Pernicious Anemia

Copyright 2009, American Society for Investigative Pathology 32 In 1855, Thomas Addison at Guy's Hospital described a lethal, idiopathic anemia that in 1872 was given the name pernicious anemia by Biemer. For decades following, a commonly held view was that pernicious anemia reflected the positive-acting, deleterious influence of an infectious agent or a microbial product. A popular concept was that the injurious agent caused excessive destruction of red blood cells.

1. That the blood destruction in pernicious anemia is caused by some hemolytic agent.
2. That specific treatment cannot be begun until thi s hemolytic agent is found.
3. That aplastic anemia is the result of an etiological factor totally different from the exciting cause of Addison ~s anemia. BLOOD PI;TURE IN PERNICIOUS ~lIA 1.. low red cell count (usually below 2,,000,,000 and perhaps less than 500"oooh anisocytosis,. with marked eccentric achromia; abundance of macrocytes, microcytes and poikilocytes; considerable polychromatophilia, basophilic stippling and sometimes nucleated red cells of all kinds.
2. jonsiderable decrease in hemoglobin, yielding color index of plus and plus 1.5 -occrasional1y higher.
3. leukopenia -with absolute decrease in polymorphonuclear neutrophiles and eosinophiles and relative increase in lymphocytes and mononuclears.
Because of the striking remissions in this disease, the blood picture varies considerably from time to time, and repeated examinations are necessa.ry for a correct diagnosis. The amounts given daily have usually varied from the extract derived from 300 to 600 gm. of liver. A few cases have been given daily extract from 800 to 1200 gm. of liver'.
The amount of this extract given has, therefore, varied usually from about 10 to 20 gm. per day.
Sometimes cases with less than 2 million red blood cel1 corpuscles per cu. rom. of blood, fed daily extract from 500 to 600 gm. of liver, have had their cells increased by 3 million per cu. mm. in a month, but on the average either of these amounts of extract has caused an increase of about 2.5 million cells per cu. rom. in this period of time. Cases treated daily with liver extract obtained from 800 to 1200 gm. of liver for the first six to fourteen days and then daily an amount from 500 gro.t yield no definite evidence that these large amounts cause the manufacture 0 f ceHs at a faster rate. No definite distinction in the number of cells produced during ~he first thirty days of therapy has been observed when the standardized extract derived from 400 to 500 and 500 gm. of liver has been given daily to entirely comparable cases. 11here is perhaps a /"'.' slightly greater rate of increase of the corpuscles. especially in the first ten days. when the larger amounts are given. and a statistical study of the maximum productions of cells further suggests that extract derived from 500 to 600, gm. of liver is slightly more efficacious than 400.
The ac ::mmrnulated evidence indicates that the red. cells continue to rise in an orderly manner when the d~ily feeding of sui table amounts of potent fractions is continued beyond thirty days. '.tthe exact rate of their inc:rease after a month as a result of taking fraction cannot be determined yet. since until recently there has been little potent material available.
In many instances as soon as the patient had improved distinctly and his red blood cells had increased two million per cu. mm. he was placed on liver or kidney. reserving the supply of fraction for individuals who were in a more serious condition. 4 T,he necesd ty for prolonged continua tion of liver therapy mus t be emphas ized. Up to the present time the chief' cause for pat ients with pernicious anemia to develop significant decreases in the level of their red blood cells, after they have once reached normal, following the eating of liver or kidney has been the omission of these foods from their diet, or the ingestion of an inadequate amount. It is possible that a suitabR maintenance dose of liver extract will be found to vary for different pat1ents. The further experience of many observers will unquestionably establiBh concrete information, concerning dosage, particularly when the concentration of red blood cells is above 4.5 million per cu. mm. lrumerous cases with high eoun ts have been placred daily either upon the standard extract from 200 to 100 gm. of" liver., a!1d it appears that more than this latter amount is often a desirable quantity_ It is important not to allow the dose to become too small to maintain at normal the red blood cell level. It is also desirable not to put'an unnecessary strain upon the bone marrow. Red blood cell counts in the vicinity of six million per cu. mm. have oc~Yrred as a result of liver therapy.
Under thesecircumstanees the amount of active principle administered should be Cllrtailed.
Blood of patients should be examined from time to time, and the amount of active principle prescribed be dependent upon the state of blood, and upon symptoms or signs manifested by the paUent"" If neurological disorders appear to progress, more of the active prinCiple should be given.
An infectious process may cause the red blood cell count to fall, or prevent its rise, and under such circumstances maximal amounts of potent material should be fed.
Although the rate of increase in the concentration of red blood cells often has been more rapid in patients upon fraction than in those given whole liver, the rate of hemoglobin format ion on the average has appeared to be somewhat slower. In adminis tering these larger doses of acid, well diluted, with each meal, it was found that many patients were unable to tolerate single doses of more than l ... li-drams; but doses of fa dram, or 1 dram at a time, well diluted were tolerated by nearly all patients.
In a study of 110 cases of pernicious anemia, on the liver diet it was noted that a relatively high percentage of s patients suffer from a flatulent dyspepsia frequently associated with diarrhea. AS a rule neither of these symptoms has been relieved by the liver aiet, either with or without the addition of dilute hydrochloric acid; in some cases they have been inereased. In these cases there was always found, in add i tion to the absenc~ of hydrochloric acid, a marked diminution of peptic activity. The persistence of achylia, despite the striking improvements shown in the blood c'ounts, and indeed in the patient~s condl tion generally. has been observed by many workers.
In all cases of pernicious anemia, in addition to liver" a mixture of three parts Official glycerinum pepsini and one part aC'id hydrochlor. dil., two drams, was prescribed, to be taken as a routine measure in six to eight ounces of water, flavored if necessary wi th lemon or arange juice--and sipped throughout each meal. This has never failed to relieve the symptoms of dyspepsia and diarrhea. Patients take it four times til_aily at first, later three times daily.. Three cases in the series reported call for comment ..

1.
A man developed urticaria when put on the liver diet; this was marked with fresh liver, less marked with liver extract. He was troubled also with flatulence and a perSistent diarrhea. All these symptoms cleared up at once when the prescribed pepsin and hydrochloric acid mixture was taken.
2. .li. woman was found to have achlorhydria and diminished peptic activity_ She was not at the time suffering from Pernicious Anemia, although several members of her family had the disease. The routine mixture was prescribed, but unfortunately developed urtiC'aria, which was cured only when the medicine was discontinued.
3. A man was unabl e to tolerate hydrochloric acia in any way", not even in the form of betaine hydrochloride. which has been used occasionally as a Gource of hydrochloriC' acid.
':'he value of pepsin as an adjunct in the treatment of pernicious anemia has been recognized for some time. I1urst advocated the addition of a grain of pepsin to each dram of dilute acid in order to i:r:prove gastric digestion, although this suggestion does not appear to be widely known. It should. of course, be remembered that commercial pepsin and hydrochloric acid alone do not constitute an adequate treatment for pernicious anemia; liver treatment must be the standard. but the combination is efficacious in the relief of the frequently dis tressing< gas trointes tinal symptoms associated with the condition--the fla tulen t dyspepsia associated with diarrhea and the occasional oases of urticaria developed by the liver therapy.
The use of hydrochloric acid in the treatment of pernioious anemia has been advised and practiced for many years.
The attempt to replace the acid whioh is absent from the stomach o:f these patients is certainly rational, but it is extremely doubtful whether the maximal dosage ordinarily employed accompl ish-10.
es very mu~h in this direction. However. one or two drams (4 or 8cc.J of the U.S.P. dilute acid in a glass of water before or during meals and again upon retiring is frequently followed by remissions of long duration.
The use of the acid, and the good resul ts which sometime follow thereon, accord well with one 0 f the theories of the etiology of the disease, namely, that one which holds the disease to be due to the fact tha t the absenee Of gas tria acid permits the fecal flora to contaminate the small intestine and also allows pathogenic organisms to enter from above; these organ~sms, once established in the absorptive portion of the tra"ct, give rise to hemolytic and neurotoxic substances which cause the characteristic symptoms of the disease. as it had very 1 i ttle odor and practically no taste.
Daily feedings of from 15 to 30 Gm. of this residue in suspension in water were given to three consecutive patients-wi th typiaaI pernicious pnemia. In all three there was a prompt and very active response characterized by an increase in the percentage of reticulated red blood cells which was at least comparable wi th. if not greater than. the increase in the reticulocyte percentage indueed by feeding an active commerCial extract made from 300 to 600 Gm .. 0 f fresh liver.
The observation that the feeding of desiccated whole hog~s stomach produces a complete remission in pernicious anemia supplements and SUbstantiates the work of (Jastle, since it indicates that stomach tissue contains a red blood cell maturing substance. When the liver or liver extract is taken by a patient with perniciOUS anemia whose blood count is two and one half million or less, the number of reticulocytes increases appreciably in the peripheral cireula tion during the first one or two weeks. When the liver or liver extract is taken by a Fatient with pernicious anemia whose count is higher (three million pel" cubic millimeter or abovel or by a normal person, the increase in the number of reticulopytes in the blood stream is very slight or negligible~ This appears to be related to the stage of red blood cells in ~he bone marrow. The active principle, when given in the form of liver extract, does no t appear especially to influence hemoglobin formation, a1 though other substances in who 1 e liver may be effective in this respect.
Even before the first morphologic blood changes can be noted, there is a very definite subjective improvement in the patient... On the third day" occasionally sooner, there is an increase in the appetite, a feeling of new strength, and a're~wakening of interest in the surroundings. During the next week, before there is any demonstrable Change in the red blood cell count, the pads of the fingers and palms, the chin, the cheeks and the tip of the nose may become flushed. This reaction appears to be a vasomotor phenomenon and is very striking, especially when the red blood cell count has been as low as one million per cubic millimeter.
~e creases in the palms of the hands remain pale, however, wld do not take on their red color until the M.ood count approaches about two and one-half to three mill ion red blood cells per cubiC' millimeter. N'ausea, if it has been present, rarely lasts after the fourth day, and diarrhea or constipation usually is relieved.
Some patients, especially those taking whole liver, may complain of a mild diarrhea during the first week, but this soon disappears.
The feeling of heaviness in the epigastrium is lost, although some patients continue to be bothered with abdominal distention for long periods. ~he stools, which often have a very offenSive, putrefactive odor during the relapse, become more normal after a few weeks.. 'l'he tongue, which is frequently sore when the treatment is first begun, usually becomes normal. Occasionally the condition of the tongue may be greatly improved by painting the lesion with one or two percent silver ni trate solution. However, the glossitis may recur in a mild way during the remission as the ingestion of liver does not seem to be entirely specific for this symptom .. There is an actual increase in the musoular power. 'rne tingling sensation in the hands and feet may persist for months after the blood has returned to normal, but it usually becomes less prominent as time goes on. The tingling appears to be due to involvement of the peripheral capillar~es, as stasis and hyperemia. produced by a tourniquet. have no effect in relieving it. Edema of the ankles, which is frequently observed, usually disappears as the red blood count approacbes normal, but in some patients the edema may persist long into convalescence.
The latter patients are unable to hold their breath, without previous deep breathing. for fifteen seconds or longer as can '!the former group. Al though these patients show no oefini to cardiac.
changes it is possible that this factor may be of importance in this eonnection. The "hemic· cardiac murmurs slowly decrease in intensity and finally are replaced by normal heart sounds. Sexual aetivi ties, which are usually lost during the first stages of the disease, are gradually brought back to normal when the blood count reaches normal.
For the average patient, without aomplications .. onehalf pound (O.2kg.l of beef, calf's or other 1 iv-er should be prescribed daily. They may be taken raw and finely ground, or it may be eooked in any way tha t makes it pal a tabl e and eas 11y d igested.. As the active principle is soluble in water, any liquid used in bOiling should be added to the liver when it is eaten. 'l'be liver is more easily digested if it is finely ground. ~en liver extraet is used the contents of from three to six vials, or the equivalent of one half-pound {O.2kg. I of raw liver, may be dissolved in water or a suitable liquid, and taken onee a day. Each vial contains the extraot made from 100 gm. of liver. For very siQk patients, the larger dose should be used. There is some evidence that a very large dose taken at one time is as effective as the same amount taken at intervals. 1~ere are several liver extraots available commercially, but evidence has not been produced which proves that they are all potent. An effective liver extraot should cause an appreciable rise in the n~~ber of reticulated red blood oells in from the fourth to the sixth day, in patients whose initial ~ed blood cell count, is below two and one-half million per cUbic milltmete~. The higher the initial red blood ~ell count, the less marked is the immaturity of the newly delivered red blood cells, and those showing a reticulum are but few in number in the l'e:dpheral circulation. Some prescribe dilute hydrochloric acid (2 to 4 or more cc.) in a glass of water or lemonade wi th meals.
The liver diet is effective without this, but many feel that it has a therapeutic action. The rest of the diet should be liberal and well balanced, and should include meat, eggs, greens, vegetables fresh frui ts, especially peaches, apricots and strawberries" Fat does no t appear to hinder the development of the remission but heavily fried foods, especially liver, are not desirable.
~omatose or semicomatose patients may be revived with a blood transfusion, and the liver may then be given in the form of the extract. In these very sick patients it may be necessary to resort to the use of the stomach tube.
Patients should be watched carefully to note whether there is retention of urine, as the bladder sensations may be lost with the neurologic changes in the spinal cord •. If retention is noted, it may be necessary to use the catheter. jfue patient should be urged to try ~ void every three hours. In this way the sensory part of the process is not an important factor, and control of the bladder may be regained. crontrol of the bowels is a more difficult matter, but several pa tients who had been incontinent at times clears, and the parts then exposed to air without dressings. }ben the blood count is below two million 'per cubic millimeter, especially if the patient is weak, bed rest Should be prescribed; but the patient should be allowed to get up as soon as his strength will allow it, in order to avoid the ~in irritation.
When the patient is unable to control his legs, he should be given passive and active exercises and should be encouraged to try to walk with aid. The muscles may be massaged.
coincident with the application of dry heat. flome patients are· able to walk better if they separate their legs and use a wide base.
l~ny apparently hopeless patients have regained the use of their legs under this regimen, although they remain somewhat spastic.
In patients with mild loss of joint sensation, every effort should be made to teach them to take advantage of other sensations to guide their movements. Bandages may be tied about the legs, or adhesive tape may be strapped frOlDl areas of no sensation to areas Where the senaation is nonnal. Oooasionally enough sensation may 20 be obtained when the shoe-strings are tied very tightly to aid the patient in walking more normally. The vibration sense 0 f the tibias may be regained as th.e patient improves.
The blood count usually reaches normal in from two to four months. During this time the liver diet or the taking of liver extract must be carefully followed. IVhen the red blood cell coun t is normal, the amount of liver may be reduced to one~half pound (O.2kg.} five times a week, and later, with periodic blood examinations, to three times a week. The maintenance dose of liver" extract has not been determined, but the minimum probably is around the equivalent of 300 gm. of liver three times a weak. Some patients will require more. In reducing .the amount of liver or liver extraot, it must be remembered that a spontaneous remission lasts for varying lengths of time and the blood count may be maintained not because of the small amount of ingested liver, but because of the natural duration of the induced remission. When this terminates there will be a relapse if the liver intake is too low. Several patients have shown a tendency to a form of relapse even while on an adequate liver intake.. This manifests itself by a loss of appeti te t sore tongue, and aversion for liver, and when it is discontinued, the development of anemia. It is during this periOd that liver extract will be found valuable to tide over the days when the patient oannot take I iver. There appears to be less tendency to develop an aversion to liver extraot than to liver ..
While the liver extraot appears to be speeific for per"", nioious anemia it has little or no effect on most seoondary anemias.

PERNICIOUS ANEMIA -TRANSFUSION
Prior to the institution of liver treatment, undoubtedly blood transfusion produced bet ter and more permanent results than any 0 ther the rap eu tic measure. I t is by no means a cure but it has certainly brought many a moribund patient back to 1i£e 9 and in some cases it has been responsible for the ocaurrence of a remission.. Suoh cases as do respond with a remission may require anywhere from five to fifteen transfusions before a normal blood count is approached. The utmost extension of acrtive life attainable by the use of this measure probably follows upon the restorat.ion of the blood volume to normal by several large transfusions and the maintenancre of a relatively normal blood volume by repeated small transfusions to offset the hematopoiesis. 1'he usual procredure is to transfuse every two weeks, but there are objections to this.
In pernicious anemia the hemoglobin and red blood cells are increased following a transfusion, but in from three to seven days, in mos t instancres, a drop of these elements occurs. 'l'his reduction is often greater than the previous increase, bringing the blood count to a lower level than before the transfusion.
Because of this, when the interval between the transfusions is 23.
too long, the gOOQ accomplished by a single transfusion is 10st~ The resul t is similar when a seoond transfusion is given.. Recently, a patient was seen who had reoeived six transfusions of from 500 to 800 00. every two weekS, whose red blood oells and hemoglobin were lower after the series of transfusions than before.
Permitting too long an interval to elapse between transfusions is responsible for more of the poor results in pernicious anemia than any other single factor. To overcome this, the transfusions are given every three to five days, thereby adding blood elements before there is a decided decrease. "iVi th the use of these smaller amounts of Whole blood, from 350 to 450 ca. t depending on the weight of the patient, from every three to five days, it has been possible to bring the red blood cells and hemoglobin to a normal pOint in nearly every instance. In acdition when smaller amounts are given, a donor can be used more frequently.

ARSENIC IN THE TREATMENT OF PERNICIOUS ANEMIA
It has long been felt that arsenic has some value in the treatment of pernicious anemia. Usually it is employed as in the treatment of secondary anemia, but recently the arsenical shook treatment, the administration by mouth of subcutaneous injeotion of a few large doses of arsenic, has apparently, been followed by 1"" ..

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striltingly good results in a few instanaes. One has always to be wary in a condition so prone to wax and wane as in this disease. Most practitioners use the drug in the belief that it is a stimulant to blood building tissues, but Barker has very well asked~ "is this tissue not overstimulated at all times in Pernicious Anemia"" He suggests that arsenic because of its toxici ty may produce its good effects by inhibition of phagocytic aativity wi thin the reticulo endothelial system ..

IRON IN THE TREATMENT OF PERNICIOUS ANEMIA
It has not been shown that Iron has any value whatever in the treatment 0 f Pernicious Anemia.