1.4.4. Review of the studies on prevalence and predictors of
anaemia in IBD
An extensive literature search was carried out, using Pubmed and searching the reference lists of original papers and reviews providing information on the prevalence of anaemia in IBD. Adult studies were excluded, as the primary scope of this review was to evaluate the prevalence of anaemia only in children with IBD.
Overall nine original articles and one study published in abstract form reported the prevalence of anaemia in paediatric IBD. Two systematic reviews including mainly adult studies (229;236) described in total four of these paediatric studies. In two other studies, measurements of haemoglobin were carried out and mean values were reported without reference to the overall prevalence of anaemia (20;83).
All but two studies were conducted in North America (Table 1.4.5); one study with 32 UC children in Europe (237), and one from Israel (228). Most studies measured anaemia in children younger than 18 years. Three studies expanded their inclusion criteria to young adults (228;241;242). The sample size varied from 11-526 children with only one reporting prevalence of anaemia in over 100 patients (243).
The definition of anaemia within the studies varied remarkably. All but two (241;242) used haemoglobin measurements to define anaemia, two used haematocrit cut offs (241;242), and in another (244), no definition of anaemia was given. The lower haemoglobin cut offs to distinguish between anaemic and non anaemic patients ranged from 10.5 to 13 mg /dl. All but three studies used generic cut offs to define anaemia in both girls and boys
61
whereas three studies used age adapted thresholds, as age related changes in haematologic indices are well recognized (221). All but two studies assessed anaemia close to the time of diagnosis. One study enrolled only patients with severe colitis (Table 1.4.5).
On the whole the prevalence of anaemia in paediatric IBD ranged between 41% and 88%. A mean estimate cannot be drawn. Neither can temporal changes be evaluated due to differences in the definition of anaemia between studies (245). Compared with the two systematic reviews which reported studies in mainly adult patients, prevalence of anaemia in children overall is reported to be higher. Wilson et al (229) estimated the prevalence of anaemia to be between 6-74% numerically lower than the range reported in the paediatric studies reviewed.
As documentation of anaemia was usually a secondary outcome in most of the paediatric studies only a few authors linked anaemia with disease and sociodemographic characteristics. Mack and his colleagues (243) showed that anaemia was associated with severity of disease activity. They observed that anaemia was more common in patients with severe disease than those with mild disease activity. The same group showed that in young patients (6-11 y) with severe disease, haemoglobin concentration was higher in CD than in UC (p< 0.006). No such difference was observed for the older group of children (≥ 12 y) or for children with mild or moderate disease. A negative association between haematocrit levels and disease activity has been described previously for CD patients particularly those who had isolated disease in the small intestine (246). Although Weinstein et al. (83) did not report the prevalence of anaemia, they found that mean haemoglobin concentration was lower in CD than UC, a finding that was more marked in the older group of patients (≥ 11 y). No such difference in the mean haemoglobin concentration was found between UC and CD in a state population based study in the United States (20). In a study published in abstract form only, Thayu et al (247) measured prevalence of anaemia in paediatric CD and tried to identify disease predictors associated with it. Anaemic patients had higher values of PCDAI and ESR than non-anaemic patients and the presence of upper GI tract disease was significantly associated with anaemia. Gender, duration of symptoms, body composition, or growth parameters were not predictors of anaemia.
Similar data from adult studies suggested an association between the presence of anaemia and high scores on the disease activity indices (214;235). Schreiber (235) found that anaemia was more common in CD than in UC patients whereas in a study from Israel, that accounted for the prevalence of anaemia by sex, the prevalence of anaemia was higher in women than in men (66.6% vs. 27.5% respectively) (248). Reilly (249) in a study of the impact of parenteral nutrition on clinical outcome found that the prevalence of anaemia was lower in CD patients with only small bowel involvement (33.3%) than in patients with disease involving the large bowel with or without small bowel. In contrast, RBC, haemoglobin and
anaemia were lower in patients with ileocolitis than in patients with small intestine involvement in a Japanese cohort of CD patients (250). Undernourished patients were more likely to be anaemic than well-nourished CD patients in another study (251).
63 Table 1.4.5: Studies that measured the prevalence of anaemia in paediatric IBD
Study Country Age n (Male) Disease Definition of anaemia Prevalence of
anaemia Predictors of anaemia Comments
Mack et al 2007 (243) US & Canada <16 526 (310) 392 CD < 6 y; Hb<11 6-11 y; Hb<11.5 >11 y; F: <12 M: <13 68% Severe disease; In 6-11
y group with severe disease Hb was lower in UC than CD Howarth et al 2007 (252) UK <16 32 (11) 32 UC Hb < 12 62.5% N/A Khan et al 2002 (211) US ≤18 90 (45) 51 UC 1-10 y; Hb<10.5 >10 y; Hb <11.5 41% N/A
Thomas & Sinatra 1989 (253)
US ≤18 24 (17) 24 CD Hb < 12 71% N/A
Beeken 1979 (254) US 8-21 11 (8) 11 CD Hct < 36 72.7% N/A Did not
measure anaemia at diagnosis Burbige et al 1975 (213) US <16 58 (37) 58 CD Hb < 11 51.7% N/A Revel-Vilk et al 2000 (228) Israel 9-22 63 (34) 5 CD MCV < 77 fl F: Hb < 12; Ferritin < 6 µg/l M: Hb < 12.5; Ferritin < 23 µg/l 41.3% 11 IDA 15 ACD
N/A Did not
measure anaemia at diagnosis
Werlin & Grand 1977 (242)
US 6-20 19 (8) 5 CD Hct ≤ 30 73.7% N/A New and
patients with long-standing disease; Only with severe colitis
Thayu et al 2005 (247) US 5-18 78 (44) 78 CD <5 centile for age & sex 77% High PCDAI and ESR;
Upper GI disease involvement
Gryboski 1994 (244) US ≤10 N/A 40 CD N/A 75% CD;
88.4% UC
Upper GI disease involvement
1.4.5. Conclusion
The prevalence of anaemia in paediatric IBD is not well documented and the evidence comes from a limited number of studies with methodological flaws. Most studies included small sample sizes with only one study documenting the prevalence of anaemia in more than 100 patients. The definition of anaemia between the studies is heterogeneous and does not allow a direct comparison between the studies or assessment of secular trends in anaemia prevalence. Indeed the prevalence of anaemia in most of the current studies was a secondary outcome rather than a primary aim, and may have resulted in unrepresentative selective groups of patients that does not allow the extrapolation and generalization of findings. Thus the need of population based studies measuring anaemia at diagnosis before medical treatment has been applied is necessary to appropriately characterise prevalence and determinants of anaemia in paediatric IBD.
There is a lack of evidence on factors that might predispose to anaemia. Knowledge of this could help tackle the development of anaemia at an early stage. In light of new consensus guidelines on the categorization of disease location and behaviour new studies should be conducted to address whether disease phenotype favours anaemia. Undernutrition, growth faltering or demographics may also differ between anaemic and non anaemic IBD patients and should be investigated further.
To the best of our knowledge no study has measured the outcome and prognosis of anaemia during the natural history of the disease. As new treatments are now available which achieve mucosal healing (90) and tackle inflammatory cascade activation at the initial stages, temporal changes in the prevalence of anaemia and lower incidence at follow up should be expected. In particular possible association with specific treatment modalities deserves to be studied further. Such a study is described in Chapter 6 of this thesis.