Acta Medica Scandinavica. Vol. 174, fasc. 6,1963

From Medical Department F (Head: Mogens Iversen, M. D.), Frederiksborg County Hospital, Hillerad, Denmark

Polycythemia Vera Following Treatment of Megaloblastic Anemia with Folic Acid

BY PALLE GR~NBBK and JBRGEN VIVE LARSEN

Polycythemia Vera following treatment of megaloblastic anemia is rare and has been reported in only a few cases (2, 5, 6, 7, 8, 11, 12, 13, 14, 16, 17, 18, 19).

In all reports the cause of megaloblastic anemia was considered to be an Addiso- nian pernicious anemia. The patients were achlorhydric, responsive to treat- ment with B,, or liver extract, and showed no signs of any of the other conditions which are able to cause a megaloblastic anemia. Such evidence does not verify the diagnosis of Addisonian pernicious anemia beyond all doubt, but it is strongly suggestive.

Megaloblastic anemia during treat- ment with anticonvulsive drugs is not common, and in the past only about 60 cases have been reported (4, 9). In 1954 Badenoch (1) reported a hitherto unde- scribed form of megaloblastic anemia in two patients who were receiving diphenyl- hydantoin. This association was sub- sequently confirmed by others. In addi- tion the use of related drugs has been im- plicated in the production of megalo- blastosis, one such drug being Mysolinem. An excellent hematological response to large doses of folic acid occurred in most

Submitted for publication June 26, 1963.

cases. Although the mechanism of the anemia in question remains obscure, it is suggested that the anticonvulsants may interfere with the utilization of folic acid even if the absorption of folic acid from the intestine is normal. However, this group of patients seems suitable for asses- sing the value of FIGLU excretion fol- lowing histidine loading as an index of folic acid utilization (1 0).

The present report concerns a patient who developed polycythemia following folic acid therapy for megaloblastic anemia caused by an anticonvulsive drug (Phenantoin).

Case report A 55-year-old woman was admitted to

medical department F, Frederiksborg County Hospital, November 1961, with chief com- plaints of severe fatigue and slow cerebration. Her previous history was as follows:

There was no familiar disposition to blood disorders.

From 1938 she developed symptoms of epilepsy, and she suffered equally from attacks of absences and grand mal.

Her epilepsy, untreated for several years, was later considered as a genuine type. From 1943 she was treated with Phenemal, Phenan-

78 1

782 PALLE GR0NBB.K AND J0RGEN VIVE LARSEN

--*\. -*\.

-*-.

DAYS Fig. 1. Details of blood states.

I Blood transfusion @-a Hemoglobin (g/100 ml) 0-0 Erythrocytes (mill/ml)

toin was not given before 1947. The first information of her blood state was dated 1945 where the hemoglobin concentrations were 11.5 g/100 ml and 13 g/100 ml respectively.

In 1949 she was referred to the medical department, Frederiksborg County Hospital, because of ecchymoses. However, there were no obvious signs of blood disease (ESR 12 mm/ h, red blood-cell count and platelet count normal (4,18 mill./mms and 205,500/mms respectively)).

In 1955 she was referred on the same de- partment because of a severe anemia. Her hemoglobin concentration was 4.5 g/100 ml, red blood-cell count 2.52 mill./mms, white blood-cell count 4,960/mms, serum iron 0.243

Bone marrow, obtained by sternal puncture, however, showed signs of a pernicious anemia, but no achlorhydria was found.

The patient was now treated with vitamin BI1, intrinsic factor and iron without effect. Only treatment with liver extract (Hepsol

mg Yo.

0 --0 Reticulocytes (%) 0 FIGLU in urine (pmol)

Folk acid treatment.

fortior@) gave a rise, albeit insufficient, in hemoglobin concentration and reticulocytes. Her antiepileptic treatment with Phenemal and Phenantoin continued unaltered. After leaving the hospital her blood state was con- trolled elsewhere.

On admission in 1961 physical examination revealed a deeply anemic and slow cerebrated patient somewhat overweight. Her tongue was normal, her spleen and liver could not be palpated. Neurologic examination including vibration sense was normal.

Laboratory jindings On admission hemoglobin concentration

was 4.5 g/100 ml, red blood-cell count, white blood-cell count and platelet count 2 mill./ mm8, 4,440/mms and 42,300/mms respectively. Serum iron elevated as earlier (0.270 mg %), vitamin B,, in serum 285 ,uclg/ml. Her colour index was not elevated, but a new bone mar- row specimen gave evidence of a pernicious anemia as earlier. X-ray photos of ventricle

POLYCYTHEMIA VERA 783

and small intestine were normal. An achlor- hydria had now developed. Unfortunately Schilling’s tests were not performed on ac- count of the patient’s incooperability.

Up to now the patient has been treated with Phenantoin for 14 years. So a disturbance in her folic acid utilization could be expected. However the folk acid concentration in serum was normal (0.25 y/ml) (normal values > yO.O18/ml).

A disturbed folk acid metabolism was now established by examination of formimino- glutamic acid (FIGLU) excretion in the urine after administration of 15 g Histidine, a very elevated value (2,700 pmol) being found (normal values <p160 mol)’.

The patient was now treated with folic acid 10 mgX 3 and iron perorally. Unfortunately the antiepileptic treatment was altered from Phenantoin to Mysolinem simultaneously with the beginning of folic aicd administration. However disturbances in the folic acid utili- zation may be caused by both drugs.

During folic acid therapy her blood state was normalised and the FIGLU content in the urine fell to normal values (70 pmol).

On May 1962 the patient was admitted to the hospital again for controlling procedures.

Surprisingly a polycythemia Vera had de- veloped. Laboratory findings showed hemo- globin concentration 18.5 g/100 ml, red blood cell count 6.89 mill./mms, white blood-cell count 16,000/mm8, platelet count 280,000/ m m a , vitamin B,, in serum 300ppg/ml. ESR 1 mm/h. Furthermore, radioactive sodium chromate blood-volume studies demonstrated an increase above normal in blood volume and red cell mass (6,900 ml and 3,350 ml respectively). Physical examination gave no further information, and in particular liver and spleen were not palpable. After reduction of her folic acid dose to 5 mg x 3 for some months, the hemoglobin concentration fell to normal values, as did red blood cell, white blood cell and platelet counts.

She was last seen in the hospital September 1962 where she continued to do well during treatment with folic acid 5 mg x 3 and un- changed anticonvulsive therapy.

Details of blood states during all the history are given in fig. 1.

1 We are greateful to dr. Kjell Jacobsson, M. D., Centrallasarettet, Vaxjo, Sweden.

Discussion The present case is interesting con-

sidered from two points of view. I n spite of a normal concentration in serum, the folic acid utilization was insufficient be- cause of therapy with Phenantoin or Mysoline@ or both. During treatment with folic acid and Mysoline@ the ex- cretion of FIGLU in the urine diminished and finally reached normal values. Two months later a polycythemia Vera oc- curred. The development of polycythemia Vera in this patient was established not only by the presence of the elevated red blood-cell, white blood-cell and platelet counts, but also by radioactive sodium chromate blood-volume studies, which demonstrated an increase above normal in the blood volume and red cell mass.

Current hypotheses on the occurrence of polycythemia during treatment of mega- loblastic anemia are :

1) Erythremia may be caused by the antianemic drug.

2) The two diseases may tend to mani- fest themselves in such a sequence in the same patient without causal relationship.

3) The tendency to polycythemia may have been veiled by the anemic state. After restoration of the hematopoiesis by treating the megaloblastic anemia the polycythemia becomes manifest.

4) An instability of the hematopoietic tissue in the patient may be suggestive.

The development of polycythemia after treatment of megaloblastic anemia with liver extract or vitamin B,, has been noted only infrequently in the past. I n some of the earlier case reports of poly- cythemia occurring after treatment of megaloblastic anemia with liver extract, no mention was made of leucocytoses and thrombocythemia commonly associated with polycythemia. In some of these pa- tients the polycythemic red blood-cell

784 PALLE GR0NB1EK AND J0RGEN VIVE LARSEN

values reverted to normal when the dosage of liver extract was reduced (3).

As far as we know, polycythemia fol- lowing treatment of megaloblastic anemia with folic acid has never been reported.

In most cases in the literature the latent tendency for polycythemia Vera may have been evcked by the anemic state or, alternatively, the two diseases tended to manifest themselves indepen- dently in such a sequence.

Most investigators therefore agree that the occurrence of both diseases in the same patient is caused by chance.

In our patient, however, no evidence of a polycythemic state was found before the treatments with anticonvulsive drugs, vitamin B,, and folic acid. The evolution of one myeloproliferative disorder into another is not unusual. Thus, poly- cythemia Vera, myeloid metaplasia and myelotic leukemia may follow or im- perceptibly merge into one another. Pernicious anemia may also be followed by myelotic leukemia, and the incidence of myelotic leukemia in the relatives of patients with pernicious anemia has been reported to be higher than in the general population. Therefore an instability of the hematopoietic tissue in some pa- tients is conceivable (1 5).

In our patient, however, the hemo- globin concentration fell to normal values after reduction of the folic acid dose. At present no common pathophysiological basis is evident for the occurrence of polycythemia Vera and megaloblastic anemia in the same patient.

Summary A case of megaloblastic anemia caused

by anticonvulsive drug treatment and developing polycythemia Vera during treatment with folic acid is reported.

The deficiency of folk acid utilization

was demonstrated by FIGLU tests, which showed falling values during administra- tion of folic acid. Besides of red blood-cell, white blood-cell and platelet counts the polycythemia was verified by radioactive sodium chromate blood-volume studies.

No evidence of polycythemia before the treatments with anticonvulsive drugs, vitamin B,, and folk acid was found.

The mechanism of the different dis- orders is briefly discussed.

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