Actn Medica Scnndinwicn. Vol. CXLI, fasc. IV, 1952.

From Medical Department C, Copenhagen County Hospital, Hellerup, Denmark.

The Occurrence of Pernicious Aneinin and Polycythemin in the Same Patient.

BY

ARNE P. SKOUBY.

(Submitted for publication May 24, 1951.)

When raw liver anemia a transient

or liver extract is administered t o patients with pernicious abnormal increase of red blood cells often occurs (Minot and

Murphy 1926). An erythrocytosis of long duration has been described in few cases only.

The present paper describes a case of pernicious anemia in a patient, who during treatment with vitamin B,, (Merck) developed a polycythemia-like picture. Based on this and the few similar cases previously described the mechanism of the dis- order is discussed.

Case: J. 979/50. Woman born 2818 1879. No blood diseases in the family. A t the age of 40, jaundice of long duration but with-

out later complications. The year before admission to hospital she lost appetite and weight, was constipated, developed weakness of the legs and tingling in the feet and toes, dyspnoea and pains in the chest.

Examination revealed a smooth tongue, reduced power of the legs, and hypesthesia of the finger tips to touch. No enlargement of the liver, spleen or lymph glands was dem- onstrated. Hemoglobin 60 yo, R. B. C. 1 . 8 mill./mm3, Colour index 1.6. W. B. C. 2,200/mm3. The peripheral blood showed ))a shift to the left)) and eosinophilia (table 1). The bone marrow showed megaloblastic degeneration (table 2 ) . Complete achylia after histamine stimulation was demonstrated. X-ray examination of the colon showed colitis. Sedimentation rate 25 mm/hour. Blood pressure 120/70 mm Hg. Wassermann reaction negative. Stools, proctoscopy and E. C. G. showed nothing abnormal.

She was treated with vitamin B,, (15 pg daily for 12 days). The number of reticulocytes and erythrocytes, the H b yo and colour index found a t examina- tions during and after treatment are given in the figure. After one month the Hbyo and colour index were normal and she felt well. During subsequent treat- ment with twice-monthly and later once-monthly injections of 15 pg the H b % and number of erythrocytes increased further bu t with increasing colour index.

OCCURRENCE OF I’ERSICLOUY AKEMIA A K D POLTCPTHEMIA. 245

Table 1.

I Sumber of leucocytes and differential count 1 ~ -

A t l b t After At 2nd ~ admission treatment ad m 1 s s i o n

~~ ~

Date . . . . . . . . . . . . . . . . . . . . . . . . 21 4 50 8 6 30 i 8;ll 50

W. B. C. . . . . 2,200

! - -~ -

....................... 4,300 I 4,700

.................... 0 3 4 I ~ -~ ~ -.

................ 5 1 3 8 ~. 1 -~ - ~~

~ 21 7 1 ~ .I0

..... ...................... 24 1 26 Lymphocytes I 1

I 33 I 5G 51

J 1 ........................ 0 I I

~~ ~~~ .- ~-

Table 3.

i ?;umber of cells of the wed system)) found per 400 cells of the ))white system)). Sternal marrow

Date . I 2G,4 50 1 11 11 50 ............................ ~~ ___

Proerythroblasts ...................... . I 0 5 (1 In mitosis) ~- 1 -~~ _ _ ~ -

1 Erj throblast\, basophil . . . . . . . . . . . . . . . . . 2 I 8 I - 1 Erythroblasts, eosinophil . . . . . . . . . . . . . . . 0 i 13

~~ .. ~

I Promegaloblasts ....................... 25 4 1 ~- ~

I &Icgalohlasts, basophil . . . . . . . . . . . . . . . . . . 81 40 ( 3 in mitosis) - . 1 Megaloblasts, eosinophil . . . . . . . . . . . . . . . . 31 .XI

....... -. ._ .-

As the patient again felt weak with a sensation of coldness in the legs and hands, palpitations and dyspnoea, the treatment was stopped. A month later the Hb% was 150 and the erythrocyte count was 5.8 mill./mm3. Her mucous membranes were reddish-blue. 2 months later she was again admitted to the department. Hb% was then 130, R. B. C. 4.64 mill./mm3 and the colour index 1.88. The bone- marrow showed megaloblastic degeneration (table 2 ) In addition numerous eosinophil myelocytes and leucocytes were found, together w-ith considerable numbers of megacaryocytes lying in groups. No changes in the reticulum cells

1 The bone-marrow was examined by A. Seeborg Ohlsen. 18 -5128.19. Actrc m c d . scnndinrtn. V a l . CXLI.

246 ARNE P. PBOUUY.

I 1 '! ?!y,\ C-, - -srS. . i ,.I ,

78. L 21 3 7 9 7 3 5 7

AprJ% June &9 S c N h Novdr Drcdr lun. fi& fiorch

Number of reticulocytes and erythrocytes, Hb % and Colour index before, during and after treatment. The amounts of vitamine B,, and liver extract (Hepsol fortior) are given in the figure. X Number of reticulocytes ( o / o o ) . 0 R. B. C. in mill./mm3. 0 Hb%. + Colour index. Abscissa: time in months. Ordinate: See figure.

were demonstrated. Serum iron 0.302 mg%, blood platelets 291,000, sedimenta- tion rate 1 mm/hour, coagulation time 63 seconds, bleeding time 5 minutes. Test meal again showed complete achylia. X-ray examination of the thorax, examina- tion of the eye, red cell fragility test, serum calcium and serum protein showed no abnormality.

During treatment with small amounts of vitamin B,, the colour index returned to normal, but Hbyo and R. B. C. rose. As the condition might be due to the un- balanced action of B,, a concentrated liver extract fortified with B,, was used for the subsequent injections. Examination on 713 1951 however showed the fol- lowing figures: Hb% 129, R. B. C. 6.5 mill. per mm3, colour index 0.9.

Comment. A few earlier reports are given on pernicious anemia having developed an ery-

thremia during or after treatment with raw liver. In one case a long-standing car- diac insufficiency was treated with digitalis and diuretics during the period of one month in which the erythrocytosis was demonstrated (Hogler 1930). I n an- other case a concurrent untreated diabetes may have caused a dehydration (Fer- rary 1942). A hemoconcentration may therefore be the cause of the large num- ber of red corpuscles found in these two cases. However 3 other cases described by gmile-Weil and Boic (1932) and Birnie (1936) can only be explained by the development of a true erythremia during treatment. I n 2 cases the erythremia persisted a t examination six months after the cessation of treatment @mile-Weil and Boic). In the third, in which phenylhydrazine was given after the cessation of treatment with liver, the blood picture changed to that of pernicious anemia and was again corrected by the liver extract Campolon (Bayer). Similar reports without documentation are given by Pal (1927) and Bauer (1931).

I n the present case the leucocytes showed ))a shift to the left)) and eosinophilia as in polycythemia (table 1) . 3 months after treatment with vitamin B,, the bone-

OCCURRENCE OF PERNICIOUS ANEMIA AND POLTCYTHEMIA. 2 4 i

marrow showed niegaloblastic degeneration with accumulation of megacaryo- cytes. Simultaneously the Hb% was increased and the sedimentation rate was 1 mm/hour. This indicates a simultaneous occurrence of a predisposition for poly- cythemia and pernicious anemia. The same seemed to be the case in Birnie’s pa- tient, who had an enlarged spleen a t the first examination.

Development of macrocytic anemias in the later stages of polycythemia has been reported, especially following treatment with substances injuring the bone- marrow (For references: Harrop 1928), or when leukemia developed (Minot and Buchman 1923). No return to normal or supernormal values for Hb% or num- ber of erythrocytes has been reported following treatment of such cases. As the complaints of the patient described in the present paper did not appear before an anemia had developed and she later felt ill, when the polycythemia was es- tablished, i t seems reasonable to suppose that the polycythemia did not exist in a corresponding degree before the occurrence of the anemia. It must therefore be assumed that the anemia was not secondary to an erythremia of long duration.

The development of the polycythemia is hardly due to the treatment. Only a few cases have been reported in spite of the treatment with liver or concentrated extracts of thousands of patients with Addisonian anemia. Furthermore raw liver, liver extracts and choline have been used in the therapy of polycythemia with the intention of decreasing the Hb% and number of erythrocytes; in no instance was an increase of the number of red corpuscles found (Major 1938, Meyer and Thewlis 1940). My patient, treated with vitamin BIZ, received cobalt, but the amounts were negligible compared with the doses necessary to produce polycyth- emia in animals (For references: Davis e t al. 1945). It is therefore reasonable to assume that the treatment did not produce the polycythemia here discussed, but exposed a latent polycythemia masked by the anemia and perhaps stimulated by the long-standing hypoxemia in the tissues.

It has been suggested that pernicious anemia and polycythemia were due to deficiency or excess of a common regulating factor (Adamson and Storey 1940, Stoger 1941). It has not been possible however to produce a polycythemia in an- imals by administration of large doses of liver extracts (Gingold 1939). Blood from a patient with polycythemia transfused into a patient with pernicious anemia did not affect the erythropoiesis, while liver extract evoked a remission (Franke 1943). These investigations and the alternating or simultaneous occurrence of polycythemia and megaloblastic degeneration of the bone-marrow in the same patient indicate, that the two diseases sometimes if not always are due to dis- turbances in two different regulating systems.

Siinimo ry. From a case of the author’s and the few cases previously published it is assumed

that the occurrence of polycythemia in patients treated for pernicious anemia is due to a chance association of a predisposition to polycythemia and pernicious anemia i. e. the two diseases are sometimes if not always due to disturbances in two different regulating systems.

%48 ARNE P. SKOUBT.

References. Adamson, W. B. and J. E. Storey. Texas Med. J. 1940, 36, 26. - Bauer: Wien.

klin. Wschr. 1931, 44, 656. - Birnie, G. A.: Med. J. Australia 1936, 23: 11, 498. - Davis, J. E., A. W. McCullough and R. H. Rigdon: J. Lab. & Clin. Med. 1945, 30, 327. - Emile-WeiI, P. and Boic: Sang 1932, 6, 685. - Ferrary, P. B.: J. Med. SOC. N. J. 1942, 39, 19. - Franke, H.: Klin. Wschr. 1943, 22, 434. - Gingold, N.: Sang 1939, 13, 312. - Harrop, G. A.: Medicine, Baltimore 1928, 7, 291. - Hogler, F.: Klin. Wschr. 1930, 9, 2054. - Major, R. H.: J. Lab. & Clin. Med. 1938, 24, 65. - Meyer, 0. 0. and E. W. Thewlis: J. Lab. & Clin. Med. 1941,26,1137. - Minot, G. R. and T. E. Buckman: Am. J. Med. Sci. 1923, 166, 469. - Minot, G. R. and W. P. Murphy: J. A. M. A. 1926, 87, 470. - Pal, J.: Lancet 1927, 2, 1315. - Stoger, R.: Klin. Wschr. 1943, 22, 342.