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E. Meulengracht, Copenhagen. Pernicious anemia and liver treatment. Ladies and Gentlemen! I ask your permission, before I read my paper, to assure you that I speek on the subject of Pernicious Anemia and Liver Treatmeni only at the request of our high pre- sident, who - about 1/2 year ago - made me promise him to do so. Otherwise I should not have cared to discuss this question, because I have nothing particular on my mind in this respect. For it is a matter of fact, as you know, that the American reports on this subject, published during 1926-28, have given everything that may be said about this matter for the present. These works from MINOT and his collaborators, MURPHY, COHN, ET AL. originated from master-hands. What has later been published by other investigators has merely been the confirmations and some weak reflections of the others’ pioneering works. Otherwise, in my eyes, there has been presented but two new facts: a demonstration - particularly by Finnish investigators - of the liver treatment being effective in Botriocephalus anemia, too; and the demonstra- tion by CASTLE, that the therapeutically active substance may be produced artificially, outside the organism, by letting muscle meat be digested by normal human stomach juice, which is with- drawn after administration of histamin. When this digestive product has been given -trough stomach tube -to patients with pernicious anemia, it has proved to be highly effective. These, still unpublish- ed, investigations by CASTLE are bound to turn out to be a mile- stone on the road to the final elucidation of the problem. For the present they are most suggestive of the previously advanced theory: that the active principle is one or more albuminous split products. On request, however, I shall briefly mention some of my own experiences and experiments. I have treated altogether 54 patients

Pernicious anemia and liver treatment

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E. Meulengracht, Copenhagen.

Pernicious anemia and liver treatment.

Ladies and Gentlemen! I ask your permission, before I read my paper, to assure you that I speek on the subject of Pernicious Anemia and Liver Treatmeni only a t the request of our high pre- sident, who - about 1/2 year ago - made me promise him to do so. Otherwise I should not have cared to discuss this question, because I have nothing particular on my mind in this respect. For it is a matter of fact, as you know, that the American reports on this subject, published during 1926-28, have given everything that may be said about this matter for the present. These works from MINOT and his collaborators, MURPHY, COHN, ET AL. originated from master-hands. What has later been published by other investigators has merely been the confirmations and some weak reflections of the others’ pioneering works. Otherwise, in my eyes, there has been presented but two new facts: a demonstration - particularly by Finnish investigators - of the liver treatment being effective in Botriocephalus anemia, too; and the demonstra- tion by CASTLE, that the therapeutically active substance may be produced artificially, outside the organism, by letting muscle meat be digested by normal human stomach juice, which is with- drawn after administration of histamin. When this digestive product has been given -trough stomach tube -to patients with pernicious anemia, it has proved to be highly effective. These, still unpublish- ed, investigations by CASTLE are bound to turn out to be a mile- stone on the road to the final elucidation of the problem. For the present they are most suggestive of the previously advanced theory: that the active principle is one or more albuminous split products.

On request, however, I shall briefly mention some of my own experiences and experiments. I have treated altogether 54 patients

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suffering from pernicious anemis, with liver. 50 out of the 54 patients showed the typical rise and relative cure. Out of the 50 ,cured$, 2 have later died from malignant tumors, 1 from influenza and pericarditis, and 1 died from a disease with fever and of a nature which we did not succeed in establishing. This last patient was treated with raw liver, and the treatment had already begun to show a very good effect, when death occurred -a few weeks after the institution of the treatment. But the other 4 deaths should and could have been prevented. They were patients who were admitted with deep anemia and with fever, and who died within a few days, before the liver treatment had a chance to exert its effect, and a t times when i t was rather difficult for us t o obtain sufficient blood for transfusions. One wonders that, in our days, a patient whith pernicious anemia may get down to such a low level without his condition being recognised, or without the patient being admitted. But the reason hereof is probably connected with the fact, that an exacerbation of the disease under certain circumstances may proceed so rapidly that i t steals up upon patient and physician alike. In such cases one ought to do his utmost to carry the patient through by means of blood transfusion.

The level obtained in the patients I have treated is not as high as that reported by American authors. The average level obtained in my patients is about 80 yo Hb. and 4 millions of erythrocytes. But this hinges on the practical and - especially - economical difficulties of keeping a liberal maintainance dosis. Now, as the Danish government has diminished the economical difficulties, i t is my view - founded on experiences - that one one should not be content with the apparently perfect condition of the patient, but that one also should aim a t perfect restitution as to laboratory findings. One, therefore, should not fall for the temptation of the smaller dose, but aim a t the doses of 200-300 grams, which have proved themselves to be dependable and most capable of protect- ing the patient against eventuel later and fatal nerve condition. As you know, no case of overdosage has ever been observed. In Denmark we now use mixed treatment or extract treatment alone; and for practical reasons - right or wrong - we are more and more going over to the extract treatment.

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I have never seen any effect whatever from liver therapy in any other form of anemia than in the real pernicious anemia. To me the liver treatment is a perfectly specific therapy; it is an wither - or,; there is no gradual transitions, neither in the reticulocyte reaction, nor in the cure. While visiting MINOT in Boston, one of his collegues said jokingly to me that ,when. MINOT cannot cure a case of per- nicious anemia, then he declares, that it, is not pernicious ane- mia,. But 1 think, that this expression by MINOT just hits the right nail on the head. In a separate folder I have gathered the case-histories of about 20 patients with severe anemia, which cases I, in the first instance, might have felt inclined to make the diagnosis ,Atypical Pernicious Anemia,, or in which cases, a t any rate, I had not been sufficiently confident to exclude this diagnosis. They did not respond to liver treatment, their further course revealed - either during life or on autopsy - some quite different diagnoses. I shall mention some of these diagnoses, which now are actual to all of us: Occult large hypernephroma, Sepsis lenta, Aleukaemic Leucosis (in which the final diagnosis can first be made on microscopical examination of the bone marrow and finding this filled with leucotic tissue), Diffuse Carcinomatosis of Bones originating from a small primary cancer of the breast, or the stomach, or thyroid, or - particularly -from the prostate. And, finally the group of aplastic anemias of unknown etiology, progressing more slowly or more acutely, and, in the latter case, frequently associated with high fever. To me it looks as if this last group is increasing in frequency, a fact which is the consequence of the earlier classification of these lesions as pernicious anemias. When one is familiar with the aspects of these lesions, they differ quite markedly from the pernicious anemias: the aplastic anemias of unkown etiology lack the tongue conditions and the achylia, the blood-pictures are not identical, and the post-mortem exa- mination shows the aplastic bone-marrow. It is my experience that an natypicaln pernicious anemia, as a rule, fails to respond t o liver treatment, and that i t subsequently turnes out t o be some other lesion that was masked under the blood-picture. And for the same reasons I will still feel no doubt but that the cases which formerly were described as ,atypical, pernicious anemias with persisting hydrochloric acid secretion - as, for instance, some

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frequently cited cases of FABER -really were no pernicious anemias; judging from the case-histories I would take them to be cases of aleukaemic leucosis, or of aplastic anemia.

When I state that I never have seen any effect from liver treatment in any form of anemia other than pernious anemia, I do excempt from this rule the charactheristic disease which - after FABER - is called simple achylia-anemia, quite a typical syndrome of achylia and a severe, but hypochromic anemia, most frequent in women of 40-50 years, and characterized, IN AL., by its marked response to large doses of iron. 5 typical cases of this kind gave quite a negative response to liver treatment, that is, there did not appear any reticulocyte reaction and no rise of Hb%, whereas subsequent treatment with large doses of iron gave a weak reti- culocyte reaction and a rapid rise of Hb%. The simple achylia- anemia proves thus to be a lesion of quite a different nature than the pernicious anemia.

I shall present a couple of observations from the liver treat- ment. There is a most violent gain in weight during the period of liver treatment. I have seen the patients gain more than 30 kg. in that period. I have found this gain in weight to be equally pronounced, whether I have been giving liver in fofo, or as liver extract. I have found weight increase to, be specific of pernicious anemia, as i t was not found in patients with other lesions, nor in mon-thriving)) persons on whom this treatment had been tried. In pernicious anemia this gain in weight must be an indication of the healing process.

MINOT & MURPHY mention their finding of a marked eosinophilia in a number of their liver-treated patients. I, too, have seen the same phenomenon in several of our patients - a continuous and pronounced eosinophilia, rising in some instances to 70-80 %. I have investigated the phenomenon in quite a long series of pa- tients, and I have arrived a t the following preliminary results: Marked eosinophilia, 20-60 yo, appears within 4-5 weeks on administration of ca. 250 grams of raw liver (calf) daily, and this apparently keeps on as long as the treatment is kept up. This eosinophilia presents itself to the same degree in patients with pernicious anemia as in control individuals with other diseases. The reaction does not occur, or i t is very questionable when the XIV. N o d . Konp-. - 5

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liver is roasted but slightly before its ingestion. The reaction is not observed on treatment with liver extract. So the eosinophilia is not an indication of the process of recovery in pernicious ane- mia; it is the reaction to the ingestion of large amounts of raw liver. What other factors it may depend on, that I do not know. I have paid attention to several possibilities, but I have not so far got any result.

For economical reasons - when the price of liver went up - I addressed myself to the pharmaceutical company Medicinalco Lid., (Medix), Copenhagen, I have chiefly been using the liver extract prepared by this house, and I asked i t t o assist me in looking for and eventually finding some other and cheaper raw products. Although our experiments gave but negative results, they are still of some theoretical interest. First we made some experiments with kidneys (cow), which are claimed in American reports to contain the active substance. A kidney extract was prepared along the principal lines in the preparation of the liver extract, and i t presented itself as a nice, brown powder. But i t had a strong odor of urine, that was particularly conspicuous when the extract was dissolved in water, and i t could not be removed. So the kidney extract was unfit for use. We then made some experiments with muscles, on which there were some indefinite reports. For economical reasons we used heart muscle (cow), and by sticking to the main principles of the preparation of liver extract we obtained a brown powder, which, for one thing, contained a good deal of carbohydrates from the muscle glycogen. This extract was given in 4 cases of pernicious anemia, in doses corresponding to 300- 600 grams of muscle. The results of this treatment were perfectly negative in 3 cases; 1 case showed protracted reticulocyte reaction and protracted increase of Hb% and Erythroc. I t is most likely that this apparent improvement represents a spontaneous remis- sion in this patient, who had never before been treated. Finally, a paper which EHRSTROM published 2 years ago, and in which he assumed the presence of an essential hemopoietic hormon in the intestinal mucosa, was in part the reason why we made an extract of the mucosa of the small intestine (cow) and tried it in 2 cases of pernicious anemia. The extract was prepared after the same principles as the preceding extracts. I t was a brown

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powder, which was dissolved and given to the 2 patients in amounts corresponding to 2-3 meters of intestinal mucosa daily. The result was altogether negative.

/Name Date M. J. "/, 28

a71, ' I 1 0 '

I10 0

I10 0

3111 a Ill ' 111 I)

1s

23

14

PS

TABLE 1. Diagn. Rheumatic polyarthritis.

Poly. Lymf. Eo. Mono. T h e r a p y 70 2 1 3 6 18//p 28 Raw liver 250 grams 66 21 5 8 69 27 3 1 35 19 43 3 19 10 67 3 30 29 37 4 44 20 35 1 17 26 54 3

Rheumatic polyarthritis. Eosinophilia after ingestion of raw liver.

Name Date F. M. H. "I,, 27

"1 28 '!* '

sll* * I 4 '

a818 ' 118 '

@/a 29

18

at

TABLE 2.

Diagn. Pern. anemia. Poly. Lymf. Eo. Mono. Mast. T h e r a p y

57 41 1 1 *'I8 27: Raw liver increasing from 29 18 43 4 5 20grams to 200 grams

9 13 74 4 27 27 44 2 40 19 38 3 "I,, 28: Liverextract equiv. 300 57 10 24 10 grams 56 25 17 2 28: Liverextr. equiv. 100 27 6 4 grams + fried liver 125

grams Pernicious anemia. Marked eosinophilia on treatment with raw liver.

TABLE 3.

Diagn. Pern a n d a .

E. F. L. go/s 28 31 66 2 1 lola 28: Liverextr. equiv. 600 D 63 32 5 grams

59 35 6 D 50 46 1 3

so,!lo r) 55 35 2 8 grams 16 It, D 38 50 1 11

Name Date Poly. Lymf. Eo. Mono. Mast. T h e r a p y

ll0: Liverextr. equiv. 300 I0 "I,

29 46 47 7 Liverextr. equiv. 200

No eosinophilia on treatment with liver extract. grams.

Pernicious anemia.

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Fig. 1. Simple achylia-anemia. No effect from liver extract. Pronounced effect from large doses of iron.

lOOQ

80 6

b0 b

406

20 2

9

r

5

3

I

Hb yo .....-....._. R. cells - Retic.

Fig. 2. Pernicious anemia. No effect from heart extract. Marked effect from liver extract.

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Fig. 3. Pernicious anemia. No effect from extract of intestinal mucosa. Marked effect from liver extract.