June 1, 1939
In 1735 Gaspar Casal, a Spanish physician, first described pellagra and shrewdly pointed out that this disease is related to an inadequate diet. That diet was the controlling factor in the etiology of the disease was not suggested again until the work of Goldberger, Waring and Willets in 1915. During the next two decades, the full significance of diet in the development of pellagra gradually became evident because of the frequent association of the disease with faulty nutrition.
Later, the administration of a high caloric diet, rich in protein and vitamins, supplemented with large amounts of antipellagric materials such as yeast, wheat germ or liver extract, became the accepted form of therapy.
Although beneficial in most cases, this treatment is often impractical. It frequently necessitates hospitalization of the severely ill patients for several weeks, during which time almost constant supervision by a physician, nurse or dietitian is required. Furthermore, many of the patients who improve following this therapy are unable to buy, after discharge from the hospital, the relatively expensive foods which will protect them against recurrences of the disease.
In addition, failure to recognize pellagra in its subclinical or mild form continues to be an obstacle to effective and lasting treatment, as advanced pellagra often develop’s before a diagnosis is made and therapy instituted.
It is not surprising, therefore, that efforts have been directed toward obtaining a more practical form of treatment, toward developing methods by which an earlier diagnosis can be made, and toward identifying and isolating the anti-pellagric factors.
For ease of description, the recent advances in our knowledge of pellagra will be divided arbitrarily into those concerned with: Therapy in the classic case; the vasodilator effect of nicotinic acid and related anti-pellagric compounds; the recognition and therapy of subclinical deficiencies in adults and in children; and the evidences of multiple deficiencies in Pellagrins subsisting on their usual deficient diets.
Nicotinic acid has been used in treating hundreds of cases of classic pellagra. In these types of cases, the outstanding symptoms arise from the skin, the digestive(alimentary) tract and the nervous system, although all three systems are not necessarily involved nor do the symptoms appear in any regular order.
Dr. Leon Schiff and Dr. Richard Stevens, of the University of Cincinnati School of Medicine, have performed gastroscopic examinations on two Pellagrins and noted that the diseased mucous membranes of the stomach are similar in appearance to those of the oral cavity. The mucous membranes of the urethra and vagina are frequently swollen and ulcerated, and appear identical to the affected portions of the alimentary tract.
The dermal lesions of pellagra may develop on any part of the skin although the dorsa of the hands and feet, the axillae, elbows, wrists, knees, areas beneath the breasts, and the perineal region are the most common sites. The lesions are usually bilaterally symmetrical and are separated from the healthy skin by a sharp line of demarcation. At the onset, the affected area is erythematous and often burns and itches severely. Later it becomes swollen, tense, and often fiery red. Sometimes vesicles and bullae develop. After a variable period of time, ranging from a few days to several months, the swelling decreases, the color becomes reddish brown, and desquamation begins. The underlying skin may remain abnormally thickened and permanently pigmented.
Various types of psychoses occur. The most common symptoms are confusion, loss of memory, disorientation and confabulation. One frequently sees excitement, mania, depression and delirium.
The presence of certain symptoms arising from involvement of the peripheral nervous system which, in themselves, are not diagnostic of pellagra frequently helps to confirm the diagnosis. The pellagrin often complains of burning, numbness and tingling of the extremities long before any diagnostic symptoms of the disease appear. (These symptoms are characteristic of peripheral polyneuritis; indeed, pellagrins often have co-existing beriberi.) As the disease in the peripheral nerves increases, alteration of the tendon reflexes occurs; at first their activity is increased, later decreased, and finally absent.
The administration of adequate amounts of nicotinic acid or one of its compounds is followed by the disappearance of many symptoms of the disease. Within 24 to 72 hours, the fiery redness and swelling of the tongue, gums, mouth, throat, and vagina subside, and the associated Vincent’s infection disappears. Within 24 to 72 hours, nausea and vomiting cease, increased salivation decreases, and bowel movements become normal. Abdominal distention, pain and discomfort disappear and, in most cases, the desire for food returns. The acute, fiery red erythematous dermal lesions in which the epithelium is intact blanch within 48 hours after the administration of nicotinic acid, but where the continuity of the skin is broken and the lesions are moist, ulcerated, dry or pigmented, there seems to be no specific benefit. Perhaps the most dramatic response of a Pellagrin to nicotinic acid therapy is the disappearance of the acute mental symptoms.
These symptoms, varying from slight confusion to delirium and mania, disappear rapidly, often over night. The maniacal patients become calm and the confused patients, mentally clear. After therapy they become readjusted, and often have excellent insight and memory of their actions, ideas, and surroundings during the psychotic period. Apathy and lassitude give way to interest.
In sharp contrast to the prompt and beneficial response of the mental symptoms to nicotinic acid is the lack of improvement in symptoms arising from the peripheral nervous system. The administration of crystalline vitamin B-1 however, gives prompt relief from these symptoms.
Nicotinic acid, nicotinic acid amide, and sodium nicotinate are all effective in the treatment of pellagra. They may be administered orally in tablet or capsular form, or parenterally in physiological solution of sodium chloride.
Unless the powers of absorption are greatly impaired, oral administration is preferred.
Opinion in regard to dosage differs. Although the dosage probably varies considerably in different pellagrins, experience with a large series of cases has shown that 500 milligrams daily, administered orally in 50 milligram doses, is a safe and effective dose for the average case of pellagra. We have observed that only 50 milligrams daily may be required by the mild case but that in rare instances as much as 1000 milligrams per day may be required for the very severe case. Administered parenterally(outside the G.I. tract), the total daily dose varies from 40 to 80 milligrams, dissolved in sterile physiological solution of sodium chloride and injected intravenously, in divided doses of 10 to 15 c.c. each. The dosage of nicotinic acid amide and sodium nicotinate is similar to that of nicotinic acid.
Vasodilation effect of nicotinic acid and related anti-pellagra compounds.
It has been noted that the administration of large amounts of nicotinic acid to human beings is often followed by sensations of heat and tingling of the skin. This feeling of heat is accompanied by flushing and a rise in skin temperature, especially over the face.
In normal adults increased temperature of the skin follows the intravenous injection of 20 milligrams of sodium nicotinate, ammonium nicotinate, ethyl nicotinate, and the monoethanolamine salt of nicotinic acid, as well as nicotinic acid itself. The administration of these substances which provoke the vascular response is frequently followed by some epigastric distress, increased peristalsis, and occasionally belching.
The Recognition and therapy of subclinical deficiencies in adults and children.
The development of severe pellagra can, in most instances, be avoided if the disease is recognized in its early forms and treated appropriately. It is apparent, from a study of many pellagrins, that there is a long prodromal(relating to or denoting the period between the appearance of initial symptoms and full development.) period of ill health. This period has insidiously advancing symptoms, all trivial in nature, but gaining in importance by their persistence.
Loss of weight, strength, and appetite precede the appearance of any diagnostic oral or dermal lesions.
During this early stage, ill-defined disturbances of the alimentary tract, including indigestion, ” dyspepsia,” diarrhea or constipation, as well as weakness and lassitude develop without obvious reason. Irritability, depression, loss of memory, headache and insomnia are noted.
Other characteristics of nutrient deficiencies include abdominal pain, burning sensations in various parts of the body, vertigo, numbness, nervousness, palpitation, distractibility, flight of ideas, apprehension, and mental confusion.
There is obviously much that is abnormal but nothing which is pathognomonic. The entire syndrome of vague, grumbling complaints appears to be without objective cause and if a patient is seen at this stage of the disease and pellagra is not suspected or suggested, a diagnosis of neurasthenia may be entertained by the physician.
Tom Douglas Spies – In the 1930s, he contributed significantly to finding a cure for pellagra, a nutritional disease that once afflicted millions in the American South. Later, he also made a large contribution to finding cure for tropical sprue.
The development of clinical pellagra can be prevented in these subclinical cases by the administration of adequate amounts of nicotinic acid. Following its administration these persons experience an increase in sense of well-being and vigor almost immediately. Indigestion is relieved, nausea ceases, and bowel function is restored to normal. Nervousness, irritability, and mental confusion disappear rapidly following adequate dosage, and the vague burning sensations in various parts of the body disappear soon after treatment is initiated. Although improvement in symptoms arising from the alimentary tract and cerebral cortex is striking, many of the Pellagrins develop polyneuritis which becomes worse in spite of continued therapy with nicotinic acid or related compounds. (The administration of massive doses of nicotinic acid does not relieve either the painful symptoms of beriberi, arising from involvement of the peripheral nerves, or the symptoms of riboflavin deficiency which arise from the lesions around the mouth, nose, eyes, and ears, whereas the administration of synthetic thiamin hydrochloride and synthetic riboflavin, respectively, is followed by prompt disappearance of these symptoms.)
The amount of nicotinic acid needed to relieve these early symptoms and to prevent the development of clinical pellagra cannot be predicted, nor can it be determined other than by frequent examination of the patient. The amount needed by an individual may vary from time to time and often it is necessary to adjust the dosage to meet this changing need.
There is also considerable variation in the amount needed by different patients. As little as 50 milligrams daily may be effective in some cases, while 500 to 1000 milligrams is sometimes required in others, although this is seldom necessary. The therapeutic effect of these substances is proportional not only to the total dosage, but also to the size and frequency of the individual dose. That is to say, the oral administration of ten doses of 50 milligrams each at hourly intervals is more effective than a single dose of 500 milligrams. This suggests that the controlling factor is the concentration of compounds of nicotinic acid in the blood and tissues.
Observations on the children in several hundred “Pellagra families” have shown that many of these children have early clinical signs of pellagra.
Such children often have a history as follows: For years they have been somewhat below normal in weight and height; their progress in school has been slow; their inability to concentrate is apparent; and they have few interests. Frequently they complain of poor appetite, indigestion, vomiting, soreness of the tongue and lips, and constipation. Their parents report that they are cross, ” fretful,” and cry easily.
A careful check on the dietary history of the family often shows that the diet of the mother during pregnancy was inadequate and that shortly after birth the child had to be given food of some sort as the mother gave insufficient milk; hence, from a short time after birth, such children have frequently been a ” feeding problem.” In addition, many of these children show a preference for only one or two foods and refuse all others. The diet is usually rich in carbohydrates, and when milk, eggs and meat are included, they rarely are given in sufficient amounts. When the children have clinical evidence of the disease as shown by characteristic glossitis or dermatitis, there can be no question of the diagnosis, and nicotinic acid therapy is as effective as it is in adult pellagrins. However, spectacular improvement following therapy with nicotinic acid or some closely related anti-pellagric compound has been noted in many children who have subsisted over long periods of time on an inadequate diet but who show none of the diagnostic symptoms of pellagra.
In general, the complaints of these children have been similar to those of adults. Likewise, the method of study was similar but the amount of nicotinic acid given was less. Within 24 to 36 hours after the administration of nicotinic acid there was prompt improvement in general health and disappearance of the various complaints. Usually, these children were given a total daily dose, varying from 50 to 300 milligrams. We recommend that this total dose be given in from 5 to 10 tablets at least one hour apart. Children from two to six years of age are usually given tablets of the 10 milligram size, and those up to puberty are given tablets of the 25 milligram size. In treating clinical beriberi and clinical riboflavin deficiency occurring in these children, we gave one-half the amount of synthetic thiamin hydrochloride and synthetic riboflavin recommended below for an adult.
Still more recent studies on a large series of Pellagrins subsisting on their usual inadequate diets, have shown that the administration of nicotinic acid in adequate amounts prevents or improves the alimentary tract symptoms, the erythematous dermal lesions, and the mental symptoms of pellagra, but that it does not prevent, retard or relieve the symptoms of peripheral nerve involvement. These symptoms, however, are relieved when adequate amounts of thiamine are administered. Thiamine may be administered either orally(enterally) or parenterally, depending upon the patient’s ability to absorb it.
For the mild case of pellagra with peripheral neuritis we recommend the oral administration of 10 milligrams twice a day. Severe cases should receive at least twice this amount. The parenteral(IV) administration of 50 milligrams daily, in physiologic solution of sodium chloride, by intravenous injection, is preferable in the very severe case as it shortens convalescence and affords prompt relief from pain.
The administration of vitamin B1 should be continued until after improvement has taken place. The acute case will often show improvement within a few hours and the mild case, within 24 to 48 hours. Chronic cases often experience relief from pain within a few days, but some of the abnormal physical signs may remain for a long period of time.
Riboflavin deficiency occurs in either sex at any age and is not uncommon in persons ingesting, over a considerable period of time, a grossly inadequate diet.
This deficient state is characterized by a feeling of ill health, lack of strength, and loss of weight. Diagnosis depends upon the recognition of characteristic angular stomatitis associated with transverse fissures in the corners of the mouth and lips, and an abnormal shiny redness of the mucous membranes of the lips.
Other diagnostic lesions, occurring less frequently, are the comedones giving a ” sharkskin ” appearance from collections of greasy, seborrheic material around the alae nasae, eyes, and occasionally over the ears and cheeks.
Some of these patients give a history of visual disturbances. These symptoms disappear within four to six days following the administration of riboflavin in adequate amounts. The minimal and optimal therapeutic dosages have not been determined, but we have found that the oral administration of from 5 to 50 milligrams per day is effective and it seems likely that even smaller doses may be beneficial.
Riboflavin is a safe therapeutic agent when administered either orally or intravenously(in sterile physiological solution of sodium chloride). Improvement in these lesions is associated with an increased sense of well being. If these patients continue to eat only their usual diet, the symptoms usually return within 10 to 20 days after the administration of riboflavin is discontinued.
(The diet which as a rule consists of corn bread, biscuits, corn syrup, and fat meat, is deficient in riboflavin.)
The time has come when we are forced to accept the belief that clinical pellagra, clinical beriberi, and clinical flavin deficiency are responses of the body to deprivation of these essential chemical substances over a long period of time. Within our own group we have used the terms ” chemical pellagra’ ” chemical beriberi,” and ” chemical flavin deficiency,” to describe that stage between optimum nutrition and the frank appearance of diagnostic evidence of the particular disease; that is, the period which might be termed the deficiency development time.
The latter portion of this period has been called the prodromal period and is characterized by many vague symptoms of subclinical deficiency states. In such early stages a diagnosis of neurasthenia is apt to be made, yet these symptoms disappear following the administration of specific therapeutic agents.