Nutritional Disorders: Vitamins B1, B6, Folate (B9) & B12
Disorders of Vitamins B1, B6, B9 (Folate), & B12
Overview
Vitamin B12 (cobalamin) deficiency:
- Anemia is macrocytic, megaloblastic anemia from nuclear-cytoplasmic asynchrony
- The cytoplasmic contents mature but the nuclear contents do NOT.
- Classic myelopathy (the spinal cord disorder): subacute combined degeneration of the spinal cord.
- So-named because it combines both motor and sensory divisions of the spinal cord.
- Beriberi has two variants:
- Dry variant (neuromuscle disorder).
- Wet variant (high-output heart failure)
- Wernicke-Korsakoff syndrome
- Midline hemorrhagic neuropathology that manifests with ataxia, opthalmoplegia, and confabulation.
Folate trap and elevated homocysteine levels: This biochemistry will help explain much of the laboratory assessment and clinical presentation of vitamin B12 and folate deficiency and their relationship to vitamin B6.
Folate and methionine cycles
- Tetrahydrofolate (THF) is the metabolically active derivative of folate.
- THF converts to N5, N10-methylene THF (this is an intermediate form), which methylates deoxyuridylate (dUMP) to thymine (dTMP).
- We cover this in detail in the pyrimidine biosynthesis tutorial.
- From there, the N5, N10-methylene THF becomes dihydrofolate (DHF).
- Dihydrofolate reductase is required to convert DHF back to THF.
- Because this loop is key for thymine formation and cells that are rapidly growing (eg, cancer cells) requiring DNA products, indicate that dihydrofolate reductase inhibitors, such as methotrexate, are used to block this step.
- Thus, patients on methotrexate must take folic acid as a supplement.
- Now, let's introduce cobalamin (vitamin B12), specifically methyl-cobalamin.
- BUT the goal is to transfer the methyl group to methionine and on to S-adenosylmethionine, which is a major methyl donor, because N5-Methyl THF is actually a poor methyl donor whereas SAM has a positively charged sulfur that makes it highly reactive and a good methyl donor.
- This methyl transfer requires methylcobalamin (B12) as a coenzyme and N5-Methyl THF converts to THF, completing the folate cycle.
- Consider that the major source of folate is N5, N10-methylene THF, which then is reduced to N5-Methyl THF and then forms THF.
- To finish the methionine cycle, SAM converts to S-adenosylhomocysteine (SAH), which then converts to homocysteine, which is what combines with N5-Methyl THF in the interlinking of the folate and methionine cycles.
- Thus, in the setting of B12 deficiency, two key things happen:
- There is relative folate deficiency, because it is trapped as N5-Methyl THF.
- Homocysteine is elevated because it is unable methylate back to methionine.
Odd Chain fatty acid degradation & B12:
- B12 is key to the pathway from the 3-carbon propionyl CoA to succinyl CoA.
- Propionyl CoA is carboxylated to 4-carbon methylmalonyl CoA.
- It undergoes an isomerization that is catalyzed by methylmaonyl CoA mutase with a derivative of vitamin B12 as a coenzyme.
- Thus, in vitamin B12 deficiency (but not in folate deficiency) there is elevated methylmalonic acid levels because this fatty acid degradation pathway is disrupted.
Vitamin B12 (Cobalamin) deficiency
Folate Trap
- Folate is trapped as N5-Methyl THF, which prevents SAM-requiring methyl donation pathways, which are numerous.
Laboratory Assessment
- Elevated homocysteine
- Elevated methylmalonic acid
- Macrocytic, megaloblastic anemia because there is nuclear-cytoplasmic asynchrony from inadequate synthesis of thymidine – thus, the cytoplasm grows at a normal rate BUT the nucleus does NOT.
- Hypersegmented neutrophils (5+ nuclear lobes, rather than 3-4) (note some authors describe this as 6 or more lobes).
Clinical Presentation
- Anemia: fatigue and pallor
- "Beefy red tongue" (from megaloblastic changes to the oroepithelium).
- Myelopathy (a spinal cord disorder).
- Subacute combined degeneration combines both the motor and sensory pathways of the spinal cord and develops subacutely. We address the clinical features of this disorder, separately.
- Neuropathy is possible in B12 deficiency.
B12 Absorption & Causes of Deficiency
- Sources of B12: animal products: meats, shellfish, poultry, dairy
- Thus, veganism (diet restriction) is a cause.
Next, let's address a simplified rendition of the physiology of its absorption.
- B12 complexes with R factor in the saliva
- Stomach parietal cells synthesize intrinsic factor (IF) in the body and fundus of the stomach.
- Pernicious anemia is another cause of B12 deficiency; in this disorder, autoantibodies destroy the parietal cells and cause intrinsic factor deficiency.
- Similarly, gastrectomy can cause B12 deficiency.
- Pancreatic enzymes cleave the R factor (which was applied in the saliva), so that B12 can bind with intrinsic factor in the duodenum.
- Chronic pancreatitis: prevents the R group from being cleaved.
- Bacterial intestinal overgrowth: destroys the B12-Intrinsic Factor complex.
- Fish tapeworm (Diphyllobothrium latum): a form of parasitic infection that can be acquired by ingesting raw or undercooked fin fish, can deplete the host's B12.
- Finally, within the ileum, the B12-intrinsic factor complexes are absorbed.
- Thus, Crohn's disease (a form of terminal ileal disease) is another cause of B12 deficiency.
Vitamin B9 (Folate) Deficiency
Several key differences from B12 deficiency.
- First, for folate, think: foliage (ie, leafy vegetables) (whereas the source of B12 was animal products).
- Folate deficiency is usually due to inadequate dietary intake, especially in patients with poor diet (for a variety of reasons).
- Increased metabolic needs (eg, pregnant patients need folate supplementation).
- Those on medications that interfere with folate absorption (eg, phenytoin) or folate metabolism (eg, methotrexate).
- Folate is absorbed in the upper 1/3rd of the intestine, thus celiac disease or tropical sprue are also potential causes.
Laboratory Assessment
- Macrocytic, megaloblastic anemia
- Hypersegmented polymorphonuclear cells
- Elevated homocysteine level
- BUT the methylmalonic acid level is NORMAL
- This is because the elevation of methylmalonic acid in B12 deficiency came from B12's involvement in fatty acid degradation, not its involvement in the folate cycle.
Clinical Presentation
- Classically in folate deficiency, although the hematologic symptoms of B12 are present, the neurologic symptoms are not.
Vitamin B6 (Pyridoxine) Deficiency
Vitamin B6 (pyridoxine) - its active form is pyridoxal phosphate.
- It is, in large part, associated with glycogen phosphorylase (a key enzyme in glycogen breakdown).
- The phosphate group of the PLP, itself, is catalytically quite important.
- B6 serves as a coenzyme in the conversion of homocysteine to cystathionine (catalyzed by cystathione beta-synthase), which goes on to cysteine.
- Elevated homocysteine levels place individuals at risk for cardiovascular disease, thus B6 supplementation is often used to help reduce homocysteine – it maximizes the ability for cystathione beta-synthase to convert homocysteine to cystathione. Similarly, B12 is given to maximize the methylation of homocysteine to methionine.
- Transamination reactions (reviewed at length in the amino acid section)
- ALA synthesis – its deficiency directly leads to a hemoglobin synthesis defect and sideroblastic anemia, which we'll see a clinical consequence of B6 deficiency.
- Neurotransmitter synthesis (eg, serotonin: we saw this in the phenylalanine/tyrosine tutorial).
Key Pyridoxine Disorders
- Vitamin B6 deficiency is rare, because it is found in a variety of sources (cereals, eggs, meat, fish, vegetables, and nuts), but can specifically occur in alcoholics and in patients taking isoniazid (INH) for TB and can manifest with the following clinical manifestations:
- Sideroblastic anemia
- CNS symptoms of convulsions/hyperirritability.
- Vitamin B6 toxicity can also occur, mostly for iatrogenic reasons, and can cause a profound sensory neuronopathy.
Vitamin B1 (Thiamine) Deficiency
Thiamine is key to carbohydrate metabolism, specifically oxidative carboxylation, and to review its biochemistry is beyond the scope of this tutorial.
- A memory device: The acronym ATP-B-B1, which stands for four of the key enzymes for which thiamine is a cofactor one of its key pathologies:
- "A" for Alpha-ketoglutarate dehydrogenase, as part of the citric acid cycle.
- "T" for Transketolase, part of the pentose phosphate pathway.
- "P" for Pyruvate dehydrogenase, which links glycolysis to the citric acid cycle under aerobic conditions.
- "B" for Branched-chain ketoacid dehydrogenase, which metabolizes the branched chain amino acids: leucine, isoleucine, and valine.
- "B1" will help us link B1 deficiency with the its key pathology: beriberi (the B1 emphasizes the "BI" in beriberi).
Berberi
- Dry beriberi manifests with neuromuscle disease (polyneuropathy and muscle atrophy) because thiamine triphosphate is key to nerve conduction.
- Wet beriberi manifests with high-output heart failure (dilated cardiomyopathy) and peripheral edema.
Wernicke-Korsakoff
- We show a coronal view of the diencephalon and upper brainstem.
- CN3 exits midline out the inferior midbrain and CN 6 exits out of the midline at inferior pons.
- Thiamine deficiency produces Wernicke-Korsakoff syndrome, which manifests, classically, with confabulation, ophthalmoplegia, and ataxia in the Wernicke type. The confabulation becomes irreversible in the Korsakoff type.
- Relevant localization levels: mammillary bodies for memory impairment, oculomotor nerves for ophthalmoplegia, pontine fibers for ataxia).
- It involves hemorrhagic damage, specifically, to walls of the 3rd and 4th ventricles and key memory centers: the mammillary bodies and dorsomedial thalamic nuclei (think: Papez circuit).
- It is primarily associated with chronic alcohol abuse.
- Importantly, you must give thiamine prior to glucose in thiamine deficient patients to avoid precipitating Wernicke encephalopathy because with thiamine deficiency comes carbohydrate metabolism impairment, meaning and inability to breakdown glucose and a depletion of ATP: so you can't give glucose without first giving thiamine.