( Originally Published 1956 )
Scurvy was described with accuracy several centuries ago and satisfactory treatment was devised long before ascorbic acid was isolated. Only recently, however, has a role for ascorbic acid in conditions other than scurvy been suggested. Extensive investigation has indicated the many biologic functions of this vitamin but its chemical action in metabolic processes remains unclear.
In evaluating dietary intake of ascorbic acid, it should be remembered that this water-soluble vitamin is easily oxidized and that loss in the storage and preparation of food may be great The vitamin may be destroyed in the upper intestinal tract in subjects-who have achlorhydria or who have received alkaline medication. The minimal amount of ascorbic acid which will prevent scurvy is about 10.0 mg. daily. The amount which should be recommended for the maintenance of good nutrition is a subiect of controversy. The allowances suggested in this country are given in Table 3. It is believed by proponents of other dietary standards that smaller quantities will suffice.
In ascorbic acid deficiency, connective tissue is defective presumably due to the essentiality of this vitamin for the production of collagen (142). The changes in bones, teeth and gums which occur in scurvy and the poor healing of wounds, are believed to be secondary to this fundamental defect. The hemorrhagic phenomena represent a capillary defect due perhaps to abnormal pericapillary connective tissue.
One metabolic function of ascorbic acid has been elucidated recently: it acts as a coenzyme in the oxidation of tyrosine . This finding explains the abnormal excretion of tyrosine metabolites in scurvy and the return to normal after ascorbic acid has been administered. Folic acid will also correct this metabolic defect.
Relationships of ascorbic acid to adrenal cortical function have been investigated extensively (144). Stimulation of the adrenal cortex leads to depletion of ascorbic acid stores in the gland but cortical function is maintained even in severe depletion. Investigations using ascorbic acid and acetate labeled with C"' indicate that the vitamin exerts an effect on the conversion of acetate to cholesterol and other steroids (145). Ascorbic acid has been reported to prevent the alarm reaction of acute stress in experimental animals. While much remains to be learned about the function of ascorbic acid in the adrenal cortex, available evidence suggests an increased utilization and requirement of ascorbic acid under conditions of stress. It seems advisable therefore to administer ascorbic acid in chronic stress states, particularly following burns or other trauma and during prolonged administration of corticotropin.
The ascorbic acid requirement appears to be increased in hyperthyroidism. Plasma ascorbic acid decreases in a number of infections, particularly those of long duration such as tuberculosis or rheumatic fever. Whether this decrease represents an increase in ascorbic acid requirement or a redistribution of the vitamin in the body is not clear. Although the role of ascorbic acid in infection is not known, it would seem logical to supplement the diet with this vitamin when infections are prolonged.
Ascorbic acid has a number of biologic functions in addition to those discussed above such as an influence on the hyaluronidase-hyaluronic acid reaction, an effect on the reaction of small blood vessels to adrenaline and some relationship to secretion of steroid hormones in the ovary (146). Many of the activities of this vitamin suggest that it may function as a respiratory catalyst but, to date, this has not been demonstrated.
Ascorbic Acid Deficiency
Ascorbic acid deficiency has been induced experimentally in adults on several occasions (147). Clinical signs of deficiency included hyperkeratotic papules surrounding hair follicles, exacerbation of acne, perifollicular hemorrhages and petechiae, small hemorrhages in the tips of the interdental papillae and poor wound healing. The gums became purplish, spongy and swollen in subjects who had previously shown periodontal disease and interruptions of the laminal dura were noted in x-ray films of the teeth. In spontaneous scurvy in adults, findings similar to those noted above are observed. When deficiency becomes severe, bleeding may occur into any tissue of the body or from any mucous membrane. Swelling of joints, edema and anemia are additional findings. The gums may be very red, swollen and bleed on slight pressure; loosening of the teeth and atrophy of alveolar bone may occur. Anemia is common in severe scurvy in adults and responds to ascorbic acid.
In infants, the majority of cases of scurvy occur between the ages of 7 and 11 months. The most frequent presenting complaints, according to Woodruff (143), are irritability, tenderness of the legs and pseudoparalysis, i. e., failure to move or use the legs. Involvement of the arms is less common. A history of bleeding or its manifestation is another frequent presenting symptom. Non-specific complaints often noted are anorexia, diarrhea and fever. In typical scurvy, the infant lies quietly in the "pithed frog" position with legs flexed at the knees and hips flexed and externally rotated. The slightest jarring or motion causes crying due to the pain which is invoked. Costochondral beading, the most frequent physical finding in Woodruff's series of cases, may cause con-fusion with rickets. Beading in scurvy is typically "sharp," consisting of sublimation of the cartilaginous portion of the anterior chest wall on the bony lateral portion producing an abrupt transition, the so-called bayonet deformity. However, a rounded type of beading similar to rickets may be encountered. Hemorrhage around erupting teeth is a constant finding, with bleeding after manipulation in advanced cases. Palpable subperiosteal hemorrhages are frequent, particularly in the distal end of the femur and proximal end of the tibia. Bleeding may occur from any of the mucous membranes although hemorrhages into the skin are relatively uncommon, in contrast to scurvy in adults.
Radiographic examination of the long bones shows characteristic changes at the cartilage shaft junction appearing earliest at the sites of most active growth, e.g., the sternal ends of the ribs, distal end of the femur, proximal end of the humerus, both ends of the tibia and fibula and distal ends of the radius and ulna. Findings include cortical atrophy, the cortex being unusually thin in relation to the shaft, and atrophy of the trabecular structure with increased transparency producing a "ground glass" appearance. The provisional zone of calcification at the end of the shaft is widened casting a dense shadow; similar changes occur in the periphery of ossification centers, best illustrated about the knee. This latter change, in conjunction with rarefaction and loss of trabecular markings in the epiphyseal center, is almost specific for scurvy. A zone of rarefaction is visible shaftward from the zone of provisional calcification, being apparent first near the cortex; this, plus the extremely thin cortex constitute the "corner sign" or "fracture" de-scribed by Park. This area of rarefaction is weak and fractures may occur here and also in the brittle zone of provisional calcification. Comminution of the latter zone into the shaft causes the appearance of spur formation. Separation of the epiphysis with lateral displacement may occur. Shadows of subperiosteal hemorrhages are also seen on the roentgenogram, the area of hemorrhage be-coming clearly outlined by bone formation in the periosteum after several days of treatment. Following therapy, the normal architecture of the bone is fully restored.
Anemia is quite common in infantile scurvy usually being hypochromic and due to iron deficiency. Occasion-ally megaloblastic anemia is encountered. The leukocyte count is often elevated except in subjects with megaloblastic changes in the bone marrow. There is an increased output of tyrosine metabolites in the urine when large amounts of this amino acid are ingested.
The diagnosis of scurvy in infants or adults is dependent on a history of extremely low intake of ascorbic acid for a period of months, at least three in infancy and longer in adults, the presence of symptoms which suggest the disease and characteristic physical findings. In infants, radiologic changes are of great assistance.
The diagnosis of ascorbic acid deficiency in its incipiency is dependent on laboratory tests. The concentration of ascorbic acid in the plasma reflects dietary in-take. In adults, levels of 0.6 to 1 mg/100 ml. indicate a daily intake of 70 mg. or more, levels of less than 0.2 mg/100 ml. an intake of less than 25 mg.. Unfortunately, low concentrations do not indicate the degree of depletion of bodily stores of ascorbic acid and absence of ascorbic acid in plasma does not indicate scurvy. When such levels are encountered, the ascorbic acid content of the white cell-platelet layer of blood should be measured. Concentrations of ascorbic acid in leukocytes below 2 mg/100 ml. should be considered presumptive evidence of scurvy. In well nourished adults receiving 70 to 100 mg. of ascorbic acid daily, the level of ascorbic acid in white blood cells is 20-30 mg/100 ml.
Some type of "load" test may also be used in evaluating ascorbic acid stores of the body. The vitamin may be administered orally or intravenously and the urinary excretion or concentration in the blood measured for several hours thereafter. These tests and others involving urinary excretion of ascorbic acid have been evaluated in a recent review. Woodruff employed the saturation test of Kadji and associates to differentiate scorbutic infants from infants with no ascorbic acid in serum as a result of a poor recent diet. In this procedure, 200 mg. of ascorbic acid is administered intramuscularly and serum concentration determined four hours thereafter. In practically all infants with scurvy, the four hour level was less than 0.4 mg/100 ml. and in about half of the subjects this level was zero.
Lowry has proposed a test for measuring tissue deficit under carefully controlled conditions. Ascorbic acid is administered in amounts of 500-2000 mg. daily, in divided doses to avoid raising the plasma level above 1.4 mg/100 ml. which is the renal threshold, and the quantity of the vitamin excreted in the urine is deter-mined. Tissue retention should equal tissue deficit when suitable correction is made for destruction of the vitamin.
Capillary fragility tests, which have been widely used, are of almost no value in the diagnosis of ascorbic acid deficiency in view of the many conditions which influence capillary strength.