Time to Revise ImproveCareNow Micronutrient Recommendations

With ImproveCareNow, there have been efforts to minimize variation in care.  As such, there have been suggestions to monitor labs like vitamin D, vitamin B12, and folate routinely. I have voiced concern that some of this testing is unnecessary.  For vitamin B12, deficiency in pediatrics is rare; at risk populations include those with extensive small bowel resections, gastric resections or strict vegan diet.

A recent article (J Fritz et al. Inflamm Bowel Dis 2019; 25: 445-59) which is a systematic review of micronutrients in pediatric inflammatory bowel disease provides further support for the approach of less testing.

Key points:

  • A total of 39 studies were included in the final review (2903 subjects, 1115 controls)
  • Iron deficiency and vitamin D deficiency are common in pediatric patients with IBD
  • Vitamin B12 and folate deficiency are rare
  • Zinc deficiency is uncommon but increased in patients with Crohn’s disease compared to healthy controls.
  • The authors recommend routine (at least yearly) testing for iron, vitamin D and zinc and that there is “insufficient evidence to support routine screening for other micronutrient deficiencies.”

My take: Except in patients with surgical resections and in those with unusual diets (eg. vegan), routinely checking vitamin B12, folate and most other micronutrients is unnecessary & low value care.

Related blog posts:

Vitamin B12:

Vitamin D:


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.

Methylmalonic Acid as a Biomarker of Vitamin B12

A recent case study (L Jimenez et al. J Pediatr 2018; 192: 259-61) showed that methylamalonic acid (MMA) can be elevated in the absence of vitamin B12 deficiency.


  • Risk factors for vitamin B12 deficiency: terminal ileal resection and gastric acid blockade
  • Manifestations of vitamin B12 deficiency: megaloblastic anemia, bone marrow failure, demyelinating diseases, thrombosis, and psychiatric symptoms
  • Early assessment of vitamin B12 deficiency can be aided by MMA levels and homocysteine levels both of which are metabolized via vitamin B12-dependent pathways and are elevated in vitamin B12 deficiency.
  • MMA levels have higher sensitivity for vitamin B12 deficiency than vitamin B12 levels alone.

Key findings of this report:

  • In three children with short bowel syndrome, MMA levels were persistently elevated despite vitamin B12 supplementation and without other evidence of vitamin B12 deficiency
  • MMA levels declined after treatment of bacterial overgrowth
  • “It is hypothesized that propionate, a precursor to MMA, produced by excessive gut fermentation, is responsible for the elevation in plasma MMA levels.”

My take: this study is a good reminder of how MMA is useful in detecting vitamin B12 deficiency and points out that bacterial overgrowth may be an alternative explanation for elevated MMA levels.

Related blog posts:

Resources for Short Bowel Syndrome:

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.

Bright Angel Trail, Grand Canyon

What’s Often Missing in Vegan Diets

From NPR: Can A Vegan Diet Give You All You Need? German Nutritionists Say ‘Nein’

An excerpt:

“With a pure plant-based diet, it is difficult or impossible to attain an adequate supply of some nutrients,” states the German Nutrition Society’s new position on the vegan diet. “The most critical nutrient is B-12,” which is found in eggs and meat. The group says if you follow a vegan diet, you should take supplements to protect against deficiencies.

According to the German nutritionists, other “potentially critical nutrients” that may be a challenge to get in a vegan diet include omega-3s — found in fatty fish — as well as minerals such as calcium, iron, iodine, zinc and selenium. So the group recommends that vegans get advice from a nutrition counselor and be “regularly checked by a physician.” In addition, the society recommends against a vegan diet for pregnant women, women who are breast-feeding, children and adolescents…

“B-12 only comes from animal products,” says Cimperman. “It’s necessary for proper red blood cell formation, as well as normal neurological function.”

Many foods — including some breakfast cereals, as well as some nondairy creamers and milks — are fortified with B-12. So it’s possible to get all the nutrition you need this way, if you eat enough of these fortified foods regularly.

But to make sure you’re covering all your bases, “I would recommend [taking] a standard multivitamin,” Cimperman says. It’s a good insurance policy for vegans.

Pat O'Brien's Patio, New Orleans

Pat O’Brien’s Patio, New Orleans


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

What I Didn’t Know About Vitamin B12 and Crohn’s Disease

This month I learned from a recent publication (Inflamm Bowel Dis 2014; 20: 1120-23) that Crohn’s disease without ileal resection does not seem to increase the risk of Vitamin B12 (cobalamin) deficiency.  To reach this conclusion, the authors did an extensive literature search and identified 42 relevant articles with 3732 IBD patients.

Key findings:

  • Ileal resections >30 cm were associated with B12 deficiency.
  • Resections <20 cm were not associated with B12 deficiency; whereas the findings were inconsistent when resections were 20-30 cm.

Take home message:  Crohn’s disease, regardless of disease location, did not increase the risk of B12 deficiency in the absence of ileal resections >20 cm.

Related blog posts:

Risk of Vitamin B12 Deficiency with Persistent PPI Usage

From NY Times, nyti.ms/1kwQHPF :

People who use certain acid-suppressing drugs for two years or longer are at increased risk of vitamin B12 deficiency, which can lead to anemia, neurological problems or dementia, researchers reported on Tuesday.

The drugs in question are called proton-pump inhibitors, or P.P.I.’s, and histamine 2 receptor antagonists, and they are available by prescription and over the counter under brand names like Prevacid, Prilosec and Nexium. Nearly 157 million prescriptions were written for P.P.I.’s alone last year.

“People who are taking these medications are more likely than the average person to be vitamin B12 deficient, and it’s a potentially serious problem,” said Dr. Douglas A. Corley, senior author of the new study, published in The Journal of the American Medical Association. “This raises the question of whether people taking these medications for long periods should be screened for vitamin B12 deficiency.”

Dr. Corley has received funding from Pfizer, which makes a P.P.I. called Protonix.

He and his colleagues at Kaiser Permanente in Oakland, Calif., examined the medical records of 25,956 adults who received vitamin B12 deficiency diagnoses between 1997 and 2011, comparing them with 184,199 patients without B12 deficiency during that period.

Patients who took P.P.I’s for more than two years were 65 percent more likely to have a vitamin B12 deficiency, the researchers found. Higher doses of P.P.I’s were more strongly associated with the vitamin deficiency, as well.

Twelve percent of patients deficient in vitamin B12 had used P.P.I.’s for two years or more, compared with 7.2 percent of control patients. The risk of deficiency was less pronounced among patients using H2RA’s long term: 4.2 percent, compared with 3.2 percent of nonusers.

The new study is the largest to date to demonstrate a link between taking acid suppressants and vitamin B12 deficiency across age groups. Earlier small studies focused primarily on the elderly.

Robert J. Valuck, a professor of pharmacy at the University of Colorado in Aurora, was surprised that the association in the new report was strongest in adults younger than age 30. “It’s not safe to assume vitamin B12 deficiency is only an issue in the elderly,” he said.

Bottomline: patients (not just elderly) on chronic PPIs may need to be tested for vitamin B12 deficiency.

Related blog entries:

Are we missing Vitamin B12? | gutsandgrowth

Neurological Complications Associated with Inflammatory Bowel Disease

Though I have not seen much in the way of neurological complications in our pediatric inflammatory bowel disease (IBD) population, nevertheless I worry about them.  A recent article provides some insight into the incidence, the pathophysiology and approach to these complications (Inflamm Bowel Dis 2013; 19: 864-72).

Types of neurologic complications: The most common neurologic complication is peripheral neuropathy.  The frequency is quite variable based on data collection method.  In large administrative healthcare data, the prevalence has been reported around 2% whereas in cohort studies the range has been 8-15%. Other complications include meylopathy, cerbrovascular disease, cranial nerve palsy (eg. Melkersson-Rosenthal syndrome), seizures, and demyelinating diseases.

With regard to demyelinating diseases, this has gained additional attention in the setting of biologic agents which have been associated with this complication.  However, the authors note that a pre-biologic treatment study from Olmstead County, observed a prevalence of multiple sclerosis of 1% which was 3.7 times higher than expected.  In addition, similar studies have confirmed this finding.

Potential mechanisms vary greatly depending on the neurologic complication. With regard to cerebrovascular disorders, “venous thromboembolism (VTE) has been shown to occur 3 times more frequently in patients with IBD (the risk increases to 8-10-fold in patients with active colitis) than the general population.”  Hence, VTE prophylaxis is recommended by the authors in hospitalized IBD patients, especially if they are experiencing a disease exacerbation.

In addition to the underlying disease, vitamin deficiencies (eg. Vitamin B12) and medications can trigger neurologic complications.

  • Natalizumab: progress multifocal leukoencephalopathy (PML)
  • Metronidazole: peripheral neuropathy (typically reversible with drug discontinuation)
  • Anti-TNF-α agents (infliximab, adalimumab, certolizumab): demyelination, rarely seizures, and rarely PML
  • Cyclosporine: various neurotoxicity in ~25%

Related blog entries:

Are we missing Vitamin B12?

This is the question that I wonder after reading a recent review (NEJM 2013; 368: 149-60) -especially since effective treatment is readily available.

While vitamin B12 deficiency is most common in individuals 70 to 80 years, it affects all age groups.  A particularly vulnerable group are infants of mothers with vitamin B12 deficiency.  These infants may be born with deficiency or it may develop if exclusively breast-fed, usually between 4 and 6 months of age.  Indications of this deficiency include failure of brain development, poor growth, hypotonia, and feeding difficulties.  Some infants develop tremors, lethargy, and hyperirritability.  Imaging may show atrophy and delayed myelination.

Mothers who are at most risk:

  • unrecognized pernicious anemia
  • history of gastric bypass
  • short gut syndrome
  • long-term vegetarian or vegan diet

Other pediatric conditions that cause B12 deficiency: ileal resections, Imerslund-Grasbeck syndrome (ImerslundGräsbeck syndrome (selective vitamin B12 malabsorption ..), inflammatory bowel disease, and pernicious anemia.

Other Key Points from this review:

  • B12 deficiency causes reversible megaloblastic anemia, demyelinating neurologic disease or both
  • B12 deficiency is the major cause of hyperhomocysteinemia in countries with folate-fortified food and contributes to a risk of vascular disease and thrombosis
  • Autoimmune gastritis (pernicious anemia) is the most common cause of severe deficiency (in adults).  Tests to determine underlying reason for B12 deficiency include the following: anti-intrinsic factor antibodies (must be checked off treatment for at least 7 days), anti-parietal cell antibodies -both help detect pernicious anemia, gastrin level (high level) & pepsinogen I (low levels) both suggestive of atrophic gastritis.  The Schilling test of radioactive B12 is no longer available.  Endoscopy is frequently performed in adults with B12 deficiency.
  • Methylmalonic acid (MMA) is the best indicator for untreated B12 deficiency; MMA >400 nmol/L has 98% sensitivity for B12 deficiency.  Other causes of increased MMA include renal failure and volume depletion.
  • Serum B12 has poor sensitivity and specificity -though performs adequately at higher cut-off value (<350pg/mL has 90% sensitivity)
  • Many individuals require lifelong treatment with either parenteral B12 or high-dose oral tablets (see article for dosing recommendations)

Additional references:

  • -J Pediatr 2010; 157: 162.  B12 deficiency in newborns –especially if mother has had bariatric surgery or vegan diet.
  • -J Pediatr 2001; 138: 10 (review) At risk for deficiency: strict veggie, abnl absorption (gastric resection, pernicious anemia), long term PPI, bacterial overgrowth, ileal disruption (Crohn’s), or ileal receptor d/o (Imersund-Grasbeck),  inborn B12 metabolism d/o

Clinical Sx: FTT, weakness, anorexia, neuro/psych sx, macrocytic anemia, pancytopenia, glossitis, vomit/diarrhea

Dx: low vit B12, incr methylmalonic acid & incr homocysteine.  MMA specific for B12; homocysteine incr also if folate deficient.

If Vit B12 deficient, reason for this needs to be determined.