IX. EFFECTS OF DEFICIENCY 215 



It is of iiit(M"c\sti to nu'iilioii in coniu'clioii witli llic (lisciission of P(!A 

 antagonists that pernicious anemia patients arc unusually susceptible to 

 the action of the l-amino analojis, which is presumably attributable to 

 their already defective metabolism or limited supply of F(IA. Kurthei'more, 

 administration of aminopterin prexiMits therapeutic response in peinicious 

 anemia to vitamin B12 .""■ -'^ This observation suggests that in the growth 

 of blood cells PCiA functions secondarily to vitamin Bi.> , a topic which is 

 discussed further in the section dealing with \itamin B12 . 



8. Summary 



The pathology of PGA deficiency in man is expressed in a number of 

 clinical manifestations but especially in altered hemopoiesis, resulting in 

 anemia, granulocytopenia, and thrombocytopenia. The characteristic 

 changes in the bone marrow are megaloblastic erythropoiesis, qualitative 

 abnormalities in granuloc3^tic and megakaryocytic development, and (juan- 

 titative changes in the absolute number and relative proportions of erythro- 

 cytic and granulocyte elements. 



The factors which may contribute to the de\'elopment of PGA deficiency 

 states are multiple and complex. Decreased dietary intake of PGA is prob- 

 ably rarely the sole cause of clinically apparent deficiency, although the 

 etiologic importance of a poor diet is evident in a group of clinical cate- 

 gories including nutritional megaloblastic anemia, megaloblastic anemias of 

 pregnancy and of infancy, and certain cases of the sprue syndrome. Lack 

 of other dietary constituents may play important roles in contributing to 

 disturbances of PGA metabolism. Among such substances are vitamin B12 , 

 ascorbic acid, and amino acids. 



Deficiency of PGA may result from non-absorption or non-utiUzation of 

 the naturally occurring conjugated forms of the \'itamin, owing to inability 

 to hberate the free material. The mechanism involved in this process is 

 an enzymatic breakdown of a peptide linkage. The enzymes, or conjugases, 

 responsible for the liberation of free PGA may be ciuantitatively deficient, 

 or they may be rendered inert by the presence of inhibitory substances, 

 which have been demonstrated in animal and plant materials. One of the 

 metabolic defects present in pernicious anemia and some other related con- 

 ditions results in relatively poor absorption of dietary PGA, and probably 

 also in impaired utilization of such amounts of the vitamin as are absorbed 

 and stored in the tissues. 



The metabolic function of PGA involves its enzymatic conversion to a 

 formyl derivative, the citrovorum factor. The most extreme degrees of 

 PGA deficiency may be rapidly produced by the administration of the 



2'« L. M. Meyer, N. D. Ritz, A. Cacce.se, J. Rutzky, and A. Sawitsky, Am. J. Med. 

 Sci. 218, 197 (1949). 



