Iron Metabolism Improves after Anti-TNF Therapy for Crohn’s Disease

A previous study has shown that low vitamin D levels improved with anti-TNF therapy for Crohn’s disease in the absence of supplemental vitamin D.  Similarly, a recent study (MA Atkinson, MB Leonare, R Herskovitz, RN Baldassano, MR Denburg. JPGN 2018; 66: 90-4) showed improvement in iron metabolism with anti-TNF therapy.

In 40 children and adolescents with Crohn’s disease, the authors measured serum hepcidin-25 and hemoglobin at baseline and then 10 weeks after anti-TNF therapy.

Key findings:

  • Median hepcidin concentrations decreased (27.9–>23.2 ng/mL) and mean hemoglobin increased (10.6–>10.9).
  • Disease activity and markers of inflammation also decreased.

My take: This study shows that improvement in inflammation is associated with meaningful improvement in anemia.  However, most patients will need additional treatment for anemia, particularly as anemia may be related to blood loss in addition to anemia of chronic disease/inflammation.

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February Briefs

JM Powers et al. J Pediatr 2017; 180: 212-6. This retrospective study details a protocol for using intravenous ferric carboxymaltose (FCM) (Injectafer) in children.  This product has become available for adults in U.S. since June 2013; it had been available in Europe since 2009. In this retrospective study, 72 pediatric patients received FCM for iron deficiency anemia (off-label); there was a good safety profile and a good response with hemoglobin increasing from 9.1 to 12.3 (4-12 weeks post infusion).  FCM is a relatively costly IV iron formulation, but can be given over 15 minutes.

L Peyrin-Biroulet et al. Clin Gastroenterol Hepatol 2017; 15: 25-36.  This systemic review with more than 2800 patients showed that TNF antagonists were effective for extraintestinal manifestations of inflammatory bowel disease, including cutaneous disorders (eg.. pyoderma gangrenosum, erythema nodosum), hematologic problems (eg anemia), ocular disorders, and rheumatologic symptoms( eg. arthralgias/arthritis).

AE Mikolajczyk et alClin Gastroenterol Hepatol 2017; 15: 17-24. Useful review of the GI/Liver manifestations of autosomal-dominant polycystic kidney disease. “There is not a role for therapy [for the liver] in asymptomatic patients.” Other problems reviewed included pancreatic cysts, hernias, and diverticular disease. Related posts:

T Rajalahti et al. JPGN 2017; 64: e1-6.  Among 455 patients <18 with Celiac disease, anemia was noted in 18%. This resolved in 92% after one year of a gluten-free diet.  Anemia is associated with more severe histological and serological presentation. Related posts:

FL Cameron et al. JPGN 2017; 64: 47-55. This retrospective review of 93 children treated with infliximab and 28 children with adalimumab provides data on growth after anti-TNF therapy.  This study shows that anti-TNF therapy is more likely to be associated with growth improvement when used at earlier stages of puberty.

Related blog posts:

Chattahoochee River

Chattahoochee River

Celiac Studies

Three reports on celiac disease:

  • KM Simmons et al. J Pediatr 2016; 169: 44-8.
  • NR Reilly et al. J Pediatr 2016; 169: 40-54
  • MMS Wessels et al. J Pediatr 2016; 169: 55-60.

In the first study, the authors examined bone mineral density (BMD), glycemic control with hemoglobin A1c, and celiac autoimmunity in children with type 1 diabetes (T1D).  This was a cross-sectional study of 252 children with T1D; 123 had positive serology were anti-tissue transglutaminase (tTG) antibody.  In addition, another cohort (n=141) of children without T1D were examined who carried HLD-DR, DQ genotypes with (n=71) and without (n=70) tTG.  Key findings:

  • Children with T1D: those positive for tTG had significantly worse BMD L1-L4 (-0.45 ± 1.22 vs 0.09 ± 1.10, P= .0003).  Higher tTG and higher HgbA1c were independent predictors of lower BMI.
  • In children without T1D: no differences in BMD were found based on tTG status.
  • The authors concluded that celiac autoimmunity and hyperglycemia had synergistic effects on low BMD.

In the second study, the researchers used a population-based cohort study and compared 958 individuals with both T1D and celiac disease (CD) to 4598 similar individuals with T1D alone. Key finding: Over a 13 year period, 12 patients with both T1D and CD had a fracture (1 osteoporotic fracture). CD did not influence the risk of any fracture (aHR 0.77) in patients with T1D.  The researches concluded: “CD does not seem to influence fracture risk in young patients with T1D.”

My take: Looking at these studies in juxtaposition shows how important it is to consider multiple studies and how frequent discrepant results occur.  While the second study does not show a significant fracture risk, the preponderance of evidence does show an association between celiac disease and low BMD particularly in adults. In addition, a gluten free diet has been shown to reverse low BMD in those with CD.

Relevant studies:

  1. Gastroenterology 2010; 139: 763.
  2. Aliment Pharmacol Ther 2000; 14: 35-43.
  3. JPGN 2003; 37: 434-6.
  4. Gut 1996; 38: 322-7.

In the third study, the investigators looked at “complementary” investigation in children with CD.  These included tests like hemoglobin, ferritin, folate, vitamin B12, calcium, vitamin D, and thyroid assays.  Between 2009-2014, 182 children were evaluated included 119 with new diagnosis. Key findings:

  • At time of diagnosis: Iron deficiency (28%), iron deficiency anemia (9%), folate deficiency (14%), vitamin B12 (1%), and vitamin D deficiency (27%) were identified. No hypocalcemia or thyroid dysfunction was found.
  • At followup: iron deficiency (8%), iron deficiency anemia (2%), folate (3%), vitamin D (25%) were identified and no other abnormalities were evident.
  • The investigators concluded that these complementary tests “are relevant at the time of diagnosis of CD but have little diagnostic yield during followup-visits” after institution of gluten-free diet.

My take: Particularly at followup, identification of nutrient deficiencies is typically similar to the general population.

Related posts:

Castillo San Felipe del Morro, San Juan

Castillo San Felipe del Morro, San Juan

Be Aggressive! Treating Anemia Associated with Inflammatory Bowel Disease

A number of recent publications have made the point that anemia is a biomarker for severe inflammatory bowel disease and undertreatment affects quality of life. Reading one of the more recent studies (IE Koutroubakis et al. Clin Gastroenterol Hepatol 2015; 13: 1760-66) brought to mind the high school football cheer: Be Aggressive!

This particular retrospective study involved 410 patients (245 with Crohn’s disease, 165 with ulcerative colitis) from 2009-2013.  This study is from the same group that published data on a somewhat smaller cohort and showed that IBD treatment alone often will not resolve anemia (Koutroubakis, IE et al. Inflamm Bowel Dis 2015; 21: 1587-93–see previous blog links).

Key findings:

  • Prevalence of anemia: 37.2% in 2009 and 33.2% in 2013
  • Anemia was associated with increased hospitalizations (P<.01), clinic visits (P<.001), telephone calls (P<.004), surgeries for IBD (P=.001), and lower quality of life scores (P<.03)

The associated editorial (pgs 1767-69) suggests that IBD-related anemia, if mild (w/in 1 g/L below normal) to treat with oral iron replacement and if moderate-to-severe, then to replace intravenously (using Ganzoni’s formula calculator). In addition, if anemia is not improving, looking for alternative explanations (e.g. vitamin B12 or folate deficiency) is recommended.

Ganzoni Equation: Total Iron Deficit = Weight {kg} x (Target Hb – Actual Hb) {g/l} x 2.4 + Iron stores {mg}.   Iron stores: { 500 if W > 35kg } & { 15 mg/kg if W < 35kg }

My take: Anemia is a biomarker for severe disease.  While treating the underlying inflammatory bowel disease, don’t forget to make sure the patient’s anemia is addressed.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Central Park

Central Park

Is It Right? Anti-TNF Therapy Does Not Fix IBD-Related Anemia

A surprising study (Koutroubakis, IE et al. Inflamm Bowel Dis 2015; 21: 1587-93) of prospectively-collected data from 430 patients with inflammatory bowel disease (IBD) showed that the rate of anemia did not change after 1 year in patients treated with anti-tumor necrosis factor (anti-TNF) therapy and oral iron.

The data was derived from 2010-2012 and included 324 patients with Crohn’s disease (51.6% females) with a median age of 41 years.  Anemia was defined as hemoglobin (Hb) <13 g/dL in men and <12 g/dL in women.  Patients with Hb <10 g/dL were considered to have severe anemia. Key findings:

  • Prevalence of anemia in IBD patients treated with anti-TNF was 38.1% at baseline and then 36.6% at 1 year.
  • Severe anemia was identified in 10% at baseline and 9.9% at 1 year.
  • A hematopoietic response with a Hb ≥2 g/dL was observed in 33.6% (n=45 of 134 anemic patients) and 14 (40%) of those with severe anemia.
  • There were 45 new anemic patients at 1 year; 64.4% were nonresponders to anti-TNF treatment.
  • Using multivariate logistic regression analysis, the author noted that use of immunomodulators was associated with an odds ratio of 2.56 of improvement in hemoglobin levels.

The authors state that anemia is the most common extra intestinal manifestation of IBD and remains underappreciated.  Anemia in IBD correlates with the extent of intestinal disease and activity.

Bottomline: “Use of anti-TNF therapy had only a modest effect on patients’ Hb level.”

From related post: IBD Update January 2015 (Part 2)

Inflamm Bowel Dis 2014; 20: 2266-70.  This study with 749 patients from Sweden showed that a large number of inflammatory bowel disease patients did not receive with iron supplementation: “Only 46% of patients with anemia were treated with iron supplementation or blood transfusion.”  This study showed frequent persistence of anemia one year after diagnosis, especially in children. At time of diagnosis, 55% of children and 27% of adults had anemia and 28% and 16% at one year followup, respectively.

My take: Treatment of the underlying IBD, often helps anemia.  However, in some patients treating the anemia with iron may help improve symptoms as much or more than other aspects of treatment.

Related blog post: Microcytic Anemia Review | gutsandgrowth

Sandy Springs, Georgia

Sandy Springs, Georgia


IBD Update January 2015 (Part 2)

1. A retrospective study (Inflamm Bowel Dis 2014; 20: 2292-98) of 217 patients with inflammatory bowel disease(108 infliximab-treated, 109 adalimumab-treated) provides data which indicates that combination therapy (mainly with thiopurines) resulted in higher trough levels and lower antibodies to infliximab (ATI) than monotherapy in patients treated with infliximab (IFX).  This was not evident in the adalimumab (ADA)-treated patients. Overall, approximately 90% of study population had Crohn’s disease.

Key points from this study:

  • The majority of trough level/antidrug antibody levels were drawn due to loss of response.  This is a major limitation of this study.
  • Among IFX-treated patients, those with combination therapy had trough level of 7.5 mcg/mL compared with 4.6 mcg/mL.  In combination therapy patients, the incidence of ATIs was 5.7% compared with 29.8% in monotherapy patients.
  • According to this study, the dose of the immunomodulator (IM) did not significantly influence the infliximab trough level or antibody formation; that is, more than half of patients were receiving “suboptimal dosed IM” and their infliximab levels/ATIs were similar to those who were optimally-dosed.
  • Among those who were receiving combination therapy, the incidence of antibody formation was lower in IFX-treated patients who started IM concurrently with IFX compared with those in which IM was added subsequently.
  • There were many other limitations in this study, including the finding that 94% of monotherapy patients had received previous immunomodulator therapy.

Bottomline: This study suggests that combination therapy is beneficial for patients receiving infliximab (in agreement with the previous SONIC study) and may not be beneficial for patients receiving adalimumab; however, only a well-designed prospective study

2. Inflamm Bowel Dis 2014; 20: 2266-70.  This study with 749 patients from Sweden showed that a large number of inflammatory bowel disease patients did not receive with iron supplementation: “Only 46% of patients with anemia were treated with iron supplementation or blood transfusion.”  This study showed frequent persistence of anemia one year after diagnosis, especially in children. At time of diagnosis, 55% of children and 27% of adults had anemia and 28% and 16% at one year followup, respectively.

My take: Treatment of the underlying IBD, often helps anemia.  However, in some patients treating the anemia with iron may help improve symptoms as much or more than other aspects of treatment.

3. Inflamm Bowel Dis 2014; 20: 2433-49.  Reviews pain management approaches for patients with IBD. The article emphasizes how pain can be multifactoral and that opiod-induced hyperalgesia may worsen pain.

Related blog posts:


Bryce Canyon

Bryce Canyon


Less Red Meat, More Anemia

The title of this entry is not particularly surprising.  A recent study (JPGN 2013; 57: 722-27) showed that among 263 children (1.5-6 years in age) in Jerusalem, that anemia was present in 11.2%, iron deficiency in 22%, and iron-deficiency anemia in 3.7%.

Key finding:

Children with extremely low red meat consumption had 4-fold higher rates of iron deficiency than those who consumed ≥2 servings per week.  Poultry intake was not protective.

Bottomline: As more families choose a ‘health-conscious diet,’ iron deficiency may become more frequent.

Related blog entry: Help with hepcidin | gutsandgrowth