Advertisement

Disease- and gender-related characteristics of coeliac disease influence diagnostic delay

Published:September 28, 2020DOI:https://doi.org/10.1016/j.ejim.2020.09.023

      Keywords

      Coeliac disease is a high-prevalent, immune-mediated, chronic enteropathy caused by the ingestion of gluten in genetically susceptible individuals [
      • Di Sabatino A
      • Corazza GR
      Coeliac disease.
      ,
      • Di Sabatino A
      • Lenti MV
      • Giuffrida P
      • Vanoli A
      • Corazza GR
      New insights into immune mechanisms underlying autoimmune diseases of the gastrointestinal tract.
      ]. From the clinical viewpoint, coeliac disease is a proteiform condition, spacing from the complete lack of signs or symptoms to a severe malabsorption syndrome characterised by steatorrhea, weight loss, anaemia, hypo-proteinemia, and electrolyte imbalance. In most cases, complete and long-life withdrawal of gluten from the diet is able to revert villous atrophy. However, some patients, especially those who are diagnosed with coeliac disease later in life and who do not adhere to a strict gluten-free diet [
      • Biagi F
      • Schiepatti A
      • Malamut G
      • et al.
      PROgnosticating COeliac patieNts SUrvivaL: the PROCONSUL score.
      ,
      • Biagi F
      • Schiepatti A
      • Maiorano G
      • et al.
      Risk of complications in coeliac patients depends on age at diagnosis and type of clinical presentation.
      ], may develop complications, including refractory coeliac disease and enteropathy-associated T-cell lymphoma. Hence, a timely and flawless diagnosis of coeliac disease is warranted. Proper serological and histopathological assessment are needed for diagnosing adult coeliac disease. Indeed, both serology and histopathology may be a source of misdiagnosis themselves, and a possible approach in clinical practice for avoiding sources of misinterpretation has already been proposed [
      • Lenti MV
      • Corazza GR.
      Measuring too much or too little in adult coeliac disease.
      ,
      • Corazza GR
      • Lenti MV.
      Does biopsy still have a role for adult coeliac disease?.
      ].
      Similar to other immune-mediated gastrointestinal disorders characterised by a wide clinical spectrum, such as inflammatory bowel disease and autoimmune atrophic gastritis [
      • Cantoro L
      • Di Sabatino A
      • Papi C
      • et al.
      The time course of diagnostic delay in inflammatory bowel disease over the last sixty years: an Italian multicentre study.
      ,
      • Lenti MV
      • Miceli E
      • Cococcia S
      • et al.
      Determinants of diagnostic delay in autoimmune atrophic gastritis.
      ], diagnostic delay seems to be common for coeliac disease, and this is responsible for a greater risk of mortality [
      • Corrao G
      • Corazza GR
      • Bagnardi V
      • et al.
      Mortality in patients with coeliac disease and their relatives: a cohort study.
      ]. According to a landmark study, the median diagnostic delay for coeliac disease was 17 months, with an interquartile range (IQR) of 4-122 months, and the standardised mortality ratio increased by a diagnostic delay of more than 12 months [
      • Corrao G
      • Corazza GR
      • Bagnardi V
      • et al.
      Mortality in patients with coeliac disease and their relatives: a cohort study.
      ]. Also, misdiagnosis, especially with other functional gastrointestinal disorders, is rather common in coeliac disease [
      • Corazza GR
      • Brusco G
      • Andreani ML
      • Biagi F
      • Stefano MD
      • Gasbarrini G
      Previous misdiagnosis and diagnostic delay in adult celiac sprue.
      ], as in the case of inflammatory bowel disease and autoimmune atrophic gastritis [
      • Cantoro L
      • Di Sabatino A
      • Papi C
      • et al.
      The time course of diagnostic delay in inflammatory bowel disease over the last sixty years: an Italian multicentre study.
      ,
      • Lenti MV
      • Miceli E
      • Cococcia S
      • et al.
      Determinants of diagnostic delay in autoimmune atrophic gastritis.
      ]. Nonetheless, data regarding factors associated with greater diagnostic delay and gender differences in coeliac disease clinical presentation are still scant.
      For these reasons, the paper by Tan and colleagues [
      • Tan IL
      • Withoff S
      • Kolkman JJ
      • Wijmenga C
      • Weersma RK
      • Visschedijk MC
      Non-classical clinical presentation at diagnosis by male celiac disease patients of older age.
      ], that focuses on coeliac disease clinical presentation in relation to age, gender, and diagnostic delay, is more than welcome. In this research conducted in the Netherlands, the Authors performed a questionnaire study in adult patients with biopsy-proven coeliac disease, exploring, as the main outcome, whether diagnostic delay influenced improvement of symptoms after starting a gluten-free diet. Overall, 380 questionnaires were sent, and 211 coeliac adult patients eventually took part to the study (median age at diagnosis 41.8 years, IQR 25-58; 67 males). Only coeliac patients with at least a Marsh 2 duodenal histology, either diagnosed in academic and non-academic hospitals, were enrolled. The Oslo classification was used for classifying patients as having “classical” symptoms (i.e., diarrhoea, fatigue, abdominal pain, weight loss) or “non-classical” symptoms [
      • Ludvigsson JF
      • Leffler DA
      • Bai JC
      • et al.
      The Oslo definitions for coeliac disease and related terms.
      ]. According to this classification, “classical” symptoms were more frequent in female patients, and gender was not significantly associated with age at diagnosis. Notably, regardless of the type of clinical presentation, anaemia was very common (61% in those with “non-classical” vs 32.6% in those with “classical” presentation). At multivariate analysis, a “non-classical” presentation and a negative family history of coeliac disease were predictors of older age at diagnosis. Finally, a diagnostic delay of more than 3 years between the occurrence of the first symptom and definite coeliac disease diagnosis was associated with slower improvement of symptoms after commencement of a gluten-free diet, but not with gender, “classical” symptoms or age at diagnosis.
      Despite the undoubted interest of the topic covered by this study and of the novel results, a few limits and considerations should be mentioned. As a general comment, the relatively small sample size and the nature of the study (questionnaire-based) might have under- or overestimated differences for some parameters. More than the entity of the diagnostic delay, which we already knew it was substantial for this condition, the focus on gender differences is certainly the most intriguing datum. Although the patient-dependent (i.e., the time span between the onset of symptoms and the first medical consultation) and the physician‐dependent (i.e., the time span between the first medical consultation and the definitive diagnosis) diagnostic delay were not separately evaluated in this study, it is reasonable to assume that the overall diagnostic delay may depend on both physician- and patient-related (especially gender) factors. Different genders may present with different clinical pictures, being the association with other autoimmune diseases more common in female patients. Also, iron deficiency anaemia might be commonly considered as a consequence of blood loss in females, secondary to menstrual cycles, rather than investigated for coeliac disease. Family history of coeliac disease is a well-established risk factor for the development of this condition, and these individuals should be screened for making an early diagnosis. Besides this, other high-risk categories should be screened for coeliac disease, including, among others, patients with autoimmune thyroid disease, type 1 diabetes mellitus, Down's syndrome, vitiligo, unexplained iron deficiency anaemia, delayed menarche, and infertility. A proactive screening strategy proved useful in detecting asymptomatic coeliac disease, especially in a primary care setting [
      • Catassi C
      • Kryszak D
      • Louis-Jacques O
      • et al.
      Detection of Celiac disease in primary care: a multicenter case-finding study in North America.
      ]. Hence, it is not surprising that in the study by Tan and colleagues [
      • Tan IL
      • Withoff S
      • Kolkman JJ
      • Wijmenga C
      • Weersma RK
      • Visschedijk MC
      Non-classical clinical presentation at diagnosis by male celiac disease patients of older age.
      ] the negative family history of coeliac disease was associated with older age at diagnosis. Also, “non-classical” symptoms might be under-recognised by primary care physicians and by patients themselves, thus prolonging the diagnostic delay.
      Regarding the clinical response to a gluten-free diet, this datum is quite difficult to be interpreted. It is well known that dietary measures are burdened by a high placebo or nocebo effect [
      • Ferguson A
      Food sensitivity or self-deception?.
      ]. Hence, only a double-blind dietary regimen would allow to avoid this issue, even if this would be, indeed, unfeasible in a clinical setting. Although we do acknowledge the importance of the Oslo classification, we have already raised some concerns about its use [
      • Di Sabatino A
      • Corazza GR
      Some clarification is necessary on the Oslo definitions for coeliac disease-related terms.
      ]. An objective measure of response to a gluten-free diet still needs to be found, and this is a matter of current debate, in both a clinical and a research setting [
      • Lenti MV
      • Corazza GR.
      Measuring too much or too little in adult coeliac disease.
      ]. Indeed, assessing clinical symptoms through the available tools, such as a visual analogue scale or the Gastrointestinal Symptoms Rating Scale, is open to many biases that make it difficult to interpret the actual response, at least in a subset of patients and in a research setting. Similarly, the use of serology has many shortcomings, and did not prove useful in this specific setting [
      • Corazza GR
      • Lenti MV.
      Does biopsy still have a role for adult coeliac disease?.
      ]. The repetition of an upper gastrointestinal endoscopy for collecting duodenal specimens should be considered for proving villous regrowth using qualitative scales (i.e., Marsh-Oberhuber, Corazza-Villanacci classifications). A more precise, quantitative method of duodenal histology assessment may be applied in a research setting only, especially when studying new drugs for treating coeliac disease or its complications [
      • Lenti MV
      • Corazza GR.
      Measuring too much or too little in adult coeliac disease.
      ].
      To conclude, the study by Tan and colleagues [
      • Tan IL
      • Withoff S
      • Kolkman JJ
      • Wijmenga C
      • Weersma RK
      • Visschedijk MC
      Non-classical clinical presentation at diagnosis by male celiac disease patients of older age.
      ] adds further insights into an important issue for patients with coeliac disease. More studies assessing gender-related and disease-related variables in determining diagnostic delay and misdiagnosis are needed.

      Statement of author contributions

      All authors significantly participated in the drafting of the manuscript or critical revision of the manuscript for important intellectual content and provided approval of the final submitted version.

      Conflict of Interest

      None.

      Acknowledgements

      None.

      References

        • Di Sabatino A
        • Corazza GR
        Coeliac disease.
        Lancet. 2009; 373: 1480-1493
        • Di Sabatino A
        • Lenti MV
        • Giuffrida P
        • Vanoli A
        • Corazza GR
        New insights into immune mechanisms underlying autoimmune diseases of the gastrointestinal tract.
        Autoimmun Rev. 2015; 14: 1161‐1169
        • Biagi F
        • Schiepatti A
        • Malamut G
        • et al.
        PROgnosticating COeliac patieNts SUrvivaL: the PROCONSUL score.
        PLoS One. 2014; 9: e84163
        • Biagi F
        • Schiepatti A
        • Maiorano G
        • et al.
        Risk of complications in coeliac patients depends on age at diagnosis and type of clinical presentation.
        Dig Liver Dis. 2018; 50: 549‐552
        • Lenti MV
        • Corazza GR.
        Measuring too much or too little in adult coeliac disease.
        J Clin Pathol. 2019; 72: 341‐342
        • Corazza GR
        • Lenti MV.
        Does biopsy still have a role for adult coeliac disease?.
        Lancet Gastroenterol Hepatol. 2017; 2: 773‐774
        • Cantoro L
        • Di Sabatino A
        • Papi C
        • et al.
        The time course of diagnostic delay in inflammatory bowel disease over the last sixty years: an Italian multicentre study.
        J Crohns Colitis. 2017; 11: 975‐980
        • Lenti MV
        • Miceli E
        • Cococcia S
        • et al.
        Determinants of diagnostic delay in autoimmune atrophic gastritis.
        Aliment Pharmacol Ther. 2019; 50: 167‐175
        • Corrao G
        • Corazza GR
        • Bagnardi V
        • et al.
        Mortality in patients with coeliac disease and their relatives: a cohort study.
        Lancet. 2001; 358: 356‐361
        • Corazza GR
        • Brusco G
        • Andreani ML
        • Biagi F
        • Stefano MD
        • Gasbarrini G
        Previous misdiagnosis and diagnostic delay in adult celiac sprue.
        J Clin Gastroenterol. 1996; 22: 324-325
        • Tan IL
        • Withoff S
        • Kolkman JJ
        • Wijmenga C
        • Weersma RK
        • Visschedijk MC
        Non-classical clinical presentation at diagnosis by male celiac disease patients of older age.
        Eur J Intern Med. 2020; https://doi.org/10.1016/j.ejim.2020.09.020
        • Ludvigsson JF
        • Leffler DA
        • Bai JC
        • et al.
        The Oslo definitions for coeliac disease and related terms.
        Gut. 2013; 62: 43‐52
        • Catassi C
        • Kryszak D
        • Louis-Jacques O
        • et al.
        Detection of Celiac disease in primary care: a multicenter case-finding study in North America.
        Am J Gastroenterol. 2007; 102: 1454‐1460
        • Ferguson A
        Food sensitivity or self-deception?.
        N Engl J Med. 1990; 323: 476-478
        • Di Sabatino A
        • Corazza GR
        Some clarification is necessary on the Oslo definitions for coeliac disease-related terms.
        Gut. 2013; 62: 182

      Linked Article

      • Non-classical clinical presentation at diagnosis by male celiac disease patients of older age
        European Journal of Internal MedicineVol. 83
        • Preview
          Celiac disease (CeD) is a complex immune-mediated disease that occurs in ̴1–2% of the Caucasian population [1]. In patients with CeD, ingestion of gluten peptides that are present in barley, wheat and rye activates the innate and adaptive immune system, eventually leading to the development of villous atrophy in the small intestine. The human leukocyte antigen (HLA) subtypes HLA-DQ2 and HLA-DQ8 are strongly associated with CeD and are necessary for the development of disease, as they are the molecules that present gluten peptides to the immune system.
        • Full-Text
        • PDF