Pernicious Anemia and Polycythemia Vera

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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 poly- cythemia 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 ery- thropoiesis 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 diag- nosis 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 poly- cythemia blood values

    Remission

    Satisfactory maintenance

    Death (cerebral haemorrhage)

    Death (myeloblastic leukemia)

    Relapse on withdrawal

    Satisfactory maintenance

    Not reported

    Satisfactory maintenance

    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 in- creased 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 achy- lia. 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 pro- teins: 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 phos- phatase activity. Sparse reticular iron and 4 yo sideroblasts. Total blood volume deter- mined 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 poly- cythemia 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 eryth- rocyte 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 cir- rhosis 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 prepara- tions 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 Minots and Murphys original report 1926 (28) three cases of 45 had repeated erythrocyte values exceeding 6 mill/mm3. Other authors have made similar ob- servations (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 Hodgkins 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 oc- curred in connection with treatment of pernicious anemia with liver extract (5, 12, 14, 27, 42). In many cases both the pernicious and polycythemic diag- nosis have been insufficiently estab- lished. Rigid criteria are required for the diagnosis of polycythernia Vera. Often there is a lack of information as to leuko- cytosis or splenomegaly which are characteristic findings. Skoubys (1952) and Vanottis (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 haematolog- ical 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.

  • PERNICIOUS ANEMIA AND POLYCYTHEMIA VERA 217

    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 leu- kemia, 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 re- ported 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 poly- cythemia 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 complica- tions 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, forma- tion 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 poly- cythemia Vera and pernicious anemia in the same patient depends on a coinci- dence.

    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 poly- cythemia Vera and pernicious anemia depends on a coincidence.

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  • PERNICIOUS ANEMIA AND POLYCYTHEMIA VERA 219

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