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Acta Medica Scandinavica. Vol. 169, fasc. 2,1961

From the Medical Clinic I, Sahlgrenska sjukhuset, Gothenburg, Sweden

Pernicious Anemia and Polycythemia Vera

BY

INGEMAR LIND

The occurrence of simultaneous polycythemia Vera and pernicious anemia is uncommon. Single well-established cases (table I) have been reported (10, 13, 18, 23, 33, 45). A survey of the previous literature on the subject shows a number of less well-established or doubtful cases ( 1,5, 12,27,40,42). Of particular interest is the connection between these diseases if any. When discussing the etiology and pathogenesis, polycythemia Vera has been considered as an antipode to pernicious anemia.

Case report A. J. (Record No. 941113/60) male, aged

66, who was treated at the Medical Clinic I of Sahlgrenska sjukhuset, Gothenburg, in 1943 for rheumatoid arthritis. The colour of his face was very high and he had increased haemoglobin- and erythrocyte values but no splenomegaly. He was treated with salicylic acid, physical therapy and also during one period with gold therapy. The chronic rheumatoid arthritis advanced further. In 1957 he was re-admitted due to tiredness, tachycardia and loss of weight. He now had severe anemia with a Hb value of 5.4 g/100 ml and red cells 1.5 mill/mms (table 11). Submitted for publication August 31, 1960.

Reticulocytes 2.4 %. No splenomegaly. The bone marrow showed megaloblastic erythropoiesis and giant types in the myelopoiesis as a sign of a lack of antipernicious factor. Serum vitamin B,, was low (100 pg/ml). Histamine-refractory achylia. The thymol titer was increased but the serum trans- aminase, the bromsulphalein test and the liver biopsy were normal. As there was a criterion of pernicious anemia, the patient was treated with injections of liver extracts, which resulted in a reticulocyte peak of 17.2 yo on the 7th day and increased H b to 9.9 g/100 ml.

The leukocyte numbers increased to 19,0001 mms and the platelets became normal. Parenteral and peroral administration of liver preparation continued. Normal and above normal blood counts were present all the time. Re-admitted to the hospital on 13th February 1960, due to exacerbation of rheumatoid arthritis. Pronounced objective joint changes. Physical examination showed a male, rather lean, affected with pain and with a deep red complexion and an appearance typical of polycythemia Vera. The liver could be palpated two fingers breadth below the arcus and the lower poie of the spleen reached just above the crista iliaca. No enlargement of the lymph nodes. Normal findings from heart and lungs. Blood pressure was 130/90. The ocular fundi showed fundus polycythemicus, degree I. Roentgenological

213

214 INGEMAR LIND

Table I . Summary of reported cases of pernicious anemia and fioiwythernia Vera

Author

15

112

40

135

13

'20

18

46

10

33

23

Present case

- 4gt 3ex

- 67 6

59 ?

62 ?

71 9

75 ?

55 ?

55 6

58 ?

63 ?

67 6

42 d 63 6 -

rreatment of pernicious anemia

Liver extract Cooked liver

Liver extraci

Liver extraci

Vitamin B,,

Liver extraci Vitamin B,,

Liver extrac

Liver extrac Vitamin B,, Transfusions

Vitamin B,,

Liver extrac Vitamin B,, Folic acid

Vitamin B,,

Liver extrac

Liver' extrac

W.B.C. during pernicious anemia

-

-

10,800- 16,300

2,200

17,400

8,500 - 10,500

8,000-26,500

6,400

13,000 -37,000

12,900

-

7.100

Interval from pernicious anemia treatment to polycythemia Vera

7 months (from relapse)

5 months (from relapse)

Polycythemia diagnosis established before P.A.

1 month

2.5 months

3 years

6 years

3 years

8 years

Polycythemia diagnosis establishec before P.A.

26 years

3 years

Treatment of poly cythemia Vera

Phenylhydrazine Liver withdraw1

Phenylhydrazine Venesection Irradiation

Not reported

Withdrawal of hematinics

Venesection P32

Temporary withdrawal of hematinics

Terminal diagnosis

Venesection Paa

Withdrawal of hematinics

P3 2

Not reported

P9,

Outcome

Relapse of P.A. responding to liver extract

Death (no autopsy)

Not reported

After a year's follow up polycythemia blood values

Remission

Satisfactory maintenance

Death (cerebral haemorrhage)

Death (myeloblastic leukemia)

Relapse on withdrawal


Not reported


1 Not completely documented cases

PERNICIOUS ANEMIA AND POLYCYTHEMIA VERA 215

Table II . Summary of investigations in patient A . 3.

Date

1944 26/2

1957 11/11

9 / 12

1960 14/12

7 / 3

Hb g / 100 ml

15.1

5.4

9.9

17.6

17.6

R. B. C. x 108

5.8

1.5

3.0

W. B. C. x 103

12,000

7,100

19,000 (after treatment

with liver extract)

6.4

6.2

2 7,000

24,000

Platelei

37,000

197,000

16,500

Hematological investigations

Sternal marrow: Eryt hropoiesis megaloblastic. 70 pi cent of myeloid cells are giant form Serum vitamin B, 100 pg/ml

Sternal marrow: Erythropoiesis increased and normc blastic. Myelopoies quotient normal. Granulocytes show increased alkaline phosphatase activit! Decreased fat con- tent. Reticulocytes

P.C.V. 62 per cen Total blood volumi 7.7 liters Plasma volume: 2.9 liters Erythrocyte volumi 4.8 liters Total hemoglobin: 1350 g

192-339,000.

Other observations

E.S.R. 9-31 mm/h Uric acid 2.6 mg/100 ml Gastric juicc: achylia

E.S.R. 48-5 mm/h. Serum iron: 83 mmg/100 ml. Histamine refractory achylia. Icterus index 9. Thymol turbidity 0.20. Bodansky units. Other liver function tests normal. Liver biopsy: normal. Paper electropho- resis of serum proteins: Total protein 5.5 g/lOO ml serum. Distribution normal

E.S.R. 1 mm/h. Serum iron 99 mmg/lOO ml. Histamine refractory achy lia after maximal stimu- lation. Icterus index 10. Alkaline phosphatase 18 units. Thymol turbidity D.28 Bodansky units. Pro- thrombin index 48-71. Bromsulphalein retention: 19 per cent. Paper elec- trophoresis of serum proteins: Total protein 7.8 g. Slight increase of ]'-glob- ulins. Fibrinogen 0.66 g / 100 ml. Uric acid 3.1 mgi 100 ml

findings: heart, lungs and oesophagus normal. pletely changed in appearance (table 11). Intravenous urography showed clumsy and Hb 17.6 g/100 ml; red blood cells 6.3 mill/mm3, wide renal pelves with the ureter on the left white blood cells 21,000, platelets 125,000, side originating from a slightly too high level P. C. V. 63 ()". The bone marrow showed bu t n o criterion for hypernephroma. increased erythropoiesis and a normal amount

The haematologic picture had now com- of myelopoiesis with a normal maturity

216 INGEMAR LIND

quotient and moderately increased phosphatase activity. Sparse reticular iron and 4 yo sideroblasts. Total blood volume determined with Cr61 method : 7.71. Plasma volume: 2.9 1. Red blood cell volume: 4.8 1. Total haemoglobin: 1,350 g. Thus, normal plasma volume with pronounced increase of total haemoglobin, red blood cell volume and haematocrit. These haematological findings combined with the liver and the spleen enlargement ensured the diagnosis of polycythemia Vera. No criterion for secondary polycythemia. Urinary excretion of radio- active vitamin B,, (Cots) according to Schilling was 1.2 % of the oral dose. With the intrinsic factor the excretion increased to 4.7 yo. Folic acid in the serum determined by streptococcus faecalis 1.9 mmg/ml; with lactobacillus casei 8.8 mmg/ml, i. e. normal limit values. Serum vitamin B,, > 1,600 pg/ml (following liver therapy).

The patient was treated with salicylic acid preparations and prednisone. 7.0 mC Psa was administered as treatment for polycythemia. He was discharged, the condition being slightly improved.

Summary Male, aged 66 years with rheumatoid

arthritis since 1943. Same year developed slightly increased haemoglobin- and erythrocyte values. iIn 1957 typical #pernicious anemia was diagnosed which‘ later was treated with liver injections. In-1960 fully developed polycythemia Vera with liver complication was present, possibly cirrhosis of the liver.

Discussion Heilmeyer & Begeman (17) lay

stress upon the fact that it is impossible to elicit polycythemia Vera experimentally or by administration of liver preparations to normal individuals. Gingold (15) could only provoke a retarded and in- significant increase in erythrocytes in

rabbits despite excessive doses of liver extract. This has also been confirmed by others (24, 31). A mild, non-progressive erythrocytosis has been observed. In Minot’s and Murphy’s original report 1926 (28) three cases of 45 had repeated erythrocyte values exceeding 6 mill/mm3. Other authors have made similar observations (9, 16, 21). Erythrocyte values up to 6.2 mill/mms as a normal upper limit can be regarded as a result of liver- or vitamin B,, treatment (43). In a case of Hodgkin’s disease and in one of subacute subleukemic leuko- blastosis non-progressive erythrocytosis was obtained with vitamin B,, (3, 5) . In the early literature several cases of polycythemia are reported which occurred in connection with treatment of pernicious anemia with liver extract (5, 12, 14, 27, 42). In many cases both the pernicious and polycythemic diagnosis have been insufficiently established. Rigid criteria are required for the diagnosis of polycythernia Vera. Often there is a lack of information as to leukocytosis or splenomegaly which are characteristic findings. Skouby’s (1952) and Vanotti’s (1952) cases (35, 40) are however more complete but the reports may still give rise to controversy. No doubt, earlier reported cases may have been valid but the diagnostic criteria and reliable methods of examination have for natural reasons been missing.

Galt et al. (13) described pernicious anemia developing into an extreme degree of polycythemia Vera two months after treatment with vitamin BIZ. After treatment with Paa normal haematological values were obtained. Croft (6 ) reports a case of myelofibrosis with a lack of vitamin B,,, which following vitamin B,, treatment developed into polycythemia and myeloid leukemia.


Zarafonetis et al. (46) describes a case of pernicious anemia with polycythemia Vera ending in myeloblastic leukemia. Him (18), Ellman (lo), Robinson (33) and Leeksma et al. (23) report four well- established cases in addition.

Other haematological complications are known both following polycythemia Vera and pernicious anemia. Leuko- cytosis as a rule is included in the picture of polycythemia Vera. The shift to the left may be so marked that the blood picture may resemble myeloid leukemia which occurs in 5 yo (6). Tinney et al. (38) found a leukemoid reaction in 17 yo. Absent or occurring myeloid infiltration in the spleen, liver and other organs decides the differential diagnosis. Poly- cythemia Vera may be the initial stage of typical chronic myeloid leukemia (26). It is uncommon with polycythemia Vera developing into acute myeloblastic leukemia, but not exactly rare (44, 46). In several cases polycythemia Vera has also developed in typical leukemia (43). Only once has the association of chronic lymphatic leukemia and polycythemia Vera been recorded (4).

It is Dameshek in particular (7) who regards polycythemia Vera as a myelo- proliferative disease with a possible development into other pathological con- ditions such as myelofibrosis, myeloid metaplasia, leukemia or thrombo- cythemia.

Pernicious anemia complicated with lymphatic leukemia has been described (25, 32, 39) but it is probably a matter of coincidence. It is more difficult to deter- mine cases combined with myeloid leukemia. The only superficial resem- blance is hyperplastic bone marrow. Probably there is no causal connection. These cases must be differentiated from leukemia with megaloblastosis in the

bone marrow and di Guglielmos syn- drome (8). Four cases have been reported where pernicious anemia occurred prior to the onset of acute myeloblastic leukemia several years before (43).

It is possible that pernicious anemia in a patient with polycythemia will never be diagnosed. Inversely, polycythemia Vera may be disguised by lack of iron or haemorrhage (23) or infectious anemia (11) as well as of inadequately treated pernicious anemia.

The etiology of polycythemia Vera is still unknown. As with pernicious anemia, familial occurrence has been described (22, 43). Attempts have been made to combine these two diseases pathogenetical- ly. Several authors have pointed out that pernicious anemia has anacidity as distinguished from polycythemia, which often has a hypersecretion and increased frequency of ulceration of the stomach. Using this as a basis, authors in the nineteen thirties put forward a gastro- genous hypothesis in order to explain both diseases (2, 9). In one case the intrinsic factor production was increased, in the other reduced. This theory was based on insufficient data and incorrect conclusions. Increased erythropoiesis as a result of excessive production of intrinsic factor has never been proved (2) . The positive effect which was obtained in polycythemic treatment after various therapeutic procedures in order to reduce the formation or the utilization of intrinsic factor may have been unspecific due to induced anemia (19). In several cases in the literature on the subject pronounced leukocytosis was observed long before haematopoietically active agents had been administered which points to polycythemia having been latent but disguised by simultaneous pernicious anemia.

218 INGEMAR LIND

In my case the diagnosis of pernicious anemia, was made in 1957. An excretion test with vitamin B,, CoSs according to Schilling showed that the disease was still latent when the diagnosis of polycythemia Vera was made three years later. A tendency to polycythemia could possibly be discerned already in 1943, hut the examination was then far too incomplete for a positive diagnosis to be made. In connection with reticulocytic increase after treatment with vitamin B,,, leukocytosis was also found in 19,000 white cells, the number of which later increased further. No indications of leukemia were obtained. The pathological liver function tests could depend on a simultaneous cirrhosis of the liver. This complication was first described by Mosse in 1914 (30). Sohval (36) found hepato- megaly in 2/3 of all cases of polycythemia Vera. Tinney et al. found liver complications in 25 yo of a series including 163 cases (37) . Definite clinical diagnosis of liver cirrhosis was obtained in five cases. The liver function may be impaired due to distension of the intrahepatic portal circulation as a result of increased blood volume, increased blood viscosity, formation of thromboses and impaired nutri- tion of the liver cells due to stasis. In my case the liver function was decidedly reduced which aggravated the anti- rheumatic treatment but of course no importance can be attached to this in the pathogenesis of pernicious anemia.

In this case the patient had probably suffered from polycythemia for a long time before it was disguised by the onset of pernicious anemia. After adequate vitamin B,, treatment, polycythemia could be clinically manifest. Treatment with PsS was considered justified due to the obviously rapid advancement of the disease.

Conclusion 1. In this case as in other cases it is

probably a matter of two separate diseases, one of which merely could be clinically verified when the other occurred.

2. Treatment with vitamin B,, cannot provoke polycythemia Vera, only allow the already existing disease to be clinically manifest.

3. The hypothesis that polycythemia Vera occurs due to an excess of intrinsic factor has not been proved and is probably incorrect. Polycythemia may appear partially, inter alia, in the form of leukocytic proliferation despite a lack of the intrinsic factor in pernicious anemia.

4. Simultaneous occurrence of polycythemia Vera and pernicious anemia in the same patient depends on a coincidence.

Summary One case of pernicious anemia which

after three years of treatment with liver extracts developed into polycythemia Vera is described.

A summary of previously published cases of the combination pernicious anemia and polycythemia Vera in the same patient following vitamin B,, therapy is introduced.

The connection between these two diseases is discussed.

Simultaneous occurrence of polycythemia Vera and pernicious anemia depends on a coincidence.

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