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  • Updated 09.24.2021
  • Released 10.06.1999
  • Expires For CME 09.24.2024

Vitamin B12 deficiency



Vitamin B12 deficiency may cause an extraordinary variety of progressive neurologic syndromes. In this article, the author discusses the manifestations of vitamin B12 deficiency.

Key points

• Vitamin B12 deficiency should be suspected in any patient with otherwise unexplained peripheral neuropathy, myelopathy, optic neuropathy, dementia, ataxia, movement disorder, or psychiatric disturbance and in individuals with macrocytosis with or without anemia.

• Serum B12 level should be determined in any patient with suspected vitamin B12 deficiency.

• Abnormal red blood cell indices are neither sensitive nor specific for vitamin B12 deficiency.

• In cases of borderline low vitamin B12 levels, or when vitamin B12 deficiency is strongly suspected despite reported normal levels from an automated assay, elevated serum methylmalonic acid and homocysteine levels may confirm a physiological deficiency, as may a normalization of these levels with B12 repletion.

• Daily, high-dose oral vitamin B12 supplementation appears as effective as parenteral therapy and is substantially less costly. This has really only been tested, though, in minimally symptomatic or asymptomatic patients. A brief parenteral course of therapy may still be needed for patients with significant neurologic signs of vitamin B12 deficiency.

Historical note and terminology

At a meeting of the South London Medical Society in 1849, and subsequently, in a monograph in 1855, British physician Thomas Addison (1793–1860) at Guy’s Hospital in London described several cases with “idiopathic” anemia characterized by pallor, weakness, and progressively worsening health leading to death (83). Later this condition was called Addisonian anemia, at least until German internist Michael Anton Biermer (1827-1892) in Zurich named it perniciöse Anämie (ie, pernicious or fatal anemia) when describing 15 cases of severe anemia (of mixed etiologies) in 1872 (83).

Although pernicious anemia, or Addison-Biermer disease, had been recognized clinically in the mid-19th century, the associated neurologic, gastrointestinal, and hematologic manifestations were not recognized clinically and linked with pernicious anemia until the end of the 19th century (83).

In 1884, Lichtenstein described cases of pernicious anemia with neurologic manifestations felt to be suggestive of tabes dorsalis (83). The first accurate description of spinal cord pathology associated with certain types of anemia was by German physician Ludwig Lichtheim (1845-1926), who described three cases, two with autopsy (88). Similar cases were reported by a number of authors over the next several decades (83). Guyanese-British neurologist James Samuel Risien Russell (1863-1939) and colleagues coined the term "subacute combined degeneration of the spinal cord" in their study of the neuropathological abnormalities commonly associated with pernicious anemia (133).

In 1870, British gastroenterologist Samuel Fenwick (1821-1902) in London associated stomach atrophy with this form of anemia and demonstrated that stomach mucosa from an affected fresh cadaver could not digest boiled egg white with prolonged incubation, whereas mucosa from a control stomach could do this (83). Subsequently, German internist Arnold Cahn (1858-1927) and German physician and physiologist Josef Freiher von Mering (1849-1908), working in the Strassburg clinic of German physician Adolf Kußmaul (1822-1902), showed that a patient with pernicious anemia had no hydrochloric acid in the stomach contents, a finding later demonstrated to be pervasive in this disorder and to precede the development of anemia (83).

It was not until the 1850s--after Addison’s original communication--that the first red cell counts were done by German physiologist Karl von Vierordt (1818-1884) and that hemoglobin was discovered by German physiologist Otto Funke (1828-1879) (83). In 1875, American physician and educator William Pepper Jr. (1843-1898), then a lecturer in clinical medicine at the University of Pennsylvania in Philadelphia (and subsequently Professor of Clinical Medicine, Professor of the Theory and Practice of Medicine, and the longtime Provost of the university), noted the extreme hyperplasia of the bone marrow in patients with pernicious anemia (83). In 1880, German physician-scientist (and later Nobel laureate) Paul Ehrlich (1854-1915), using aniline dyes developed by his cousin Carl Weigert (1845-1904), a German pathologist, identified large erythroid precursor cells that he called “megaloblasts” in stained blood smears of patients with pernicious anemia (83). Subsequent hematologists noted characteristics of megaloblastic anemia in the peripheral blood (ie, macrocytes, poikilocytes, and hypersegmented neutrophils) and bone marrow (eg, megaloblasts, meta-myelocytes, and megakaryocytes) (83). Later, American physician-scientist Francis Weld Peabody (1881-1927) of the Thorndike Memorial Laboratory in Boston hypothesized that this macrocytic anemia was due to maturational arrest of erythroblasts in the bone marrow (83).

In 1925, American medical researcher George Minot (1885-1950), at Peter Bent Brigham Hospital in Boston, and American physician William Parry Murphy (1892-1987) at the Collis P Huntington Memorial Hospital of Harvard University, hospitalized a group of patients with pernicious anemia to systematically assess liver as a treatment (83). By 1926, Minot and Murphy reported clinical and hematological improvement in 45 patients with pernicious anemia treated with a dietary regimen that incorporated large quantities of liver (Minot and Murphy 1926; 83). The patients improved clinically, often dramatically so, in conjunction with improvements in their hematological indices. This suggested that a factor present in calf liver could rapidly restore red blood cell counts in pernicious anemia. Moreover, this clinical improvement could be sustained for many years, well beyond the previous life expectancy of such patients. Patients with relatively mild neurologic dysfunction also improved, but patients with more severe neurologic dysfunction showed at best slow and limited improvement. Eventually, with Edwin J Cohn, a physical chemist in the Laboratories of Physiology at Harvard Medical School, they tried to isolate the active principle in the liver that resulted in clinical improvement; although they were not successful in isolating the responsible factor in liver, they did demonstrate that potent extracts could be given parenterally in very small quantities. In 1934, Minot and Murphy were awarded the Nobel Prize for their discovery of a treatment for pernicious anemia.

American physician and Nobel laureate William Parry Murphy
In 1926, American physician William Parry Murphy (1892-1987) with George Minot (1885-1950) reported the clinical and hematological improvement in 45 patients with pernicious anemia treated with a dietary regimen that incorporated ...

In 1926, after Minot and Murphy’s success with liver therapy for pernicious anemia, William Bosworth Castle (1897-1990), then an assistant resident at the Thorndike Memorial Laboratory of Boston City Hospital (which had recently come under the direction of Minot as successor to Francis Peabody), decided to pursue his belief that gastric achlorhydria (“achylia gastrica”) was etiologically linked to pernicious anemia (83). Castle noted that: (1) gastric achlorhydria precedes the other clinical manifestations of pernicious anemia; and (2) even when the blood of a patient with pernicious anemia is returned to normal with liver feeding, gastric achlorhydria persisted (83). Castle suggested that some essential step of gastric digestion was impaired, thereby disrupting absorption of an essential dietary factor. He reasoned that this defective process might be circumvented by utilizing gastric juices from individuals with normal stomachs. By an ingenious series of experiments, Castle and his colleagues showed that indeed the normal stomach secretes a substance separate from normal gastric juice that is able to interact with a dietary substance to promptly relieve the anemia of these patients. Castle later labeled the essential substance secreted by a normal stomach as “intrinsic factor” and the substance present in food as “extrinsic factor.” Subsequent studies showed that intrinsic factor serves as an intestinal transport vehicle for extrinsic factor (later identified as vitamin B12) (83).

Cyanocobalamin (vitamin B12) was finally isolated by the mid-20th century, and this greatly improved the treatment of pernicious anemia and the associated neurologic manifestations (83). By 1955, British chemist Dorothy Crowfoot Hodgkin (1910-1994) of Cambridge University determined the molecular structure of cyanocobalamin using computer-assisted x-ray crystallography, work for which she received the 1964 Nobel Prize in Chemistry (83). The complex structure of vitamin B12 included a single cobalt atom at the center of a tetrapyrrole or “corrin” macro-ring structure. A complete chemical synthesis of vitamin B12 was finally achieved in 1960 by an international consortium of chemists.

British chemist and Nobel laureate Dorothy Crowfoot Hodgkin
British chemist Dorothy Crowfoot Hodgkin (1910-1994) determined the molecular structure of cyanocobalamin using computer-assisted x-ray crystallography, work for which she received the 1964 Nobel Prize in Chemistry. (Courtesy of W...

Subsequent biochemical work demonstrated that only two enzyme systems require forms of vitamin B12 in man: adenosylcobalamin in the conversion of methylmalonyl coenzyme A to succinyl coenzyme A by methylmalonyl-coenzyme A mutase, and methylcobalamin in the conversion of homocysteine to methionine by methionine synthase (83).

In the late 1950s, studies showed that there are two mechanisms involved in vitamin B12 absorption. With physiologic (ie, 1 to 2 mg) doses of oral vitamin B12, the vitamin is absorbed by a process dependent on intrinsic factor; but with much larger oral doses, vitamin B12 appears in plasma much sooner as a result of passive diffusion, independent of the presence or absence of intrinsic factor. When vitamin B12 is released from foods by peptic digestion, it is bound to intrinsic factor, affording partial protection against gut microorganisms and parasites during transport through the gut to the terminal ileum, where the complex binds to microvilli of the intestinal epithelial cells.

Beginning in the late 1950s and continuing through the 1960s, several lines of evidence converged in support of an autoimmune basis for pernicious anemia: (1) corticosteroids improve vitamin B12 absorption and reduce anemia; (2) gastric and serum autoantibodies to intrinsic factor and gastric parietal cells are present in the majority of patients; and (3) other autoimmune diseases (eg, Hashimoto thyroiditis, insulin-dependent diabetes mellitus, Addison disease, and vitiligo) are common in such patients (83).

Pernicious anemia is now understood to be fundamentally an autoimmune disorder that begins with an autoimmune gastritis in which antiparietal cell antibodies produce atrophic gastritis with a resultant decline in intrinsic factor production, evolving over years or even decades (83). In 1988, the principal target of these antibodies was identified by Swedish internist F Anders Karlsson and colleagues as the acid-producing H+/ K+-adenosine triphosphatase (ATPase) in the cell membrane of gastric parietal cells (72).

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