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Acta Medica Scandinavica. Vol. 176, fasc. 6, 1964 The Department of Radiotherapy (Head: M. Lindgren, M. D.), the Department of Medicine (Head: N. Soderstrom, M. D.), and the Department of Clinical Chemistry (Head: C. G. Holmberg, M. D.), Lund, Sweden Blood Histamine and Basophil Leukocytes in Polycythemia BY LARS BRANDT, EBBE CEDERQUIST, HANS RORSMAN and NILS TRYDING In polycythemia the number of baso- philic leukocytes (1, 3, 6, 9, 14) and the histamine content (4,5) of the circulating blood are increased. Though this has long been known, it would appear that these changes have never been system- atically studied for their value as criteria in the classification of polycythemia. This paper is concerned with basophil leukocytes and histamine in the blood of untreated and 32P-treated cases of polycythemia Vera, and secondary poly- cythemia due to hypoxia. Special atten- tion is paid to 3 cases of polycythemia in which leukemia developed. Material The material consisted of64 patients (33 men, 31 women) with polycythemia treated at the department of radiotherapy, Lund, and followed up for one year. Only patients with a hematocrit of more than 54 yo were accepted (1 1). Examinations of the patients included blood gas analysis and determina- tion of the plasma volume. In 4 of the Suhniitted for publication May 11, 1964. patients the PO, was below 90 mm Hg, and in these polycythemia was classified as secondary. Fifteen of the patients with polycythemia Vera had not received any treatment before the time of the first examination. Forty- three had been treated previously or were treated during the time of the investigation with 32P and then orally in a dose of about 0.1 mCi/kg body weight. Most of these patients were followed up at 3-month intervals. A 50-year-old woman (E. P. table 11) was treated with repeated phle- botomy. In the course of about 6 months all together 2,500 ml of blood was tapped. One patient (0. E.) was examined 1 month after phlebotomy. Acute leukemia developed in 2 of the patients. One of them, a 76-year-old woman, with 8 years’ history of polycythemia Vera had received all together 50 mCi 32P, which was the largest total dose given in the present material. Two years after the end of treat- ment pancytopenia and acute leukemia developed. The number of basophils and the blood histamine level were then normal. The patient died two months later with terminal leukocytosis and basophilia. The findings at necropsy confirmed the diagnosis of acute leukemia. The other patient was a 745

Blood Histamine and Basophil Leukocytes in Polycythemia

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Page 1: Blood Histamine and Basophil Leukocytes in Polycythemia

Acta Medica Scandinavica. Vol. 176, fasc. 6, 1964

The Department of Radiotherapy (Head: M. Lindgren, M. D.), the Department of Medicine (Head: N. Soderstrom, M. D.), and the Department of Clinical Chemistry

(Head: C. G. Holmberg, M. D.), Lund, Sweden

Blood Histamine and Basophil Leukocytes in Polycythemia

BY

LARS BRANDT, EBBE CEDERQUIST, HANS RORSMAN and NILS TRYDING

In polycythemia the number of baso- philic leukocytes (1, 3, 6, 9, 14) and the histamine content (4,5) of the circulating blood are increased. Though this has long been known, it would appear that these changes have never been system- atically studied for their value as criteria in the classification of polycythemia. This paper is concerned with basophil leukocytes and histamine in the blood of untreated and 32P-treated cases of polycythemia Vera, and secondary poly- cythemia due to hypoxia. Special atten- tion is paid to 3 cases of polycythemia in which leukemia developed.

Material The material consisted of64 patients (33 men, 31 women) with polycythemia treated at the department of radiotherapy, Lund, and followed up for one year. Only patients with a hematocrit of more than 54 yo were accepted ( 1 1 ) . Examinations of the patients included blood gas analysis and determina- tion of the plasma volume. In 4 of the Suhniitted for publication May 11, 1964.

patients the PO, was below 90 mm Hg, and in these polycythemia was classified as secondary.

Fifteen of the patients with polycythemia Vera had not received any treatment before the time of the first examination. Forty- three had been treated previously or were treated during the time of the investigation with 32P and then orally in a dose of about 0.1 mCi/kg body weight. Most of these patients were followed up at 3-month intervals. A 50-year-old woman (E. P. table 11) was treated with repeated phle- botomy. In the course of about 6 months all together 2,500 ml of blood was tapped. One patient (0. E.) was examined 1 month after phlebotomy.

Acute leukemia developed in 2 of the patients. One of them, a 76-year-old woman, with 8 years’ history of polycythemia Vera had received all together 50 mCi 32P, which was the largest total dose given in the present material. Two years after the end of treat- ment pancytopenia and acute leukemia developed. The number of basophils and the blood histamine level were then normal. The patient died two months later with terminal leukocytosis and basophilia. The findings at necropsy confirmed the diagnosis of acute leukemia. The other patient was a

745

Page 2: Blood Histamine and Basophil Leukocytes in Polycythemia

746 LARS BRANDT ET AL.

TABLE I ~

Patients with polyeythemia Vera

Treated with Normals Untreated Secondary

No. of cases 90 15 43 4

Basophil Mean 44 'I24 110 leukocytes/nini3 Range 8-122 55-225 10--1,072 ~

Histamine Mean 7.5 19.0 14.1 6.2 pg/ I00 nil blood Range 2.5- 11.8 10.3-28.2 2.9-92.5 2.7-9.6

-

Mean value of 11 untreated eases.

TABLE 11. Cases of untreated polycythemia Vera

Basophil Histamine WBC leukocytes pg/lOO ml

Cases (per mm3) (per mm3) blood

A. 0. H. T. H. P. E. N. 1,. N. I. N. G. N. H. J. hl. M. E. E. L. I,. A. J. s. .J. L. P. s. s. s. S.' E. P. E. P.' E. P.3 0. E.'

5,000 8,800 7,100 4,700 7,300 19,700 7,200 5,300 5,000 9,600 7,700 7,500 4,800 5,300 11,700 10,800 7,500 9,100 7,500 7,200

105 28.2 150 27.5 114 24.2 94 16.4 73 15.4 158 13.5 122 12.8 95 15.3 65 10.3 - 22.3 - 13.5 105 25.8 82 21.6 -. 15.9 225 22.5 - 24.8 - 23.5 209 32.7 - 43.8 72 18.5

~

I 7 months after first determination. * 7 months after first determination (after phle-

botomy). 3 I0 months after first determination.

I month after phlebotomy.

62-year-old man with 19 years' history of polycythemia. H e received all together 39 mCi SZP. During the last 6 months the blood values fell markedly. The number of myeloblasts in the blood was 20 $;, and sternal puncture showed myeloblastic prolif- eration. T h e blood histamine and the number of basophilic leukocytes were normal a t the last follow-up examination.

Chronic myeloid leukemia was suspected in one case. The patient was a 54-year-old woman. Polycythemia had been diagnosed 8 years previously. She received all together 34 mCi Two years before the present examination the number of leukocytes rose to 1 lO,OOO/mm3. Sternal puncture suggested the diagnosis of chronic myeloid leukemia, and the patient was treated for some months with a small dose of Myleranm. The number of white blood cells fell to 15,000/mm3 during treatment. T h e number persisted at this level for some months after withdrawal of the drug and then began to rise again, and a t last follow-up it was 70,000/mm3. Dif- ferential count: 3 yo metamyelocytes, 5 OJ;,

myelocytes and 1 yo promyelocytes. The serum vitamin B,, was increased (1,800 pg/ml). T h e alkaline phosphatase score was high. Blood histamine: 93 ,ug/lOO ml. Analysis of the phagocytic activity of the leukocytes by the method of Brandt (2) showed a distribution of the type seen in chronic myeloid leukemia.

Page 3: Blood Histamine and Basophil Leukocytes in Polycythemia

POLYCYTHEMIA 747

TABLE 111. Cases of polycythemia Vera treated with *'P

Time after single oral Basophil Histamine dose of 3pP Hb WBC leukocytes pg/lOO ml

Cases (months) (g/100 ml) (per mm*) (per mm*) blood

H. P. 0 22.9 7,100 114 24.2 3 18.6 5,400 38 7.5

7.8 6 12.9 5,700 -

A. 0. 0 19.1 5,000 105 28.2 3 16.3 5,000 85 16.3

M. M. 0 19.1 5,000 65 10.3 3 12.0 5,000 55 4.2

3 14.5 9,100 191 9.0

E. s. 0 17.5 18,800 225 33.0 3 1 1 . 7 6,100 37 5.6 6 13.0 9,800 59 11.8

U. H. 0 18.7 8,600 353 56.3

9 15.0 11,200 - 20.0

A. I.. 0 17.3 5,200 57 8.3 3 12.7 3.200 10 5.1 6 11.4 3,400 14 3.8

Methods

The blood histamine was determined with a fluorometric method described by Shore et al. (15).By recrystalization of orthophthal- dialdehydes in heptane low blank values were obtained. Blood samples were collected in tubes with Versene and diaminoguanidine. An Aminco-Bowman spectrophoto-fluoro- meter was used for the measurements. The mean histamine content per 100 ml of blood from 90 registered blood donors was found to be 7.5 p g (range 2.5-1 1.8).

The number of basophil leukocytes in the blood was determined with an indirect method (12) using blood smears stained according to Undritz ( 17). As a rule 1,000 cells were counted.

Resul ts

The concentration of histamine and the numbers of basophil leukocytes found

are summarized in table I. The cases of polycythemia Vera not treated with radioactive phosphorus are presented in table 11. In 14 of the cases the blood histamine and the number of basophil leukocytes were determined simultane- ously. In 3 patients basophils were not counted.

In one patient (E. P.) the blood histamine at the first examination was found to be clearly increased, 23.5 pg/ 100 ml. After repeated phlebotomy the histamine content increased and at follow-up 7 months after the first examination the number of basophil leukocytes was also increased. At the following examination 3 months later the values were still higher, but the hemoglobin level was no longer elevated,

Page 4: Blood Histamine and Basophil Leukocytes in Polycythemia

748 LARS BRANDT ET AL.

50’

LO.

lo’

2Q

10.

Histamine )ref IQOml

blood

6ol

. . . .

. . j.: : .

,:,7. ’ . . I . .

.6.‘ ... . i’, >.I . . .... .

Fig. I . Correlation between blood histamine and basophil leukocytes in cases of polycythemia Vera.

and the serum iron was decreased. In another patient (0. E.) with normal hemoglobin level 1 month after phle- botomy the blood histamine was in- creased.

Table 111 gives values for the patients treated orally with a single dose of arP. Examination 3 months later invariably showed the number of basophil leuko- cytes and the histamine content of the blood as well as the hemoglobin had decreased. In a patient followed for 9 months after the dose of 32P the histamine had increased already after 6 months and still more after 9 months. In two patients followed for 6 months the histamine had not significantly changed after the initial decrease.

The remaining patients treated with nzP (table I) did not receive any further dose of 32P during the period covered by the present investigation. As expected, the values found in these patients differed, the blood histamine and the number of basophil leukocytes varied with the phase of the disease and the interval after the last treatment with 32P.

Fig. 1 shows the correlation between the blood histamine content and the number of basophil leukocytes per mm3 blood in patients with polycythemia Vera. The extremely high value, 93 / / g histamine/ 100 ml blood corresponding to 1072 basophils/mm3, is not included in the figure. Apart from this, the figure includes all histamine-basophil-determi- nations made in the untreated and treated cases of polycythemia Vera. Most of the patients are represented twice or more in the figure. The correlation coefficient between the number of hasophil leuko- cytes and the blood histamine in the entire series of patients with polycythemia Vera was 0.91.

Discussion

I t is clear from table I1 that the histamine content of the blood was abnormally high in 16 of 17 cases of polycythemia Vera not treated with 32P. In most of these patients the histamine was clearly increased despite a normal total number of leukocytes in the blood. Valentine et al. (18) found that cases of untreated polycythemia Vera with “no or minimal leukocyte abnormalities have shown no or slight deviation from normal”. In none of our patients with secondary polycythemia was the blood histamine increased. The findings suggest that measurement of the blood histamine might be useful for distinguishing un- treated cases of polycythemia Vera from secondary polycythemia.

As expected (4, 5 ) a close correlation was found between the number of basophil leukocytes and the blood his- tamine content. In our material the

Page 5: Blood Histamine and Basophil Leukocytes in Polycythemia

POLYCYTHEMIA 749

correlation coefficient was 0.9 1. The mean error of the basophil leukocyte count by the indirect method used is large when the number of basophils is low. Here determination of the blood histamine content gives more exact information.

It is established that polycythemia Vera can develop in leukemia (10, 13). The frequency of leukemia is higher among patients treated with 32P (8, 13, 16). But treatment with radioactive phos- phorus prolongs survival (7, 19) and may thereby increase the risk of leukemia. The leukemia in :j2P-treated patients is usually of the acute type (16) and this was observed in 2 of our cases. The blood histamine content was normal in these patients at the time of diagnosis of leukemia. In the first case terminal leukocytosis and basophilia occurred, which is remarkable in acute leukemia. Unfortunately the hlood histamine was not determined in this stage of the disease. This case of polycythemia Vera with supervening leukemia suggests that the acute leukemia in patients with polycythemia differs from ordinary acute leukemia.

In one of our cases incipient chronic myeloid leukemia was suspected. The number of leukocytes was increased to 1 10,000/mm3, but the differential count revealed strikingly few immature forms. The woman had had severe leukocytosis with a blood histamine content up to 93 pg/lOO ml. The blood histamine is, on the average, much higher in un- treated chronic myeloid leukemia. The increased serum vitamin BIZ and the phagocytic activity, as judged by the method of Brandt, might argue for

chronic myeloid leukemia. The in- creased alkaline phosphatase score, how- ever, argued against leukemia. Valentine et al. (18) stressed that the alkaline phosphatase content of the leukocytes and the glycogen content remain in- creased in polycythemia, even when the blood picture is suggestive of chronic myeloid leukemia.

Summary

Sixty-four patients with polycythemia were followed with determination of the blood histamine. The blood histamine content was determined with a fluoro- metric method. A close correlation was found between the blood histamine content and the number of basophil leukocytes.

In 16 of 17 patients with polycythemia Vera not treated with 32P the blood histamine content was abnormally high, despite normal total leukocyte counts. 32P-treatment suppressed the blood his- tamine value. The values found in 43 patients treated with 32P varied with the interval after the last treatment and the phase of the disease. Two patients treated with phlebotomy showed there- after normal hemoglobin values but high blood histamine content. Four cases of secondary polycythemia showed normal blood histamine values. Deter- mination of the blood histamine may be useful in the differential diagnosis between polycythemia Vera and second- ary polycythemia.

During the period of investigation ( 1 year) acute leukemia developed in 2 of the 43 patients with polycythemia

Page 6: Blood Histamine and Basophil Leukocytes in Polycythemia

750 LARS BRANDT ET AL.

Vera treated with One of these had a remarkably high terminal basophilia. The other patient has up to now normal values of basophil leukocytes and blood histamine. A third patient had extremely high values of blood histamine and basophil leukocytes and in some respects resembled chronic myeloid leukemia.

References 1 . ALDER, A.: Uber klinisches Verhalten und

diagnostische Bedeutung der basophilen Leukocyten (Mastzellen). Folia haemat. 28: 249, 1923.

2. BRANDT, L.: Adhesion to glass and phago- cytic activity of neutrophilic leukocytes in myloproliferative diseases. To be published.

3. FRLDRICKS. R. E., & MOLONEY, W. C.: The basophilic granulocyte. Blood 14: 57 I , 1959.

4. GRAHAM, H. T., LOWRY, 0. H., WHEEL- WRIGHT, F., LENZ, M. A. & PARISH, H. H., Jr.: Distribution of histamine among leuko- cytes and platelets. Blood 10: 467, 1955.

H. H., Jr.. MARKS, A. R. & LOWRY, 0. H.: Distribution of histamine among blood elements. Fed. Proc. 11: 350, 1952.

6. HEINIVAARA, 0. : Blood basophils in primary polycythemia. Ann. Med. intern. Fenn. 48: 127, 1959.

7. LAWRENCE, J. H.: Polycythemia. Modern medical monographs 13. Grune & Stratton, New York 1955, p. 69.

8. LEDLIE, E. M.: The incidence of leukaemia in patients with polycythaemia Vera treated by 3*P. Clin. Rad. 11: 130, 1960.

5 . GRAHALI, H. F., WHEELWRIGHT, F., PARISH,

9. MARGOU, I.. PARHON, C. C. & COSMA, G.: La teneur en histamine du sang normal et pathologique. Bull. SOC. me'd. H6p. Bur. 18: 246, 1936.

10. MASOUREDIS, S. P. & LAWRENCE, J. H.: 'l'he problem of leukemia in polycythemia Vera. Amer. J. Med. Sci. 233: 268, 1957.

1 1 . PIKE, G . M.: Polycythemia Vera. New Engl. J. Med. 258: 1250, 1958.

12. RORSMAN, H.: Normal variation in the count of circulating basophil leukocytes in man. Acta allergol. 17: 49, 1962.

13. SCHWARTZ, S. 0. & EHRLICH, L.: The rela- tionship of polycythemia Vera to leukemia; a critical review. Acta Haernat. 4: 129, 1950.

14. SHIMKIN, M. B., SAPIRSTEIN, L., GOETZL, F. R., WHEELER, P. M. & BERLIN, N. 1.: Blood histamine in leukemia and erythreniia. J. Nat. Cancer Inst. 9: 379, 1959.

15. SHORE, P. A., BURKHALTER, A. & COIIN, W. H., Jr.: A method for the fluorometric assay of histamine in tissues. J. Pharmacol. exp. Ther. 127: 182, 1959.

16. SKVERSKY, N., MENDELL, T . H. & FRUMIN, A. H.: Polycythemia Vera terminating in acute leukemia: report of case and review of literature. Arch. intern. Med. 96: 565, 1955.

17. UNDRITZ, E. : in Hamatologische Tafeln. Sandoz AG, Basel, 1950, p. 23.

18. VALENTINE, W. N., BECK, W. S., FOLLETTE, .J. H., MILLS, H. & LAWRENCE, J. S.: Bio- chemical studies in chronic myeloid leukemia, polycythemia Vera, and other idiopathic myeloproliferative disorders. Blood 7: 959, 1952.

19. VIDEBAEK, A.: Polycythaemia Vera -

course and prognosis. Acta med. Scand. 138: 179, 1950.