.A. Disappearance of endomysial antibodies in treated celiac disease does not indicate histological recovery.Am J Gastroenterol. 2000; 95: 712-714Crossref PubMed Google Scholar The main clinical value of monitoring serology may be as a marker of nonadherence to the diet rather than of adherence. Furthermore, there are substantial differences in the performances of each serologic assay and between commercial kits for each assay,8Reeves G.E. Squance M.L. Duggan A.E. et al.Diagnostic accuracy of coeliac serological tests: a prospective study.Eur J Gastroenterol Hepatol. 2006; 18: 493-501Crossref PubMed Scopus (89) Google Scholar limiting their reproducibility. The third method is the use of simple, validated, gluten-free adherence questionnaires. A 4-item questionnaire correlated significantly with endomysial antibodies and villous atrophy,9Biagi F. Andrealli A. Bianchi P.I. et al.A gluten-free diet score to evaluate dietary compliance in patients with coeliac disease.Br J Nutr. 2009; 102: 882-887Crossref PubMed Scopus (95) Google Scholar and a 7-item questionnaire, the Celiac Dietary Adherence Test, correlated highly with standardized dietitian measures and was superior to tissue transglutaminase serology.10Leffler D.A. Dennis M. Edwards George J.B. et al.A simple validated gluten-free diet adherence survey for adults with celiac disease.Clin Gastroenterol Hepatol. 2009; 7: 530-536Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar Such tools may be useful in research settings, but their clinical usefulness in the individual patient is uncertain. Finally, healing of the intestinal mucosa via duodenal biopsy has been used as the ultimate judge of dietary adherence and is discussed later. The clinical end points that to date have been the cornerstones of treatment efficacy are relief of symptoms, and correction and prevention of nutritional abnormalities. They are readily assessable and symptom avoidance is the main motivation for CD patients to adhere to the GFD.11O'Leary C. Wieneke P. Healy M. et al.Celiac disease and the transition from childhood to adulthood: a 28-year follow-up.Am J Gastroenterol. 2004; 99: 2437-2441Crossref PubMed Scopus (69) Google Scholar However, reliance on symptoms as the key indicator of success or otherwise is not evidence-based. On the contrary, symptoms are a poor guide to mucosal healing12Abrams J.A. Diamond B. Rotterdam H. et al.Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy.Dig Dis Sci. 2004; 49: 546-550Crossref PubMed Scopus (130) Google Scholar, 13Lanzini A. Lanzarotto F. Villanacci V. et al.Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet.Aliment Pharmacol Ther. 2009; 29: 1299-1308Crossref PubMed Scopus (174) Google Scholar and are not applicable to increasing proportions of patients who have few or no symptoms at diagnosis. Therapeutic targets need to be extended to those associated with reduction of long-term complications. One target might be immunologic consequences of disease activity. An emerging concept is that CD more aptly is regarded as a genetically linked, systemic immune disease as opposed to a primary malabsorptive enteropathy. This evolution in perspective is supported by strong genetic and immune data that implicate genes involved in antigen presentation (HLA-DQ2 and -DQ8) and gluten-specific CD4+ T cells,14Abadie V. Sollid L.M. Barreiro L.B. et al.Integration of genetic and immunological insights into a model of celiac disease pathogenesis.Annu Rev Immunol. 2011; 29: 493-525Crossref PubMed Scopus (362) Google Scholar rather than gastrointestinal function. Moreover, compelling clinical evidence supports the existence of a gluten-sensitive state characterized by positive celiac serology but minimal or absent enteropathy with symptoms and end-organ damage, such as impaired bone density, which favorably responds to a GFD.15Kurppa K. Collin P. Sievänen H. et al.Gastrointestinal symptoms, quality of life and bone mineral density in mild enteropathic coeliac disease: a prospective clinical trial.Scand J Gastroenterol. 2010; 45: 305-314Crossref PubMed Scopus (55) Google Scholar These observations have driven much of the changes in the revised diagnostic criteria for CD, which now place greater emphasis on genetics (HLA) and celiac serology, and less on Marsh 3 histologic changes for diagnosis.16Husby S. Koletzko S. Korponay-Szabó I.R. et al.European Society for Pediatric Gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease.J Pediatr Gastroenterol Nutr. 2012; 54: 136-160Crossref PubMed Scopus (1899) Google Scholar Currently, the only practical therapeutic target that can be used to indicate immunologic remission is normalization of celiac serology, but correlation with disease activity is, at best, modest. Despite the conceptual shift, the marker of ongoing celiac activity that is accessible in the vast majority of CD patients is ongoing intestinal injury, which is associated with higher risks of complications and death. The evidence derives from observations of patients with unrecognized CD associated with increased serology, the vast majority of whom are highly likely to have had chronic intestinal inflammation,17Metzger M.H. Heier M. Mäki M. et al.Mortality excess in individuals with elevated IgA anti-transglutaminase antibodies: the KORA/MONICA Augsburg cohort study 1989–1998.Eur J Epidemiol. 2006; 21: 359-365Crossref PubMed Scopus (79) Google Scholar, 18Rubio-Tapia A. Kyle R.A. Kaplan E.L. et al.Increased prevalence and mortality in undiagnosed celiac disease.Gastroenterology. 2009; 137: 88-93Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar and, direct observations in which those failing to heal the intestinal mucosa show increased risk of mortality1Ludvigsson J.F. Montgomery S.M. Ekbom A. et al.Small-intestinal histopathology and mortality risk in celiac disease.JAMA. 2009; 302: 1171-1178Crossref PubMed Scopus (281) Google Scholar, 2Rubio-Tapia A. Rahim M.W. See J.A. et al.Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet.Am J Gastroenterol. 2010; 105: 1412-1420Crossref PubMed Scopus (265) Google Scholar and complications.1Ludvigsson J.F. Montgomery S.M. Ekbom A. et al.Small-intestinal histopathology and mortality risk in celiac disease.JAMA. 2009; 302: 1171-1178Crossref PubMed Scopus (281) Google Scholar, 19Kaukinen K. Peräaho M. Lindfors K. et al.Persistent small bowel mucosal villous atrophy without symptoms in coeliac disease.Aliment Pharmacol Ther. 2007; 25: 1237-1245Crossref PubMed Scopus (122) Google Scholar, 20Haines M.L. Anderson R.P. Gibson P.R. Systematic review: the evidence base for long-term management of coeliac disease.Aliment Pharmacol Ther. 2008; 28: 1042-1066Crossref PubMed Scopus (153) Google Scholar Persistent villous atrophy is associated with a more than 3-fold increased risk of osteoporosis, refractory CD, and malignancy irrespective of symptom resolution on a GFD.19Kaukinen K. Peräaho M. Lindfors K. et al.Persistent small bowel mucosal villous atrophy without symptoms in coeliac disease.Aliment Pharmacol Ther. 2007; 25: 1237-1245Crossref PubMed Scopus (122) Google Scholar It is assumed, therefore, that achieving mucosal healing will prevent morbidity and mortality associated with CD. Histopathologic assessment of duodenal biopsy specimens is the only way of assessing mucosal healing because there are no surrogate markers that are highly predictive of healing.20Haines M.L. Anderson R.P. Gibson P.R. Systematic review: the evidence base for long-term management of coeliac disease.Aliment Pharmacol Ther. 2008; 28: 1042-1066Crossref PubMed Scopus (153) Google Scholar In clinical practice, the reluctance to perform repeated duodenal biopsies in patients with CD has been evident. This may be the legacy of the use of jejunal capsule biopsies or gastroscopy before adequate sedation, both unpleasant and invasive procedures, but modern gastroscopy is simple and safe. Notably, in other conditions in which mucosal healing is becoming a target of therapy such as Crohn's disease, there seems to be very little reluctance to perform repeated colonoscopies, a more hazardous and unpleasant procedure. The lack of tolerable, long-term therapeutic options for CD outside the GFD also has removed the focus on assessing the small bowel, although this may change if pharmacotherapeutics such as budesonide are shown to be effective in controlled trials. If mucosal healing is a primary goal of therapy, when biopsies are to be performed is undefined. It has been well documented that healing is slow (or incomplete) in many patients despite a strict GFD,13Lanzini A. Lanzarotto F. Villanacci V. et al.Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet.Aliment Pharmacol Ther. 2009; 29: 1299-1308Crossref PubMed Scopus (174) Google Scholar but how quickly it is achieved in those who have healed at 1 to 2 years has been the subject of minimal research. If the aim is to perform the biopsy when the majority of patients have healed to confirm dietary compliance, then no earlier than 2 years is the generally recommended interval. If the aim is to determine who has not healed so that remedial interventions (such as dietary education or adjunctive medication) can be instituted, then it seems reasonable that this should be performed earlier. There is currently no case for reviewing healed mucosa unless the clinical situation demands a relook, but even this has not been evaluated. Until the intestinal lesion is followed up more intensively, the understanding of refractory CD will continue to be cloudy. Thus, there is a strong case for a re-evaluation of intestinal biopsy policies to achieve mucosal healing. Currently, follow-up small-bowel biopsy is not recommended by most guidelines in CD patients who achieve a clinical and serologic response to a GFD. An additional aspect of long-term management is the surveillance for diseases and complications associated with CD. Once the diagnosis is made, GFD is instituted and the patients are under ongoing clinical review, the development of associated diseases, such as thyroid disease or diabetes, is likely to be relatively uncommon. The cost effectiveness of surveillance via blood tests, such as thyroid function tests or a random or fasting blood glucose test, has not been assessed. However, most of the associated conditions are insidious in their onset and early recognition would be of clear clinical benefit to the patients. Bone density evaluation within a year of diagnosis is recommended by most guidelines. Monitoring nutritional status via, for example, weight and levels of vitamin D, folate, vitamin B12, zinc, and iron studies on a yearly basis once these levels have been normalized after diagnosis seems reasonable, if not evidence-based. Quality follow-up evaluation and optimal outcomes would be facilitated by clear guidelines, the lack of which might be at least partly responsible for the generally poor follow-up evaluation described in Olmstead County.3Herman M.L. Rubio-Tapia A. Lahr B.D. et al.Patients with celiac disease are not followed up adequately.Clin Gastroenterol Hepatol. 2012; 10: 893-899Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar There is a strong case for a re-evaluation of intestinal biopsy policies to achieve mucosal healing. The report by Herman et al3Herman M.L. Rubio-Tapia A. Lahr B.D. et al.Patients with celiac disease are not followed up adequately.Clin Gastroenterol Hepatol. 2012; 10: 893-899Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar underscores that the time is right for celiac clinicians and researchers to divert some of their enthusiasm for making the diagnosis of CD to establishing clear, evidence-based guidelines for its management. Patients With Celiac Disease Are Not Followed Up AdequatelyClinical Gastroenterology and HepatologyVol. 10Issue 8PreviewAdherence to a gluten-free diet is the only effective treatment for celiac disease. It has been recommended that patients be followed up, make regular visits to the clinic, and undergo serologic analysis for markers of celiac disease, although a follow-up procedure has not been standardized. We determined how many patients with celiac disease are actually followed up. Full-Text PDF
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