Rejected by the New England Journal of Medicine in 2013.

To the Editor:

Dr. Stabler’s review of vitamin B12 deficiency (*) rightfully emphasized laboratory diagnosis, but, consequently, omitted several clinical features that may raise suspicion of its most prominent cause: pernicious anemia (PA).

For example, before Minot and Murphy’s 1926 discovery of liver therapy, PA was a relapsing/remitting disease inevitably ending in death (1,2). Infection, especially dental, could trigger relapses (2). In relapse, cardiomyopathy, nephrotic-type edema, spontaneously resolved hypertension, abdominal discomfort, diarrhea, weight loss, fever, lassitude, and a characteristic grapefruit coloration of the skin (due to pallor combined with hemolytic bilirubinemia) (1,2,3,4) might accompany the anemia and neuropsychiatric dysfunctions Stabler describes.

Also curiously, Minot (4) and others (3) note that northern European patients may have a characteristic phenotype: wide facies, hypertelorism, wide jaw, large earlobes, “a bulky frame,” early graying, and light colored eyes.

These presentations, derived from older literature and now uncommon, are not backed by modern standards of evidence – and never will be. Nevertheless, they should not be forgotten because, when a disease is both serious and curable, any clue that triggers suspicion can be life-saving.

(*) Stabler SP. Vitamin B12 deficiency. N Engl J Med. 2013 May 23;368(21):2041-2.   PubMed 23697526

(1) Cabot RC. Pernicious anemia (cryptogenic). In: Osler W, McCrae T. Modern Medicine: Its Theory and Practice. Vol. 4. Philadelphia: Lea & Febiger; 1915:619-659.

(2) Graham D. Addison’s (pernicious) anemia. Can Med Assoc J. 1926; 16: 881-886.

(3) Spivak JL, Barnes HV. Manual of Clinical Problems in Internal Medicine. 3rd ed. Boston: Little, Brown; 1983; 426-431.

(4) Vaughan JM. The gain in body weight associated with remissions in pernicious anemia. Arch Int Med. 1931; 47: 688-697

(5) Minot GR. Case 12342: pernicious anemia: treatment by a special diet. Boston Med Surg Journal. 1926; 195: 429-434.

Some “off-the-record” comments were also submitted with this letter:

Figure 2 in the paper is both pedagogically suboptimal and an inefficient use of page-space.

  • It’s spatially inefficient because it is enormous, and the drawing adds nothing. No one needs reminding of where the brain is, or where the bone marrow lies. The panel for infants and children doesn’t even fit the figure, and it’s unclear if men are infertile, too.

  • It’s pedagogically suboptimal because it’s effectively a list of signs-and-symptoms the reader must memorize. That’s hard to do, and no one does it voluntarily. Physicians learn far more easily from clinical stories.

Thus, I would have dramatically reduced the figure’s size and used the space saved to put some clinical meat around the bones of the list, including:

  • How pernicious evolves clinically over time, and how any organ system can be the presenting one,
  • How subtle changes in personality can be,
  • Vignettes of the incredible cardiac cures that B12 repletion has brought,
  • Expansion of the change in natural history since 1926,
  • The mode of death (which is not anemic).

In summary, changing from pictures to interesting clinical illustrations would, I think, be an improvement over large but fundamentally unhelpful illustrations.

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