nutrition

Vitamin B12: Function and Disease

virtualmedstudent

Vitamin B12 and its derivatives serve many roles in the body. It functions primarily as a co-factor to help enzymes perform their molecular reactions. It is composed of the metal cobalt, which is coordinated to a large corrin ring structure composed of carbon and nitrogen atoms. Several important biochemical reactions in which vitamin B12 is a crucial component include:

(1) The conversion of odd chain fatty acids (specifically propionate) into succinate.
(2) The conversion of homocysteine into methionine via methyl group donation.

In the first reaction above B12 serves as a cofactor for the enzyme methylmalonyl-CoA mutase, which converts the odd chain fatty acid L-methylmalonyl-CoA into succinyl-CoA. Succinyl-CoA can then enter the citric acid cycle (Krebs cycle).

In the second reaction vitamin B12 serves as a methyl donor (ie: a "-CH3" unit) allowing the conversion of homocysteine into methionine. Interestingly, this reaction also requires a form of vitamin B9 (aka: folate or folic acid) known as N-methyltetrahydrofolate. The reason this reaction is important is because methionine will eventually go on to form S-adenosylmethionine, which is an important contributor of single carbon fragments to various other molecules.

Additionally, vitamin B12 is needed to convert N-methyltetrahydrofolate back into tetrahydrofolate, which serves as a cofactor in a slew of other important biochemical reactions.

Role in Disease

Patients typically become deficient in vitamin B12 in one of three ways: strict vegan diets, an autoimmune condition known as pernicious anemia, or impaired absorption via the gut.

Vitamin B12 is found mainly in animal products and vegans may become deficient if they fail to supplement. Patients with pernicious anemia have antibodies that attack the cells in the stomach that secrete a molecule (intrinsic factor), which helps the intestine absorb B12 from the diet. Any damage to the gut lining (ie: inflammatory bowel disease, celiac disease, etc.) can also cause impair absorption of B12.

Deficiencies of any cause usually take several years to develop because excess vitamin B12 is stored in the liver. These stores can last several years before becoming depleted.

When a person’s vitamin B12 level is low it can cause the accumulation of odd chain fatty acids. These are thought to "gunk-up" cellular membranes. This is most noticeable in the nervous system, and can result in neurological signs and symptoms including numbness and tingling, loss of proprioception (ie: the ability to "feel" where your limbs are in space), and difficulty with coordination. In its most severe form a condition known as subacute combined degeneration of the spinal cord can occur.

Vitamin B12 deficiency can also cause a megaloblastic anemia. This occurs because rapidly dividing cells in the bone marrow require a constant supply of tetrahydrofolate for methylation reactions in order to produce enough DNA. When B12 is deficient, N-methyltetrahydrofolate cannot be converted back to tetrahydrofolate. When this occurs all of the tetrahydrofolate gets trapped in the N-methyltetrahydrofolate form, which is not used as a methyl donor in nucleotide synthesis. The resulting DNA deficiency causes red blood cells to exit the bone marrow deformed, dysfunctional, and larger than normal (hence the term "megalo"-blastic anemia).

There is no evidence that excess vitamin B12 causes any significant health problems. It is well excreted in the urine.

Diagnosis

Deficiencies of vitamin B12 are diagnosed by measuring the amount of B12 in the blood. However, "normal" B12 levels do not necessarily rule out B12 deficiency, making this test less than useful.

Other blood tests that are often sent include methylmalonyl-CoA and homocysteine levels. Both of these will be elevated in B12 deficiency since the vitamin is necessary for the enzymatic conversion of these molecules to succinyl-CoA and methionine, respectively.

Although rarely used today, another test called the Schilling test can be performed. It involves several steps in which radiolabelled B12 is given orally. If the patient is having difficulty absorbing B12 because of either intrinsic factor deficiencies or intestinal problems the Schilling test will be able to differentiate the cause.

Treatment

Treatment of vitamin B12 deficiency is, you guessed it, giving the patient B12. Patients with pernicious anemia or intestinal absorption problems are given the vitamin intramuscularly. Other patients can supplement with oral forms.

Overview

Vitamin B12, also known as cobalamin, is important in several cellular reactions including the conversion of odd chain fatty acids into succinate and the replenishing of tetrahydrofolate (a form of vitamin B9 or folate). Deficiencies may occur in those who are vegan, have pernicious anemia, or have intestinal absorption problems. Diagnosis is made by measuring blood B12, homocysteine, and methylmalonyl-CoA levels. Treatment is with supplementation, either orally or intramuscularly.

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Thiamine (Vitamin B1): Wernicke-Korsakoff and Beriberi

virtualmedstudent

Vitamin B1 (thiamine) and its derivatives serve many roles in the body. It functions primarily as a co-factor to help enzymes perform their molecular reactions. Several important biochemical reactions in which thiamine plays a crucial role include:

(1) Conversion of pyruvate to acetyl-CoA.
(2) Conversion of α-ketoglutarate to succinyl-CoA.
(3) Conversion of glyceraldehyde-3-phosphate to ribose-5-phosphate.
(4) It is used by the enzyme branched-chain α-keto acid dehydrogenase.

All of these reactions are crucial to human biochemistry. The conversion of pyruvate to acetyl-CoA feeds important molecules into the Krebs cycle, which allows the cell to produce energy.

The conversion of α-ketoglutarate to succinyl-CoA is necessary for the Krebs cycle to continue “spinning”. Without vitamin B1 (thiamine) the cycle would slow resulting in decreased energy production.

Thiamine is also important in the production of NADPH via the pentose phosphate pathway. NADPH plays a crucial role in biochemistry because it donates its electron pairs to numerous anabolic reactions.

The breakdown of branched chain amino acids such as valine, isoleucine, and leucine are also dependent on thiamine. The product that results from the breakdown of these amino acids are α-keto acids. They can also be fed into the Krebs cycle to replete molecules in the pathway that may have been siphoned off for other purposes. Maple syrup urine disease is a disorder of branched chain amino acid catabolism.

Since thiamine is involved in many energy producing pathways it is found abundantly in tissues that produce and use lots of energy. These include, but are certainly not limited to, the brain, muscle, and liver.

Role in Disease

Thiamine is a water soluble vitamin that is not actively stored in the body. It therefore must be obtained in the diet. Deficiencies can cause numerous disorders.

One such disorder is Wernicke-Korsakoff’s syndrome. It is seen in chronic alcoholics who may not be obtaining adequate nutrition. In Wernicke’s encephalopathy patients present with nystagmus (ie: jerky eye movements), ophthalmoplegia (ie: inability to move the eyes), and ataxia (ie: a wobbly unsteadiness).

These patients are often very confused. If Wernicke’s encephalopathy is left untreated it can progress to Wernicke-Korsakoff’s syndrome, in which the patient also develops short term memory problems and confabulations (ie: making up stories that aren’t true).

Another disease of thiamine deficiency is known as beriberi. There are numerous forms of this disease. It can affect infants who are being breast fed by thiamine deficient mothers, or who are receiving formulas with inadequate thiamine. In its worst case, infantile beriberi can manifest as severe heart problems.

Beriberi can also affect adults. The adult form exists in two types: wet and dry. Dry beriberi refers to the development of symmetric neuropathies (ie: damage to the peripheral nerves). Both sensory and motor nerves can be involved, and it tends to affect the parts of the nerve furthest from the spinal cord (ie: near the hands and feet). Wet beriberi is the combination of neuropathy plus heart problems, which can range in severity from cardiomegaly (ie: an enlarged heart) to congestive heart failure.

There is no evidence that excess thiamine (vitamin B1) causes any significant health problems. It is well excreted by the kidneys.

Diagnosis

Deficiencies of vitamin B1 (thiamine) are diagnosed by adding the vitamin to a preparation of the patient’s red blood cells. An increase in the activity of the transketolase enzyme is diagnostic of deficient levels.

Treatment

Treatment of thiamine deficiency is, you guessed it, giving the patient thiamine. If the patient has significant disease such as Wernicke’s encephalopathy thiamine can be given IV. Otherwise, oral supplementation and/or "prescribing" a diet rich in thiamine can be used to replenish any deficiencies.

Overview

Vitamin B1, also known as thiamine, is a vital component of numerous cellular reactions, especially those involving carbohydrate and amino acid catabolism (ie: breakdown). When deficiencies exist, several different diseases can occur. They include, but are not limited to, Wernicke-Korsakoff’s syndrome and beriberi. There are no known problems with excessive levels of thiamine since excess vitamin is efficiently excreted in the urine. Diagnosis of deficiencies are made by adding the vitamin to a preparation of the patient’s red blood cells. An increase in the activity of transketolase, an enzyme that relies on thiamine as a co-factor, is considered diagnostic of deficiency.

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