B12 Deficiency and History

In the 1850s the English physician Thomas Addison described a lethal (pernicious) form of anaemia that could be related to pathological gastric mucosa and associated with the absence of acid in the stomach.

Thomas Addison

Thomas Addison 1795 – 1860

As described by Addison, patients with pernicious anaemia had symptoms of macrocyticanaemia, glossitis, and neurological signs such as paraesthesias and abnormal gait.

There was no treatment for this disease and it was invariably fatal. Patients were left exhausted, were hospitalised, and had no hope of cure. A thorough, well researched and entertaining history of pernicious anaemia by Chanarin can be read here.

The cure, and a remarkable film

Georges Richard Minot, an MD from Harvard, had the idea that something in food might help patients. In 1923 Minot teamed up with William Parry Murphy basing their investigations on previous work by George Whipple at Johns Hopkins. Whipple had bled dogs to make them anaemic and then determined which foods restored red blood cells. Red meat and some vegetables were effective, but liver was best of all.

In 1926, at a meeting in Atlantic City, Minot and Murphy reported the sensational finding that 45 patients with pernicious anaemia had been cured by ingestion of large quantities of raw liver and that “clinical improvement had been obvious, usually within 2 weeks” There was much scepticism at the time but for their research Minot, Murphy, and Whipple received the Nobel Prize for Medicine in 1934.

On 12 December 1934 Murphy delivered his Nobel lecture and in the concluding paragraph stated “Rather than enlarge further upon the details and results of the treatment of pernicious anemia, I shall now present, with your permission, a motion picture which will illustrate many points more clearly than I could discuss them here.” What is probably the motion picture that he was referring to was re-discovered and can be viewed here. It shows the remarkable recovery of the patients after treatment with liver. Some of the typical symptoms of PA can be seen, fatigue, weight loss, unsteady gait.

These days we would expect to diagnose the B12 deficient patient before the disease had progressed to the stages shown, still, it is a salutary reminder that neurological symptoms are an important facet of B12 deficiency.

Still however, the active ingredient in liver was not known.

An ‘Intrinsic Factor’ is also involved

Three years later William Castle also at Harvard, discovered that something in the stomach must be related to the disease as people with removal of the stomach often died of pernicious anaemia, liver did not work as a cure. He postulated an “intrinsic factor”, present in the gastric mucosa, was necessary for normal absorption of the “extrinsic factor” in the liver. The “intrinsic factor” was lacking in pernicious anaemiapatients.

Another Nobel

In 1948 the “extrinsic factor” was isolated in crystalline form from liver and published (within weeks of each other) by Karl Folkers and his co-workers at Merck, and E Lester-Smith and his group at Glaxo, and named vitamin B12.

Crystalline-Vitamin-B12

Crystalline vitamin B12

Vitamin-B12-structure

Vitamin B12 structure

In 1956, the British chemist, Dorothy Hodgkin, described the structure of this large molecule, for which she received the Nobel Prize for Chemistry in 1964. In 1971 the organic chemist Robert Woodward (himself a Nobel laureate in 1965) announced the successful synthesis of the vitamin after ten years of effort.

A disease that had been fatal could now easily be treated by injections of pure vitamin B12, and without side effects. The patients recovered completely.

The diagnostic challenge

Vitamin B12 deficiency was firmly linked with the concept of anaemia. However thehaematological symptoms in vitamin B12 deficiency were accompanied by many other symptoms (as described by Addison) particularly neurologic or neuropsychiatricchanges. These symptoms were long believed to be secondary to the anaemia. The prevailing idea maintained that no vitamin B12 deficiency occurred without anaemia. Recently, It has become evident that anaemia is just one of many symptoms of B12deficiency, and that symptoms can frequently not be accompanied by anaemia at all.

The prevalence of vitamin B12 deficiency is more common than previously estimated. True pernicious anaemia with a lack of intrinsic factor, constitutes only a small fraction of all cases. Far more common may be malabsorption due to atrophic gastritis arising from decreased secretion of gastric acid and enzymes required for the cleavage of protein-bound vitamin B12 from food.

The diagnostic challenge concerns those patients that are vitamin B12 deficient, and who would benefit from treatment, who have no clear signs or symptoms or obvious anaemia. It is difficult to diagnose these patients but important to do so since the treatment is readily administered, safe and effective and neurological impairment may be irreversible if treatment is initiated too late. Active B12, which appears to be an early marker of B12 depletion, could provide a solution..