Follow-up
There is a paucity of data pertaining to adherence to a GFD being improved by follow-up in patients with CD. Only one previous historical study has assessed the impact of regular follow-up (annual review) at a dedicated doctor-led coeliac clinic. The investigators suggested that adherence was improved by having access and regular follow-up within the setting of a specialist coeliac clinic (improvement in adherence was 97.5% for those under clinic follow-up vs 40.4% for those no longer under follow-up); however as this was an observational study and there were likely to be marked biases in referral of cases, it is not possible to be confident that the associations seen were causal. There are no published data assessing the value of this approach or whether adherence to a GFD, QoL, avoidance of complications, or satisfaction with the service is improved by offering a dietitian-led coeliac clinic. One of the key factors relating to adherence is dietetic input and regular follow-up. Optimally, the clinic should have gastrointestinal and dietetic expertise. Patients should be encouraged to join disease-specific patient support groups if applicable.
Once the disease is stable and the patients manage their diet without any problems, annual follow-ups should be initiated. The physician should check on intact small intestinal absorption (full blood count, ferritin, serum folate, vitamin B12, calcium, alkaline phosphatase), associated autoimmune conditions (thyroid-stimulating hormone and thyroid hormone(s), and serum glucose), liver disease (aspartate aminotransferase/alanine aminotransferase) and dietary adherence (anti-TG2 or EMA/DGP), although the sensitivity and specificity of the latter cannot substitute for structured dietary interview.
In follow-up of CD, the key endpoints are normalisation of the health of patients judged by an absence of symptoms, and mucosal healing. A lack of symptoms or negative serological markers are not reliable or responsive surrogates of mucosal response to diet. Dickey et al reported that among 32 patients with CD and persistent villous atrophy, EMA had normalised in 27 (84%); while another British study found that 7/16 (44%) individuals with persistent villous atrophy at follow-up biopsy had a normalised TTG.
The proportion of patients who do not achieve full histological recovery on diet varies, with most reports suggesting mucosal healing in 57–76%.
Some experts favour repeat intestinal biopsy after 1 year of dietary therapy; others, however, do not believe a repeat biopsy is essential for coeliac management in typical cases. It is universally acknowledged that there is little evidence to address whether clinical outcomes are significantly altered as a result of re-biopsy and that the cost–benefit analysis of such an approach has yet to be fully established.
Assessing Adherence to the GFD
Whilst the panel of experts agree adherence to the GFD is most important for the health of a patient with CD, there are no evidence-based grade A recommendations regarding the most useful way to assess this. Dietary adherence should guarantee mucosal healing and at least remission of most gastrointestinal symptoms. At present there are no non-invasive biomarkers that indicate complete mucosal recovery and a number of studies indicate a high prevalence of villous atrophy in adult patients with CD who appear to be adherent (see Table 3). When specifically questioned, the experts agreed there is a difference between the first-year follow-up of a newly diagnosed patient and long-term follow-up of an adherent patient with stable disease. An adherent patient with stable disease needs less follow-up and testing than a patient with newly diagnosed CD in whom the GFD has just commenced, and neither the mucosa nor biochemical aberrations have yet normalised.
There are four steps to assess dietary adherence: clinical assessment of symptoms, dietetic review, serum antibodies and follow-up biopsy.
Symptoms. A meta-analysis of seven studies including more than 3000 subjects showed that the presence of gastrointestinal IBS-like symptoms is common in CD. IBS-type symptoms are more common in patients with CD who are not adherent to a GFD (OR 2.69; 95% CI 0.75 to 9.56). However, patients with CD who are also adherent to a GFD are more likely to experience (persistent) symptoms than controls.
Dietetic Review. The second step is a careful dietetic review conducted by a dietitian or dedicated physician. Apart from a visual analogue score scale which consists of an unmarked line with the anchor sentences 'I never adhere to my diet' and 'I always adhere to my diet' at each end, there are a number of questionnaires evaluating self-reported GFD adherence and food frequency in the English language that are also available in other languages. These questionnaires should be augmented by a dietetic review, which is a useful tool to tease out inadvertent gluten intake and to provide education for a balanced and adequate nutrient intake. There is no standard or quality control for dietetic review because local diets and habits require a specific structured interview, which is related to the quality of the diet. Currently, no data are available on GFD review outcomes in different countries, and there is no evidence that a careful review can substitute for other tools (eg, biopsy) to predict mucosal damage.
Studies report that poor dietary adherence due to occasional lapses is frequent and it is influenced by a number of factors, such as age at diagnosis, knowledge of disease and psychological factors.
Serology. The third step in the first year is to check the IgA-TG2 or appropriate serology. Despite contradictory results, it is reasonable to assume that positive antibody titres correspond to some gluten intake and there is also some evidence that low TTG titres do not accurately predict mucosal recovery. Tursi et al reported that out of 17 patients with persistent villous atrophy 1 year after diagnosis, only 1 (6%) was anti-TG2-positive and 3 (18%) EMA-positive. Vahedi et al reported a substantially higher sensitivity for persistent total villous atrophy (73% and 91% for IgA-TG2 and EMA, respectively), but reported no data for partial villous atrophy.
Follow-up Biopsy. The last step is the follow-up biopsy. Some authors suggested that it is important to perform a duodenal biopsy to assess the recovery of intestinal mucosa and to exclude RCD and malignancies. However, one recent study of 7648 individuals failed to show that overall mortality was increased in patients with CD with persistent villous atrophy at follow-up biopsy in patients with a median follow-up of more than 11 years.
In many cases 1 year is too brief a timespan to obtain complete recovery of duodenal mucosa. Tuire et al found that IELs were more frequent even 2–5 years after coeliac diagnosis compared with thereafter. Some experts do not routinely perform a follow-up biopsy in asymptomatic patients with negative serology and good adherence. Currently there are no studies indicating an absolute necessity of follow-up biopsy for all patients, but of eight major studies, five examined follow-up biopsies at roughly 2–5 years (Table 3). This may be related to costs (economic and psychological) of performing a procedure that in theory should be repeated many times over the years of follow-up as dietary adherence may vary over time.
The authors of this review underline the necessity of distinguishing asymptomatic patients in whom clinical improvement, negative serology, and potentially a follow-up biopsy and good adherence assessed by dietetic review are considered sufficient from symptomatic patients in whom repeated biopsies are needed to rule out RCD or malignancies. Studies report that poor dietary adherence due to occasional lapses is frequent and it is influenced by a number of factors, such as age at diagnosis, knowledge of disease and psychological factors.
Histological Recovery of Duodenal Mucosa in Adult Patients With CD
In adults, neither symptoms nor serology is reliable to predict small intestinal damage; assessing mucosal healing by biopsy is the key. Serum antibodies have poor sensitivity for persistent villous atrophy, especially 1 year or more after diagnosis and institution of a GFD.
Lymphocytic duodenosis is commonly seen on biopsy of follow-up patients. It is rarely symptomatic, although it may also correlate with transgression of adherence from the GFD. Early biopsy (at 6 months) is not considered to be optimal.
Gluten Challenge
To perform a gluten challenge, a recent study recommends a 14-day gluten intake at ≥3 g of gluten/day (two slices of wheat bread per day) to induce histological and serological changes in the majority of adults with CD. The challenge can be prolonged to 8 weeks if serology remains negative at 2 weeks (in the Leffler et al study, serology was negative after 2 weeks in all cases, but positive after another 2 weeks).
Medical Management During Follow-up
Long-term follow-up can be in secondary care clinics or in primary care as long as the expertise is available. However, prompt access to specialist centres or secondary care is recommended if any problems arise, and it should be noted that the need for long-term follow-up is controversial.
The risk of osteoporosis and bone fracture is increased with CD, with one Swedish study showing an excess risk of any fracture of 481/100 000 person-years in adults with CD and a British study (13% of individuals were children) 320/100 000 person-years. The excess risk is reduced with good dietary adherence and reduction in intestinal villous atrophy, and bone density increases during the first year of GFD adherence. However, one population-based study found a similar excess risk for fractures before and after coeliac diagnosis (eg, the incidence ratio 5–10 years before CD diagnosis was 1.8 compared with 2.2 some 5–10 years after diagnosis).
On the basis of current evidence, the suggestion should therefore be to measure calcium, alkaline phosphatase and vitamin D levels (and parathyroid hormone for compensatory increase) at diagnosis and replace as necessary. Calcium intake should be maintained at or above 1000 mg per day. Bone density should be measured in those at high risk of osteoporosis; appropriate criteria for judging this are given by the BSG (http://www.bsg.org.uk/images/stories/clinical/ost_coe_ibd.pdf). Repeat bone density investigations (generally after an interval of ≥2 years) should otherwise be considered in patients who have low bone density on index measurement following initiation of appropriate treatment, or who have evidence of ongoing villous atrophy or poor dietary adherence. Postmenopausal women with CD may require supplementation in addition to the GFD. Loss of bone density at a greater than expected rate should prompt measurement of vitamin D levels, dietary review of adherence, consideration of repeat intestinal mucosal biopsy and review of additional risk factors such as hypogonadism.
Hyposplenism associated with CD may result in impaired immunity to encapsulated bacteria, and an increase in such infections has been demonstrated in CD. Hyposplenism does not seem to correlate with duration of GFD. Vaccination against Pneumococcus is therefore recommended. However, it is unclear whether vaccination with the conjugated vaccine is preferable in this setting and whether additional vaccination against Haemophilus, Meningococcus and Influenza should be considered if not previously given. It should also be noted that patients with CD may have a weaker response to hepatitis B vaccination than normal.