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Vitamin B12: Function and Disease

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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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References and Resources

Cauda Equina Syndrome: Pee, Poop, and Leg Problems

virtualmedstudent

The cauda equina is an anatomical term given to all of the nerves that dangle off the end of the spinal cord. In Latin, the term cauda equina means "horse’s tail". The dangling nerves are housed in the thecal sac, and are normally bathed in a sea of cerebral spinal fluid. Each of the nerves in the cauda equina eventually branches from the thecal sac. From there they exit the spinal column and travel to their respective target (ie: muscle, skin, organ, etc.).

Cauda equina syndrome occurs when the nerves in the "horse’s tail" get squished by some pathologic process. The most common pathology is a large herniated intervertebral disc that pushes back on the thecal sac. Other causes include tumors, blood clots (ie: hematomas), traumatic injuries such as burst fractures or fracture dislocations, severe lumbar stenosis, as well as abscesses.

Regardless of the cause, when the nerves get impinged they are unable to perform their functions. This leads to the classic signs and symptoms of cauda equina discussed below.

Signs and Symptoms

The classic teaching is that cauda equina syndrome presents with the acute onset of lower extremity weakness, poop incontinence (ie: fecal incontinence if you want to be "scientific" about it), urinary retention (ie: patient cannot pee), loss of leg reflexes, low back pain, sexual dysfunction, and loss of sensation, especially in the "saddle" and peri-anal region. Please note urinary RETENTION is a key factor and one that is often mixed up.

It is important to note that patients with cauda equina syndrome rarely present with all of these symptoms. The most worrisome symptoms are sudden weakness and bowel or bladder issues.

Additionally, radicular type symptoms such as numbness and tingling, or sharp pains down the legs can also be present.

Classic Signs and Symptoms
of Cauda Equina Syndrome:

– Lower extremity weakness
– Bowel incontinence
– Urinary retention
– Loss of reflexes
– Saddle anesthesia
– Sexual dysfunction

Overall, there is no single definition of cauda equina syndrome. there are numerous definitions in the scientific literature based on different permutations of the above signs and symptoms.

It is also important to distinguish between acute and chronic forms of the syndrome. Acute symptoms occur with rapid onset and require emergent evaluation. However, many patients have evidence of chronic dysfunction of the nerves that compose the cauda equina; their symptoms have been slowly evolving over months or years (ie: think older people with lumbar stenosis).

The time frame in which cauda equina symptoms develop is important for determining optimal treatment, and providing patients with a realistic prognosis for recovery.

Diagnosis



Diagnosis is based on the combination of appropriate symptoms and the cause is confirmed usually with an MRI or CT myelogram that shows compression of the cauda equina.

In addition to a thorough neurological examination, patients with suspected cauda equina syndrome should also have a post void residual (PVR) measurement. PVRs help diagnose urinary retention, which is a worrisome finding if present.

Treatment

"True" acute cauda equina syndrome caused by a large mass pushing on the nerve roots is managed with urgent surgical decompression. Typically, a laminectomy (ie: a procedure in which part of the bone in the back of the spinal column is removed) is performed to relieve pressure on the thecal sac.

Other therapies including antibiotics for infections, chemotherapy for tumors, and steroids for inflammatory causes are also used.

Overview

Cauda equina syndrome is caused by compression of the nerves in the thecal sac. Classic symptoms include weakness, saddle anesthesia, fecal incontinence, and urinary retention. Furthermore, both acute and chronic forms of cauda equina syndrome exist based on the rapidity of symptom onset. Diagnosis is based on clinical signs and symptoms in conjunction with MRI or CT myelogram imaging showing compression of the nerves.

References and Resources

  • Korse NS, Jacobs WC, Elzevier HW, et al. Complaints of micturition, defecation and sexual function in cauda equina syndrome due to lumbar disk herniation: a systematic review. Eur Spine J. 2012 Dec 13.
  • Fraser S, Roberts L, Murphy E. Cauda equina syndrome: a literature review of its definition and clinical presentation. Arch Phys Med Rehabil. 2009 Nov;90(11):1964-8.
  • Mauffrey C, Randhawa K, Lewis C, et al. Cauda equina syndrome: an anatomically driven review. Br J Hosp Med (Lond). 2008 Jun;69(6):344-7.
  • Shi J, Jia L, Yuan W, et al. Clinical classification of cauda equina syndrome for proper treatment. Acta Orthop. 2010 Jun;81(3):391-5.
  • Gitelman A, Hishmeh S, Morelli BN, et al. Cauda equina syndrome: a comprehensive review. Am J Orthop (Belle Mead NJ). 2008 Nov;37(11):556-62.
  • Baehr M, Frotscher M. Duus’ Topical Diagnosis in Neurology: Anatomy, Physiology, Signs, Symptoms. Fourth Edition. Stuttgart: Thieme, 2005.