Vitamin B12 deficiency in children

Recent studies have shown that a vitamin B deficiency in children occurs more often than previously assumed.
A vitamin B12 deficiency in children often presents itself with non-specific symptoms such as developmental delays, a diverging growth curve, anorexia, irritability, neurological problems and weakness.
In the event of a diverging growth curve in combination with neurological symptoms, or in combination with developmental delays, a vitamin B12 deficiency should be considered.

The amount of vitamin B12 during the first year of life is heavily dependent on how much vitamin B12 was available during the pregnancy and is therefore highly dependent on the vitamin B12 status of the mother.
Typically, a newborn baby has a store of 25 ųg vitamin B12 in the liver, a quantity which is enough for the first year of life, even if the subsequent intake is insufficient. But this store is seriously reduced in mothers with a (untreated) vitamin B12 deficiency. This can already become apparent at the age of 3 to 4 months.

A vitamin B12 deficiency during the first years of life may lead to reduced function of the central nervous system. Serious clinical symptoms and neurological deterioration are described in children with a vitamin B12 deficiency. Even a mild deficiency can already have harmful effects. A reduced vitamin B12 status can exist with normal vitamin B12 serum values and without the classic characteristics of megaloblastic anaemia or neuropathy. A timely detection of the deficiency and adequate treatment with vitamin B12 can prevent serious and irreparable damage and improve the development of the child.

A vitamin B deficiency in children (under 19 years) is defined as a serum B12 value of < 229 pmol/L or a MMA value > 0.26 to 0.29 ųmol/L.⁴

The serum B12 value decreases significantly after the birth. From the age of 6 months the value increases to a maximum between the age of 3 and 7, after which it slowly decreases to the adult value. This decrease continues throughout life, indicating that the current laboratory reference values should not be applied to children. Those reference values are based on healthy adults.

The average value in children between the ages of 15 ½ and 19 years is around 369 pmol/L, which is considerably higher than the adult value. The folic acid level drops slowly until the age of 15, and from then corresponds with adult levels. Homocysteine levels increase with age, from an average of 5 ųmol/L in babies to 8.7 ųmol/L in the oldest group of children. From the age of 1 year the MMA remains at a stable low value (< 0.26 μmol/L).

Symptoms of a vitamin B deficiency in children:

• Weakness
• Fatigue
• Lack of appetite
• Delay in growth
• Developmental delay or even regression
• Irritability
• Tingling or burning sensation (in extremities)
• Hypotonia (low muscle tone)
• Reduced tactile sensation
• Seizures
• Ataxia (lack of muscle control)
• Symptoms of paralysis
• Involuntary movements
• Concentration problems
• Memory disorders
• Personality changes
• Depression
• Macrocytosis
• Anaemia
• Hypersegmented neutrophils (type of white blood cells)
• Leukopenia (low white blood cell count)
• Thrombocytopenia (low blood platelet count)
• Glossitis
• Hyperpigmentation of the skin
• Vomiting
• Diarrhea and/or intestinal symptoms
• Jaundice
• Headache

Causes

The causes of a vitamin B12 deficiency in children can be divided into 3 categories: reduced intake, malabsorption, and congenital errors in the transport & metabolism of vitamin B12.

Reduced intake:

• Strictly vegetarian/vegan/macrobiotic diet
• Breastfeeding by a mother with an untreated vitamin B12 deficiency, or by a mother following one of the above diets
• Untreated phenylketonuria (a genetic condition)

Malabsorption:

• Insufficient or no intrinsic factor due to: autoimmune pernicious anaemia, surgical removal of part of the intestine (bowel resection), absent/abnormal formation of intrinsic factor (hereditary)
• Reduced stomach acid, for example by long term treatment with acid reducing medications
• Reduced pancreatic function
• Competition in the intestines with vitamin B12 by parasites or bacterial overgrowth (SIBO)
• Malabsorption in the small intestine due to Crohn’s disease, celiac disease, small intestine surgery, or Imerslund-Gräsbeck syndrome

Congenital faults in the transport or the metabolism of vitamin B12:

• Disorder in the transport due to transcobalamin-II deficiency or cobalamin R-binder protein deficiency
• Metabolic disorders: adenosylcobalamin deficiency (cblA, cblB, mut), methylcobalamin deficiency (cblE, cblG), combined adenosylcobalamin and methylcobalamin deficiency (cblC, cblD, cblF, cblJ)

Diagnosis

The diagnosis should not be dependent on abnormal blood values. Macrocytosis for example is not specific to a vitamin B deficiency in children and also anaemia is not always present – as was previously assumed. It is estimated that if the values for haemoglobin, haematocrit and MCV are normal, more than 30% of vitamin B12 deficient patients will be missed. In patients with congenital metabolism disorders of vitamin B12, the serum B12 value is often normal because the vitamin B12 is present in the blood but not in the tissues. There can be a vitamin B deficiency in the tissues, even before the serum values are low.

Some people already have symptoms while the serum B12 value is still in the low-normal range. These symptoms tend to disappear after treatment with injections, which also indicates that there was, in fact, a deficiency. MMA (methylmalonic acid) is a much more sensitive test for the diagnosis of a vitamin B deficiency than the ordinary B12 test.  If a vitamin B deficiency is suspected in children but this is not clear from the serum B12 value, or from the symptoms, we recommend testing for homocysteine and MMA. After the diagnosis has been made, additional tests are often necessary to identify a cause.

Tests that can be done are: analysing the diet, testing for the presence of parasites, analysis of amino acids, transcobalamin levels, measuring the vitamin B12 binding capacity, tests for intrinsic factor antibodies and parietal cell antibodies.

Serum B12 value in children:

0 to 1 year: 326 – 591 pmol/L

2 to 5 years: 441 – 560 pmol/L

6 to 10 years: 345 – 438 pmol/L

11 to 14 years: 284 – 355 pmol/L

15 to 19 years: 216 – 272 pmol/L

These values are from a survey of 234 children in the age group 0-19 years in Nijmegen (95 % CI). ²

Another survey of 700 healthy children from 4 days old to 19 years, with a typical Western diet ⁵ showed the following values (not reference values):

Age: median (25th and 75th percentile)
4 days old: 314 (238 – 468)
6 weeks to 6 months: 217 (147 – 290)
1 to 10 years: 551 (456 – 683)
10.5 to 15 years: 436 (295 – 529)
15.5 to 19 years: 369 (294 – 452)

Treatment

The treatment depends on the cause of the deficiency. If the deficiency is mild and asymptomatic, a diet adjustment or the removal of the underlying cause plus a good supplement may be sufficient. In most cases however, the cause cannot be removed and permanent treatment with vitamin B12 injections will be necessary.

In the event of (serious) symptoms immediate treatment with vitamin B12 injections is necessary to prevent permanent damage. Children with metabolic disorders and lack of B12 binding proteins often require high doses of vitamin B12, as well as additional forms of treatment.

In other literature ¹ it is recommended that daily vitamin B12-injections (1000 μg) are administered for one week and then (possibly) to repeat every week during one month, followed by a maintenance dose. This advice is mainly empirically substantiated. For teenagers the adult treatment can be followed.

The symptoms are of decisive importance during treatment. The effectiveness of the treatment cannot be measured by serum B12 levels after administration of injections because even though the transport proteins become fully saturated, this does not reflect how much B12 is actually present in the cells.

Although treatment can result in dramatic improvements in most patients, there may be some lasting neurological damage. The long term prognosis seems to be linked to the seriousness and duration of the deficiency, which clearly emphasises the need for an early diagnosis and sufficient treatment.

How prevalent is a deficiency in children?

An investigation of the B12 values in 3766 children from the age of 4 days to 19 years⁵, showed that 3 children had a value below 74 pmol/L, a frequency of 1 in 1255 and 18 children had a value below 148pmol/L, a frequency of 1 in 200. The largest group of children with values below the 148 pmol/L occurred in the 12-19 year age group, with a frequency of 1 to 112. The lowest values were found in white children from 12-19 years. If we take into consideration the higher values for children a deficiency occurs even more frequently.

References:

1. Vitamin B12 deficiency in children and adolescents. Sonja A. Rasmussen, MD, MS, Paul M. Fernhoff, MD, and Kelley S. Scanlon, PhD, RD J Pediatr 2001;138:10-7
2. Total homocysteine and its predictors in Dutch children. Ingrid M van Beynum, Martin den Heijer, Chris MG Thomas, Lydia Afman, Diny Oppenraay-van Emmerzaal, and Henk J Blom, Am J Clin Nutr, 2005;81:1110–6
3. Ontwikkelingsachterstand bij borstgevoede kinderen door ontoereikend dieet van de moeder. A.Baatenburg de Jong, J.Bekhof, P.Zwart, V.J.Langenhorst en R.J.Roorda, Ned Tijdschr Geneeskd. 2006 4 maart;150(9)
4. Signs of impaired cognitive function in adolescents with marginal cobalamin status. Marieke WJ Louwman, Marijke van Dusseldorp, Fons JR van de Vijver, Chris MG Thomas, Jørn Schneede, Per M Ueland, Helga Refsum, and Wija A van Staveren,Am J Clin Nutr 2000;72:762–9
5. Cobalamin Status and Its Biochemical Markers Methylmalonic Acid and Homocysteine in different Age Groups from 4 Days to 19 Years. Anne-Lise Bjørke Monsen, Helga Refsum, Trond Markestad, and Per Magne Ueland, Clinical Chemistry 49:12 2067–2075 (2003)
6. Determinants of Cobalamin Status in Newborns. Guttormsen, Trond Markestad, Einar Solheim and Helga Refsum, Anne-Lise Bjørke Monsen, Per Magne Ueland, Stein Emil Vollset, Anne Berit, 2001;108;624-630 Pediatrics
7. Cobalamin status in children. Anne-Lise Bjørke-Monsen & Per Magne Ueland J Inherit Metab Dis (2011) 34:111–119