This case was originally published in 2021. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.
A 51-year-old man with morbid obesity and hypertension presented with a four-week history of progressive difficulty with ambulation and upper and lower limb paresthesias, ultimately associated with urinary incontinence and inability to ambulate without a walker. MRI of the spine and spinal cord showed no structural lesion. Lumbar puncture showed a slightly elevated protein but was otherwise normal. Testing for HIV, hepatitis B and C, Lyme disease, and syphilis was negative. Electromyography showed sensorimotor polyneuropathy. CBC and peripheral blood smear showed macrocytic anemia and thrombocytopenia. The patient experienced sudden shortness of breath during a rehabilitation session and subsequently was discovered unresponsive. Resuscitative measures were unsuccessful. On postmortem examination, the patient was found to have pulmonary thromboemboli, which were felt to be the cause of death.
Whole Slide Image
The whole slide image provided is Luxol fast blue/H&E-stained sections of spinal cord from autopsy.
Which of the following nutritional deficiencies likely accounts for the spinal cord abnormalities?
Cobalamin (B12) deficiency
Folate (B9) deficiency
Niacin (B3) deficiency
Thiamine (B1) deficiency
What is the most common cause of this deficiency?
Inborn metabolic errors
Apart from the CNS, what other organ system is characteristically affected by this deficiency?
Discussion and Diagnosis
This case is an example of subacute combined degeneration (SCD), resulting from vitamin B12 (cobalamin) deficiency. In this patient, vitamin B12 levels were low, and vitamin B12 injections were begun with slow improvement in neurological symptoms before the fatal event.
Vitamin B12 is found in animal products. Normal absorption and cellular uptake begin with the release of B12 in the stomach where it is bound by salivary haptocorrin (HC). B12-HC from food is joined in the small intestine by B12-HC from the biliary system. Pancreatic proteases release B12 from HC, and B12 is then bound by intrinsic factor (IF). The B12-IF complex binds to receptors in the terminal ileum, where they are internalized. IF is degraded and B12 is released into the plasma where it is bound by transcobalamin (TC), which delivers B12 to cells, including the liver, to maintain body stores. Following uptake into cells, B12 is reduced and converted to adenosylcobalamin in mitochondria and methylcobalamin in the cytosol, and these serve as cofactors for B12-dependent reactions. B12 biochemistry interdigitates with that of folate and is therefore necessary for the rate-limiting step of DNA synthesis.
Deficiency of B12 can be due to any interruption in the B12 cycle: decreased intake, increased requirement, impaired absorption, ineffective transport, or rare disorders of metabolism. Vegetarianism is a rare cause of deficiency, since small amounts of animal products--even trace amounts contaminating vegan cuisine--usually suffice to prevent severe deficiency. Demand for B12 is increased in pregnancy, lactation, hyperthyroidism, malignancy, and chronic infection. Malabsorption results from gastric, pancreatic, or small intestinal disorders; severe deficiency of B12 is most commonly caused by pernicious anemia, an autoimmune disorder resulting in the loss of IF, which prevents effective absorption of B12 in the ileum. Finally, rare inborn metabolic errors and direct disruption of B12 metabolism caused by nitrous oxide abuse (nitrous oxide converts the active monovalent form of B12 to an inactive bivalent form) have been recorded.
B12 is required in the CNS by methylmalonyl coenzyme A mutase and folate-dependent methionine synthase. SCD is thought to result from defective methylation of CNS proteins including myelin basic protein. Although it may present in diverse ways, the clinical hallmarks of severe B12 deficiency are neuropsychiatric symptoms accompanying macrocytic anemia. Early findings include paresthesias, especially of the lower limbs, with loss of sensation. Progression can include spastic paraparesis, ataxia, and generalized limb anesthesia. Diverse additional neurological findings can be present and range from irritability and depression to visual impairment, confusion, and dementia.
Defective DNA synthesis secondary to B12/folate deficiency impairs cell proliferation, resulting in megaloblastic anemia. Since RNA synthesis is not reliant on B12, marrow elements show asynchrony between nuclear and cytoplasmic maturation, resulting in cell enlargement with nuclei appearing less mature than cytoplasm. Within the blood, this results in macrocytic anemia, with a mean corpuscular volume of 100 to 150 fL (normal: 80-100 fL), various red cell abnormalities, and hypersegmentation of mature neutrophils. Although the major clinical manifestations of mild to moderate B12 deficiency are usually secondary to anemia, neuropsychiatric effects can occur in the absence of peripheral blood abnormalities.
Serum B12 measurement is often used as a first-line test in the diagnosis of B12 deficiency, but it suffers from lower sensitivity and specificity than other tests. The TC-bound fraction of serum B12 (holoTC) can also be measured and may be a better indicator of physiologically significant B12 deficiency. In addition, elevated levels of methylmalonic acid and homocysteine are reportedly sensitive indicators of tissue B12 deficiency. Direct evaluation for pernicious anemia may also be performed, typically by identifying antibodies to IF or parietal cells. Fasting levels of serum gastrin are often increased, and levels of serum pepsinogen I are usually decreased.
Upper endoscopy is also often performed, in an attempt to identify atrophic body gastritis, the hallmarks of which include chronic inflammation of the gastric fundus with extensive loss of parietal cells and pseudopyloric metaplasia. Hypochlorhydria resulting from parietal cell loss associated with pernicious anemia prompts endocrine cells within the antrum to increase gastrin secretion, which in turn drives hyperplasia of enterochromaffin-like (ECL) cells in the gastric body. IHC for gastrin and a neuroendocrine marker like chromogranin is often helpful to demonstrate antral-like mucosa lacking gastrin cells (that is pseudopyloric metaplasia of gastric fundus) and increased nodular and linear ECL cells within the altered fundic mucosa, respectively.
Pathologic findings in the CNS may vary somewhat based on the severity and length of B12 deficiency, with demyelination of the posterior and lateral funiculi progressing to axonal degeneration, macrophage accumulation, and astrogliosis. An H&E-stained low-magnification image from this vignette shows vacuolization of the neuropil in the posterior and lateral columns (Image A). Luxol fast blue/H&E highlights myelin loss in these areas (Image B), while Bielschowsky silver stain (Image C) and neurofilament IHC (Image F) both demonstrate at least mild loss of axons. CD68 shows macrophage infiltrates in the involved regions (Image D). Although somewhat difficult to appreciate in the low-magnification image, GFAP accentuates the associated astrogliosis (Image E).
Treatment of B12 deficiency depends partly on the underlying cause of the deficiency. While oral supplementation may normalize hematologic findings including anemia and macrocytosis, parenteral supplementation may be necessary to address malabsorption syndromes. Simply administering an oral B12/folate supplement prior to determining the cause of the deficiency is discouraged, since sufficient folate can be present to normalize hematologic parameters without addressing B12 deficiency, and this can result in progression of neurologic disease.
Take Home Points
- The most common cause of B12 deficiency is pernicious anemia, although any disruption in the B12 cycle originating from decreased intake, increased requirement, impaired absorption, ineffective transport, or disorders of metabolism can cause deficiency.
- Neuropsychiatric symptoms usually occur in conjunction with megaloblastic anemia but can be seen in isolation.
- Pathologic changes characteristic of SCD include demyelination, axonal loss, macrophage infiltrates, and astrogliosis of the posterior and lateral funiculi of the spinal cord.
- The choice of B12 preparation used to treat B12 deficiency depends upon the cause of the deficiency. Options range from parenteral (intramuscular or subcutaneous) cyanocobalamin to oral preparations. Oral administration in the setting of malabsorption can be dangerous, since sufficient folate may be co-administered to treat concomitant anemia without addressing progressive neurological dysfunction.
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- Which of the following nutritional deficiencies likely accounts for the spinal cord abnormalities?
- A. Cobalamin (B12) deficiency
B. Folate (B9) deficiency
C. Iron deficiency
D. Niacin (B3) deficiency
- E. Thiamine (B1) deficiency
- What is the most common cause of this deficiency?
- A. Gastric bypass
B. Inborn metabolic errors
C. Pancreatic disease
D. Pernicious anemia
- E. Vegetarianism
- Apart from the CNS, what other organ system is characteristically affected by this deficiency?
- A. Bone marrow
- E. Hepatobiliary