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The burden of anaemia in patients with inflammatory bowel diseases

Digestive and Liver Disease, In Press, Corrected Proof, Available online 22 November 2015, Available online 22 November 2015

Abstract

Background

Anaemia (AN) is frequently associated with inflammatory bowel diseases (IBD) and can negatively influence the quality of life of patients.

Aim

To evaluate the prevalence and causes of AN in IBD.

Methods

We prospectively performed a one-year multicentre observational study including all IBD cases attending six Units. We also investigated patients’ main serological parameters.

Results

The study population included 965 IBD patients (582 CD; 383 UC), of whom 142 were in-patients and 823 out-patients. AN was diagnosed in 134 out of 965 IBD patients (14%). No significant difference in AN prevalence was observed between CD and UC. The prevalence of AN was higher in the hospitalized IBD (26% in- vs. 11.7% out-patients; p < 0.01; OR 2.2) and in active disease (CD: 34% active vs. 16% inactive; p < 0.01; OR 2.1 – UC: 26% active vs. 19% inactive; p = 0.03; OR 1.3). Iron deficiency was present in 72 patients (53.7%), AN of chronic diseases in 12 (8.2%), mixed type AN in 11 (8.2%), thalassemia in 9 (6.7%), and macrocytic AN in 8 (5.9%).

Conclusions

In Southern Italy, AN is common in IBD and is more frequent in active disease and hospitalized patients. Iron deficiency still remains the major cause of AN in IBD.

Keywords: Anaemia, Crohn's disease, IBD, Ulcerative colitis.

1. Introduction

Inflammatory bowel diseases (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), are a group of chronic inflammatory conditions affecting the gastrointestinal tract. One of the most frequent extra-intestinal manifestations (EIMs) of IBD is anaemia (AN) which affects patients’ quality of life [1] and [2], potentially limiting their ability to work [3].

The reported prevalence of AN in patients with IBD varies from 6% to 74%. A recent systematic review of manuscripts published between 2007 and 2012, reported a prevalence of AN of 27% in patients with CD and of 21% in patients with UC [4]. The aforementioned variability in the AN prevalence depends on different factors. First of all, a review of several studies showed that the definition of AN is not homogeneous. In fact, the widely accepted World Health Organization criteria for the diagnosis of AN [haemoglobin (Hb) below 13 g/dL in men or 12 g/dL in non-pregnant women] [5] has been questioned because it fails to consider racial differences, environmental conditions and eating habits [6] and [7]. Therefore, its use cannot appropriately reflect the actual prevalence of AN in different IBD populations.

Furthermore, the prevalence of AN often depends on the peculiarities of the groups of patients studied (e.g. hospitalized patients vs. outpatients). In this sense, many studies showed a higher prevalence of AN in hospitalized UC and CD patients than among outpatient populations [8], [9], [10], and [11]. AN prevalence in hospitalized IBD patients ranges from 44%, as reported by Hoffbrand et al. [12], up to 74%, as found by Werlin and Grand [13]. However, the latter numbers were reported in older studies from the 60s and 70s and, obviously, the prevalence has decreased through the years mainly due to better treatment. Finally, the presence of AN correlates directly with disease activity, which means that its prevalence may change throughout the natural history of the disease [14].

In IBD patients, several factors contribute to the development of AN. Among these, iron deficiency and anaemia of chronic disease (ACD) are acknowledged to be the most important [15] and [16].

A crucial role in iron homeostasis is played by hepcidin, a protein produced by hepatocytes, macrophages and adipocytes. Hepcidin inhibits the transport of iron into the plasma from the macrophages or the enterocytes involved in the absorption of dietary iron. Hepcidin fulfils its function by binding and inhibiting ferroportin (located on the basal lamina of the enterocyte) that is so internalized and degraded. In this way the iron, even if it is properly introduced and absorbed, is stored in the bowel deposits and therefore not present in the circulation. Increased hepcidin activity is partially responsible for reduced iron availability seen in anaemia of chronic inflammation. For example, in IBD some pro-inflammatory cytokines (such as IL-6) increases hepcidin, thus determining the sequestration of iron in macrophages and the inability to transport this element in the plasma [15].

Other rarer causes of AN in IBD include vitamin B12 and folate deficiency, drug-induced bone marrow suppression and associated celiac disease [8], [9], and [10].

The aim of our study was to evaluate the prevalence and causes of AN in patients with IBD living in Campania, a region of Southern Italy.

2. Patients and methods

From April 2014 to April 2015, we performed a one-year multicentre, prospective, observational study in Campania (Southern Italy), including all consecutive patients with CD and UC, attending six IBD Units. Patients’ characteristics were classified in accordance with the European Crohn's and Colitis Organisation (ECCO) guidelines [17] and [18]. Patients within the inclusion criteria were enrolled in the study; their demographics, disease-related characteristics, and current medications were recorded and blood samples were collected for haematological assessment. The following data were registered: gender, age, phenotype of disease according to the Montreal classification [19], incident/prevalent disease and duration of the disease.

Moreover, we investigated the disease activity, using Crohn's Diseases Activity Index (CDAI) and Clinical Activity Index (CAI). In accordance with literature [17] and [20], active disease was defined as CDAI ≥ 150 for CD patients and CAI ≥ 5 for UC patients.

According to the World Health Organization, AN was defined in presence of haemoglobin values Hb < 13 g/dl for males and Hb < 12 g/dl for females; severe AN was defined in case of Hb < 10 g/dl [5]. To explore the causes of AN, all anaemic patients underwent a second-line haematological assessment, which included an evaluation of ferritin, transferrin, vitamin B12, folic acid and homocysteine levels, and a screening for celiac disease (total IgA and anti-transglutaminase antibodies). Furthermore, in all IBD cases, CRP and ESR were evaluated. According to literature [21], iron deficiency AN (IDA) was diagnosed in case of ferritin < 30 ng/ml and transferrin saturation (TSAT) < 16%. AN of chronic disease (ACD) was diagnosed when elevated CRP/ESR values coexisted with TSAT < 16% and ferritin > 100 ng/ml; mixed type AN was considered in case of TSAT < 16% and 30 ng/ml < ferritin < 100 ng/ml. Patients not classifiable according to these definitions were categorized as having “other anaemia”.

All patients gave their written consent to participate in the study.

2.1. Statistical analysis

Statistical analysis was performed using Chi-square and Mann Whitney U test, ANOVA and odd ratio (OR), when appropriate. A p-value lower than 0.05 was considered significant.

Statistical analysis was carried out using SPSS software package for Windows.

3. Results

The study population included 965 IBD patients (582 CD; 383 UC; 357 incident cases, 608 prevalent cases) of whom 142 were in- and 823 were out-patients. Baseline characteristics of patients are summarized in Table 1.

Table 1 Baseline features of UC and CD patients.

Ulcerative colitis Crohn's disease
Number 383 582
Incident/prevalent cases 190/193 167/415
Hospitalized patients 65 77
Outpatients 318 505
M/F 181/202 282/300
Mean age 39 (16–67) 33 (15–64)
Location
L1-L2-L3
320-160-102
Behaviour
B1-B2-B3
400-160-22
Extension
E1-E2-E3
73-210-100
CAI (mean ± SD) 8 (±2)
CDAI (mean ± SD) 280 (±70)

AN was diagnosed in 134 out of 965 IBD patients (14%). The principal features of anaemic subjects are shown in Table 2. No significant difference was observed between CD and UC groups (81 CD vs. 53 UC; 13.9% vs. 13.8%; p = n.s.). We found severe anaemia in 12% of patients, with no difference between patients with CD and those with UC (Table 3).

Table 2 Baseline features of anaemic patients.

Ulcerative colitis Crohn's disease
Number 53 81
Hospitalized patients 14 20
Outpatients 39 61
M/F 21/32 34/47
Mean age 38 (18–62) 35 (17-60)
Location
L1- L2-L3
47-20-14
Behaviour
B1-B2-B3
59-19-3
Extension
E1-E2-E3
4-32-17
CAI (mean ± SD) 9 (±2)
CDAI (mean ± SD) 300 (±60)
Hemoglobin (mean ± SD) 10.8 (±1.1) 10.9 (±1)
Ferritin (mean ± SD) 70 ± 132.4 44 ± 80.4
CRP (mean ± SD) 6.5 (±12.1) 7.2 (±13)

Table 3 Principal causes of anaemia.

IDA
n (%)
ACD
n (%)
Mixed AN
n (%)
Thalassemia
n (%)
MA
n (%)
Other anaemia
n (%)
CD (81) 41 (50.6) 7 (8.6) 7 (8.6) 6 (7.4) 7 (8.6) 13 (16)
UC (53) 31 (58.4) 5 (9.4) 4 (7.5) 3 (5.6) 1 (1.8) 9 (16.9)
IBD 72 (53.7) 12 (8.2) 11 (8.2) 9 (6.7) 8 (5.9) 22 (16.4)

IDA: ferritin < 30 ng/ml and TSAT < 16%; ACD: elevated CRP/ESR values coexisted with TSAT < 16% and ferritin > 100 ng/ml; mixed AN: TSAT < 16% and 30 ng/ml < ferritin < 100 ng/ml. Patients not falling into any of these categories are classified as having “other anaemia”.

Age, gender and concurrent therapy appeared to have no influence on the prevalence of anaemia.

When considering the incident/prevalent cases, AN was evident in 54 incident cases vs. 80 prevalent cases of IBD (15% vs. 13%; p = 0.3); no difference was seen between CD and UC groups. The prevalence of AN was higher in the hospitalized IBD group (26% in- vs. 11.7% out-patients; p < 0.01; OR 2.2) and in patients with active disease (CD: 34% active vs. 16% in remission; p < 0.01; OR 2.1 – UC: 26% active vs. 19% in remission; p = 0.03; OR 1.3) (Table 4). To test whether the location/extension of the disease correlated with AN, we stratified the data set so that our results showed AN to be more frequent in patients with ileo-colic CD and in those with extensive UC (p < 0.01). We found anaemia in 82.7% of CD patients with ileo-colic disease vs. 17.3% with colic disease and in 60.9% of UC patients with extensive colitis vs. 39.1% of patients with left colitis/proctitis. For what concerns the causes of AN, IDA was found in 72 patients (53.7%), ACD in 12 (8.2%), mixed type AN in 11 (8.2%), thalassemia in 9 (6.7%), and macrocytic AN in 8 patients (5.9%) (Fig. 1). We found azathioprine-related macrocytic anaemia in 3 patients (2.2%). In 18 patients (13.4%), the causes remained unclassifiable. Additionally, vitamin B12 deficiency and folic acid deficiency were observed in 7.4% and 6.1% of CD patients and in no case of UC. No case of celiac disease was detected in our IBD population.

Table 4 Main results of AN prevalence in UC and CD.

UC (n = 383) CD (n = 582) p-Value
Entity of disease (%) 53 (13.8) 81 (13.9) n.s.
Mean age 38 (18–62) 35 (17–60) n.s.
Gender
n (%) women 32 (8.1) 47 (8) n.s.
n (%) men 21 (5.5) 34 (5.8) n.s.
Ferritin (mean ± SD) 44 ± 80.4 70 ± 132.4 p < 0.01
CRP (mean ± SD) 6.5 (±12.1) 7.2 (±13) n.s.
Hosp/outpatients (%) 14 (3.6)/9 (2.3) p < 0.01
Hosp/outpatients (%) 20 (3.4)/6 (1) p < 0.01
Active disease (%) 198 (34) p < 0.01
Active disease (%) 99 (26) p = 0.03
Location n (%)
 L1-L2-L3 14 (18)-20 (24)-47 (58) p < 0.01
Extension n (%)
 E1-E2-E3 4 (7)-17 (32)-32 (61) p < 0.01
gr1

Fig. 1 Principal causes of anaemia in IBD.

ACD was associated with higher CRP values than IDA, although no differences were observed in disease activity scores between patients with ACD and IDA. In CD patients, mean CDAI was 190 in IDA vs. 230 in ACD (p = n.s.), while in UC patients mean CAI was 8 in patients with IDA vs. 9 in patients with ACD (p = n.s.).

While patients with CD had Hb, TSAT, and CRP values comparable to those of patients with ulcerative colitis, their serum ferritin values were higher (70 ± 132.4 vs. 44 ± 80.4; p < 0.01).

Since ferritin is recognized as an acute-phase protein, we further assessed the correlation of ferritin with CRP as well as with disease activity index. We found that 17% of patients with increased ferritin levels presented elevated disease activity. However, there was no correlation between the grade of inflammation, as measured by CRP or CDAI/CAI, and ferritin (p = n.s.).

4. Discussion

Data concerning the prevalence of AN in IBD ranges from 6% to 74% [9] and [11]. In our work, we found AN in 14% of patients, a quite lower value than the one reported in other studies [22] and [23]. This discrepancy was probably influenced by the fact that, while we evaluated only patients under active treatment, the latter two studies included subjects who had yet to start therapy. Moreover, our results showed no significant difference between CD and UC groups. Besides chronic intestinal blood loss through ulcerated mucosal surface, which occurs in both disease entities, patients with CD in the upper gastrointestinal regions (e.g. jejunum, ileum) have an additional risk of iron malabsorption leading to IDA. However, in our study population, this difference was not clearly evident. Moreover, we did not find discrepancies between men and women, indicating that blood loss during menstruations in young females does not significantly affect overall iron status.

In our work, most cases of AN were classified as either mild or moderate (HB ≥10 g/dl), according to a recent European study [24] in which 91.2% of IBD patients presented HB levels ≥ 10 g/dl. The German AnaemIBD Study included only IBD outpatients, and, as a consequence, probably disregarded potential cases with a more severe AN, needing hospitalization. On the contrary, we included both in- and out-patients, and, therefore, the low rate of severe AN found was probably the result of a major control of the disease. However, our hospitalized patients were more frequently anaemic than out-patients, showing that AN could be a complication of IBD that requires careful monitoring and prompt treatment.

As shown by our data, the most frequent cause of AN, in both CD and UC patients, was iron deficiency, which was probably related to the longer course of the disease, and/or chronic overt/occult blood loss.

Iron deficiency may be related to “absolute iron deficiency” due to low dietary intake and blood loss from ulcerated intestinal mucosa (especially in UC) along with reduced iron absorption (especially in CD localized in the upper GI tract), or it may be related to “functional iron deficiency”. In case of “functional deficiency”, even if iron is abundant in the body, it is not available for erythropoiesis because some events cause its retention in the cells: inhibition of ferroportin transcription and activity, and reduced erythrocytes half-life due to oxidative stress and lipid peroxidation [25]. In our study, 53.7% of patients showed IDA and there was no difference between CD and UC. Among patients with IDA, 48 of them (66%) were treated with iron therapy: 3 patients (6.2%) received transfusion, 30 subjects (62.5%) were treated with oral iron and 15 of them (31%) received parenteral iron. We also found that 8.2% of subjects showed ACD, caused by decreased erythropoiesis due to pro-inflammatory cytokines (INFγ, IFNα, TNFα and IL-1).

Another cause of AN was macrocytic AN, that affected 5.9% of patients, and was probably induced by concomitant treatment with thiopurines (3 patients with CD treated with azathioprine for 2 years, 3 years and 5 years, respectively) or by poor absorption of folic acid and vitamin B12 after surgery, in case of CD (5 patients, 3.7%). Among other causes of AN (16.4%), we would like to report autoimmune hemolytic anaemia (AIHA), which was found in two patients with UC during therapy with azathioprine (one young man) and infliximab (one young woman). This condition was induced by the development of antibodies with cross-reactivity with erythrocytes [26].

For what concerns the correlation of AN with the location/extension of the disease, anaemia appeared to be more frequent in patients with ileo-colic CD and in those with extensive UC (p < 0.01). In fact, 82.7% of anaemic CD patients showed an ileo-colic location vs. 17.3% of subjects with a colic disease. On the other hands, 60.9% of anaemic UC patients showed an extensive colitis vs. 39.1% of patients with distal colitis or proctitis. In CD, these findings could support the argument that small bowel inflammation has a major role in determining iron malabsorption and, consequently, IDA. In UC, the correlation between low Hb levels and the extension of the disease, highlighted the importance of a greater inflamed surface in which ulcerations and erosions represent the principal bleeding source.

Moreover, some studies have found a correlation between high CDAI and AN; this result is not surprising, considering that the hematocrit value is a parameter for the calculation of CDAI. In our subjects, we found that ACD was associated with higher CRP values than IDA, although no difference was observed about disease activity scores between patients with ACD and IDA. Perhaps, no significant correlation was evident between Hb values and activity of disease, because our patients were evaluated during a mild/moderate phase of the disease. Additionally, we measured patients’ iron status at a single time-point, without considering a temporal evaluation of AN over time. Therefore, it would be interesting to assess any changes in haemoglobin level after the treatment of the underlying disease in a future prospective study.

Unexpectedly, no case of celiac disease was observed in our IBD population. This outcome conflicts with the expected data in a geographical area which is characterized by a high prevalence of celiac disease (prevalence: 1–2/100 inhabitants) [27].

In conclusion, our results confirmed that anaemia has a significant impact on IBD and represents one of the most frequent conditions associated with such diseases. Prompt diagnosis and careful treatment of anaemia in IBD should become a major concern for gastroenterologists experienced in IBD work-up.

Conflict of interest

None declared.

Acknowledgements

Many thanks to Dr. Manuela Pignata for the revision of English language and her precious support.

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Footnotes

a Department of Clinical Medicine and Surgery, University “Federico II” of Naples, Naples, Italy

b Department of Clinical and Experimental Medicine “Magrassi-Lanzara”, Gastroenterology Unit, Second University of Naples, Naples, Italy

c Gastroenterology Unit, Second University of Naples, Naples, Italy

d Surgery, Second University of Naples, Naples, Italy

e Hospital of Marcianise, Caserta, Italy

f Hospital of Sapri, Salerno, Italy

Corresponding author at: Gastroenterologia, Università degli Studi di Napoli “Federico II”, Scuola di Medicina e Chirurgia, Via S. Pansini 5, 80131 Naples, Italy. Tel.: +39 0817463849; fax: +39 0817463849.