Vitamin B 12 deficiency

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Classification according to ICD-10
E53.8 Deficiency of other specified vitamins of the vitamin B complex
ICD-10 online (WHO version 2019)
Cobalamin skeletal.svg

Vitamin B 12 deficiency , also called hypocobalaminemia , refers to low levels of vitamin B 12 in the blood . A variety of signs and symptoms can occur, including anemia and neurological disorders.

A protein, the intrinsic factor, is necessary for the absorption of vitamin B 12 in the stomach . If this z. B. in the context of autoimmune gastritis , the vitamin B 12 deficiency is referred to as pernicious anemia .

Signs and symptoms

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Vitamin B 12 deficiency can cause severe and irreversible damage, particularly to the brain and nervous system. It is possible that despite correcting the blood changes, the nerve damage may not heal. The likelihood of a complete reversal decreases with the length of time that the neurological symptoms have been present.

In principle, the symptoms can be divided into the two categories of blood changes and neurological symptoms.

Blood changes

A mild deficiency need not necessarily cause noticeable symptoms. The expression is different for every person. A more severe deficiency leads to symptoms such as anemia, weakness, fatigue, drowsiness, fast heartbeat, faster breathing, and pale skin color. It can also cause light bleeding, including bleeding gums. Side effects in the digestive system include a sore tongue, stomach discomfort, weight loss, and diarrhea or constipation.

In the case of anemia caused by a disorder of erythropoiesis , red blood cells ( erythrocytes ) are usually found that are larger than usual and have a higher hemoglobin concentration than usual, so that megaloblastic anemia is spoken of. The higher mean cell volume ( MCV ) above 98 fl distinguishes the anemia as macrocytic , the higher mean hemoglobin amount per red blood cell ( MCH ) above 34 pg or 2.05 fmol leads to (macrocytic) hyperchromic anemia. The anemia also reduces the hematocrit , and the anemia often affects the white blood cells as well, so leukopenia is also present.

Other abnormal laboratory values ​​due to premature hemolysis are often increased lactate dehydrogenase (LDH) and an increased level of indirect bilirubin (hyperbilirubinemia).

However, if there is a simultaneous iron deficiency, which leads to a hyopochromic microcytic anemia, the megaloblastic anemia may not be visible, or even microcytic anemia may be present. Then the erythrocyte distribution width (RDW) can be increased as an indication of the simultaneous presence of micro- and macrocytic erythrocytes.

Psychological complaints, neuropsychiatric disorders

Neurological complaints

The neurological symptoms caused by disorders of the central or (as neuropathy ) peripheral nervous system are very unspecific and their occurrence at the same time with different frequency and intensity, so that there is a wide range of alternative diagnoses for the neurological symptoms and, on the other hand, for non-specific neurological symptoms alongside a vitamin B 12 deficiency should always be excluded.

In severe cases, other neurological symptoms such as:

Even if there are symptoms of a vitamin B 12 deficiency, the blood count may still be normal . In a study of 141 patients with acute neuropsychiatric symptoms due to a vitamin B 12 deficiency, 40 patients (28%) did not have any anemia or macrocytemia. The hematocrit was normal in 34 patients (24%) and the mean cell volume of red blood cells ( MCV ) was normal in 25 patients (18%).

More symptoms

A disease of the tongue , the pathognomonic Möller-Hunter glossitis with an atrophy of the mucous membrane of the tongue, which gives it the impression of a lacquer tongue , can rarely occur .

It can also lead to a decreased sense of taste .

Decreased heart function and decreased fertility can also occur rarely .

Symptoms in Infants and Young Children

In infants and toddlers, irritability, apathy and loss of appetite are possible as well as severe developmental delays with motor disorders and growth disorders , which in the case of the most severe and long-lasting vitamin B 12 deficiency can also be irreversible and even fatal.

causes

Inadequate intake of vitamin B 12 with food

A long-term unbalanced diet can be the cause of a vitamin B12 deficiency. A vegan diet can also lead to vitamin B12 deficiency. Vitamin B 12 is mainly found in animal products (eggs, meat, milk) and in some algae such as Chlorella and Susabi-nori ( Porphyra yezoensis ).

Vitamin B 12 obtained from bacterial cultures is added to many foods and is available as a dietary supplement. Vegans, and to a lesser extent vegetarians, are at high risk of dietary B 12 deficiency if they do not take supplements. However, a B 12 deficiency can also occur in people who eat meat. Children have a higher risk of a diet-related B 12 deficiency because they have lower vitamin stores and a relatively high vitamin requirement.

Intrinsic factor deficiency and decreased absorption

The lack of intrinsic factor leads to a selective impairment of the vitamin B 12 absorption, which corresponds to pernicious anemia . The intrinsic factor required for the absorption of vitamin B 12 is produced by the parietal cells of the stomach . In ( atrophic ) type A gastritis , an autoimmune reaction leads to destruction of the parietal cells. Even with extensive surgical resection of the stomach or hereditary impaired synthesis of intrinsic factor, vitamin B 12 absorption is reduced.

In malabsorption syndromes , there is also impaired absorption of vitamin B 12 . This includes any form of structural damage or previous surgery. Partial or complete resections of the stomach ( gastrectomy ) or resection of the terminal ileum (the most important location for vitamin B 12 absorption) require vitamin B 12 supplementation, as is necessary in the more frequent bariatric interventions.

Also, inflammation of the pancreas , liver and kidney diseases can to vitamin B 12 lead deficiency. Likewise, a lack of gastric juice ( achlorhydria ) can cause B 12 malabsorption, as stomach acid is necessary to break down B 12 from dietary proteins and binding proteins from saliva. This can also be triggered with drugs by inhibiting gastric acid production. This is considered to be the most common cause of low B 12 levels in older people. This mechanism has no influence on the absorption of B 12 from food supplements, as they are not bound to proteins in them.

Enteropathies such as Crohn's disease and celiac disease can also affect the absorption of B 12 . This is less due to a lack of intrinsic factor and more to damage to the small intestine.

A small intestinal bacterial overgrowth or intestinal parasites can cause a B 12 lead -Resorptionsstörung. In the blind loop syndrome, the intestinal wall bulges with absorption disorders.

Hereditary diseases such as severe methylene tetrahydrofolate reductase deficiency, homocystinuria and transcobalamin deficiency, and alcohol addiction can also trigger a vitamin B 12 deficiency.

Medication

The diabetes mellitus drug metformin can interfere with the intake of B 12 from food.

Long-term use of proton pump inhibitors such as omeprazole , pantoprazole or the like as well as antihistamines (H2-receptor blockers) such as B. Ranitidine to reduce gastric acid production can also trigger a vitamin B12 deficiency. The gastric acid is important to dissolve vitamin B 12 from the food components, otherwise it cannot be sufficiently absorbed.

Antibiotics such as chloramphenicol or neomycin can also be the cause of a vitamin B12 deficiency.

The consumption of nitrous oxide disrupts the B 12 metabolism, which is why regular use can lead to a deficiency. This also applies to the improper use of so-called "whippets", cartridges filled with nitrous oxide, e.g. B. for frothing milk or cream.

mechanism

overview

The total amount of vitamin B 12 stored in the body is between two and five milligrams in adults. About half of it is stored in the liver . Approximately 0.1% is lost each day due to intestinal release and incomplete recovery. Since B 12 is mainly excreted in the bile , most of it is recovered via the enterohepatic circulation . Due to the strong effectiveness of this mechanism, the liver can store a supply of vitamin B 12 for three to four years under normal conditions . However, the speed at which B 12 levels can change when food intake is low depends on the balance of several factors.

metabolism

In humans, vitamin B 12 deficiency causes changes in the metabolism of two clinically relevant substances: homocysteine and methylmalonic acid .

Homocysteine ​​is converted into methionine by methionine synthase . Methionine is in turn activated to S-adenosylmethionine , which is involved as a methyl group donor in numerous metabolic processes, for example in the synthesis of purine , deoxythymidine , myelin , proteins , neurotransmitters , fatty acids , phospholipids and in DNA methylation . The active form of folic acid - tetrahydrofolic acid - provides a methyl group when homocysteine ​​reacts to methionine. This reaction requires cobalamin as a cofactor. The production of tetrahydrofolic acid is an irreversible reaction. If B 12 is absent, methionine formation does not take place and the formation of tetrahydrofolic acid stops. A Homocysteinemia can varicose veins cause.

Methylmalonic acid is converted into succinyl-CoA in the active form - methylmalonyl-CoA - by methylmalonyl-CoA mutase , which requires vitamin B 12 as a cofactor .

Since B 12 and folic acid are involved in the metabolism of homocysteine, the increased excretion of homocysteine ​​in the urine is not a specific marker for a B 12 deficiency. Methylmalonic acid, on the other hand, is specific for detecting a B 12 deficiency.

Pathomorphology

In the nerve tissue there is a spongy remodeling with edematous swelling of nerve fibers . The breakdown of the myelin of the internal nerve fibers leads to tissue atrophy and, in the further course, to sclerosis of the nerve tissue. These changes occur in the dorsal part of the spinal cord and the lateral corticospinal tract of the pyramidal tract . This pathophysiological condition of the spinal cord is called subacute combined degeneration of the spinal cord .

In the brain itself, the changes are less severe. Here small, mostly subcortical foci with nerve fiber decay and accumulation of astrocytes occur, as well as round bleeding foci with accumulation of glial cells. These pathological changes can also occur in the posterior root of the spinal cord and, to a lesser extent, in peripheral nerves. They can be detected using magnetic resonance imaging .

diagnosis

Description and search for the cause

MRI image of the brain in an axial view, “precontrast FLAIR image”. The abnormal lesions (circled) in the area around the cerebral ventricles are conspicuous , indicating a vitamin B 12 deficiency with damage to the white matter.

The serum B 12 levels are at B 12 deficiency often low. Serum vitamin B 12 values ​​are given in pg / ml ( pico grams / milliliter) or pmol / l (pico moles / liter). The units are to be converted according to the molar mass of B 12 as follows: 1.375 pg / ml = 1 pmol / l.

If signs of B 12 deficiency occur with normal B 12 serum levels, further investigation is indicated. A possible explanation for normal B 12 levels in a B 12 deficiency is antibody interference in patients with a high titre of antibodies against the intrinsic factor. Some researchers criticize the fact that the current normal values ​​for vitamin B 12 levels are too low. A Japanese study showed that the normal limits are 500–1,300 pg / ml.

The earliest marker for a vitamin B 12 deficiency is a decrease in holo-transcobalamin (holo-TC) to below 35 to 50 pmol / l. Holo-transcobalamin is a complex of vitamin B 12 and its transport protein. It is also known as "active vitamin B12" because the vitamin in this form circulates in the bloodstream and is transported to the receiving cells. If a vitamin B 12 deficiency is clinically suspected and the total vitamin B 12 value is low-normal, the determination of holotranscobalamin is the next diagnostic step.

Furthermore, serum homocysteine and methylmalonic acid levels (values ​​above 0.4 µmol / l) are more reliable indicators of B 12 deficiency than the concentration of total vitamin B 12 in blood. The levels of these substances are increased with a B 12 deficiency. In the case of folic acid deficiency, the serum homocysteine ​​level is also increased, but not the methymalonic acid level.

Routine monitoring of urinary methylmalonic acid is an option for people who do not get enough B 12 from food, as an increase in methylmalonic acid levels can be an early sign of B 12 deficiency.

For methylmalonic acid (MMA), a laboratory value> 32 μg / l in the serum is indicative of a probable vitamin B12 deficiency. Increased methylmalonic acid levels in combination with an only slightly decreased Holo-TC already indicate a metabolically manifest vitamin B12 deficiency. Since methylmalonic acid is excreted via the kidneys, it makes sense to relate the measured value to creatinine in order to take into account the excretion capacity of the kidneys. If there is renal insufficiency , it can be differentiated by therapeutic methylmalonic acid lowering.

If damage to the nervous system is suspected, analysis of B 12 in cerebrospinal fluid is possible, although such an invasive test should only be considered if blood tests are inconclusive.

The Schilling test has been largely superseded by tests for anti-parietal cell and intrinsic factor antibodies.

Effects of folic acid

Large amounts of folic acid can mask the harmful effects of vitamin B 12 deficiency; they prevent megaloblastic anemia, but not neurological damage. There is also evidence that high serum folic acid levels not only mask the vitamin B 12 deficiency, but can also worsen anemia and cognitive symptoms. Due to the fact that in the United States mandatory fluoridation with a folic acid supplement is used to reduce fetal neural tube defects , consumers can ingest more folic acid than they suspect. To counteract this masking effect, the NIH recommend that folic acid intake from fortified foods and dietary supplements in healthy adults should not exceed 1000 μg per day. Most importantly, a B 12 deficiency must be treated with B 12 administration. Limiting folic acid does not counteract the irrevocable neurological damage that results from an untreated B 12 deficiency.

treatment

Hydroxocobalamin solution for injection

Once diagnosed, a deficiency can easily be treated with oral preparations or injections. In some cases, treating the underlying cause can correct the deficiency. Other cases may require continued supplementation as the underlying cause is incurable. Supplementation is recommended for pregnant vegetarians , as the need is greater during this time and a deficiency can cause neurological deficits in the child.

When large doses are given orally, their absorption is not due to the presence of intrinsic factor or an intact ileum. In general, 1 to 2 mg daily is then necessary in high doses.

As parenteral preparations, cyanocobalamin and hydroxocobalamin are used. In acute deficiency disorders with neurological symptoms, 1000 µg of vitamin B 12 is usually administered intramuscularly for one to two weeks every one to two days, while monitoring the vitamin B 12 and homocysteine ​​levels. In pernicious anemia, injections are usually given once a week until the blood count returns to normal, and later once monthly injections are used to maintain normal levels.

Epidemiology

Vitamin B 12 deficiency is common. It is estimated that it occurs in around 6% of people under the age of 60 and 20% of people over the age of 60. In some parts of Africa and Asia, up to 80% of the population is affected.

A study from 2000 shows that B 12 deficiency is more common than previously thought. It showed that 39 percent of 3,000 people examined had values ​​that were too low. The study by Tufts University used a B 12 concentration of 258 pmol / l (= 350 pg / ml ) as a criterion for a too low level. However, new research results have shown that a B 12 deficiency can occur even at much higher B 12 concentrations (500–600 pg / ml), which is why the proportion of the population with a B 12 deficiency could be significantly higher. This study found no correlation between meat consumption and B 12 serum levels.

B 12 deficiency is very widespread in developing countries , especially in Africa, India and South and Central America. It is believed that this is due to the low intake of animal products, especially among the poor.

B 12 deficiency is more common in the elderly. This could be because the B 12 absorption decreases sharply in chronic gastritis , which is common in the elderly. Older people are also more likely to take drugs that inhibit gastric acid production and are associated with a risk of vitamin B 12 deficiency.

Vitamin B12 deficiency in animals

In dogs and cats, cobalamin is largely bound to haptocorrin in the stomach . The intrinsic factor (IF) is completely produced in cats and to a large extent in the pancreas in dogs. Deficiency symptoms therefore occur mainly in exocrine pancreatic insufficiency , but severe intestinal diseases and bacterial overgrowth of the intestine can also lead to a B12 deficiency. The Giant Schnauzer has a hereditary deficiency due to the lack of expression of the IF receptor in the ileum.

See also

literature

  • Sally M. Pacholok, Jeffrey J. Stuart: Could It Be B12 ?: An Epidemic of Misdiagnoses . Linden Publishing, Fresno, CA 2011, ISBN 978-1-61035-065-5 .
  • M. Hooper: Pernicious Anaemia: The Forgotten Disease - the causes and consequences of Vitamin B12 Deficiency . Hammersmith Press, London 2012, ISBN 978-1-78161-004-6 .
  • Richard Daikeler, Götz Use, Sylke Waibel: Diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , pp. 31–33.

Web links

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