498 VITAMIN Bi2 



administration of B12 accentuates the metabolic imbalance and leads to 

 rapid exhaustion of whatever PGA compounds may remain. 



Whereas the foregoing discussion includes much speculation and ques- 

 tionable analogies drawn between tissue culture phenomena, microbiologi- 

 cal processes, and metabolic disturbances in man, the theories evolved have 

 served to delineate the problems concerned with the metabolism of B12 

 and PGA and to emphasize the continuity and interdependence of their 

 functions. Certainly there is no tendency on the part of active workers 

 in this field to ignore newly discovered facts even though they may force 

 modification or rejection of a favored hypothesis. There remains to be con- 

 sidered an aspect of the pathologic physiology of B12 to which reference 

 has already been made; namely, the possible influence of injurious agents 

 produced by intestinal bacteria. Before the discovery of the effect of liver 

 on pernicious anemia the most favored etiologic explanation for this disease 

 was intestinal sepsis Avith elaboration and absorption of hemolytic toxins. 

 The introduction of liver therapy and the results of the clinical investiga- 

 tions of Castle and his group led to the concept of pernicious anemia as a 

 conditioned nutritional deficiency disease, and the hemolytic component 

 of the disorder was either disregarded or attributed to the lessened sur- 

 vival rate of defective erythrocytes. However, evidence has accumulated 

 that potentially toxic agents may be present in the blood of patients with 

 pernicious anemia and related anemias. Thus, in pernicious anemia in re- 

 lapse there is a high blood phenol level and an increased urinary excretion 

 of phenolic compounds.^'* Liver extract or desiccated stomach will correct 

 the abnormal excretion of phenols by a reduction in the output of the frac- 

 tion containing the hydroxyphenyl acids, and more recently it has been 

 shown that B12 has the same effect. ^^ Since the hydroxyphenyl acids are 

 metabolic intermediates derived from tyrosine, it seems probable that ty- 

 rosine or a tyrosine derivative plays a part in erythropoiesis. If the accumu- 

 lated products of tyrosine breakdown are toxic to circulating erythrocytes, 

 which has not been demonstrated, then one of the therapeutic actions of 

 B12 might be the arrest of excessive red cell breakdown through its effect 

 on tyrosine metabolism. This concept, which is highly speculative, is in 

 accord with the well-established fact that institution of adequate treatment 

 of pernicious anemia Avith B12, liver extract, or desiccated stomach is fol- 

 lowed within a few days by reduction in hemolysis and disappearance of 

 clinical evidences of toxicity, including fever and anorexia. 



On the other hand, hemolysis and other toxic manifestations in perni- 

 cious anemia may be due to circulating substanc^cs of intestinal bacterial 



^»M. E. Swcndseid, B. Wandruff, and F. II. Bethell, /. Lob. Clin. Med. 32, 1242 



(1947). 

 " L. D. Abbot, Jr., and G. W. James, III, J. Lab. Clin. Med. 35, 35 (1950). 



