MALIGNANT GROWTH IN THE LIVER AND SERUM-VITAMIN-B12 LEVELS

1116

MALIGNANT GROWTH IN THE LIVER AND SERUM-VITAMIN-B12 LEVELS *

N. GROSSOWICZ M.Sc., Ph.D. Jerusalem ASSOCIATE PROFESSOR OF BACTERIOLOGY

A. HOCHMAN M.D. Paris LECTURER IN RADIOLOGY

cipitation (0.6%

J. ARONOVITCH

acetate

buffer ; pH 4-6), autoclaving for

pressure of 10 lb. in the presence of cyanide (0-2 mg. per ml. of undiluted serum), and assaying the neutralised supernatant fluid. The serum -vitamin-Bvalues of 35 healthy people ranged from 200 to 500 (mean 340) ,,g. per ml. 30 minutes at

M.Sc. Jerusalem SENIOR SCHOLAR IN BACTERIOLOGY

G. IZAK M.D.

Methods

Vitamin E12 was determined microbiologically with the aid of a mutant strain of Escherichia coli as described previously (Grossowicz et al. 1954, Rachmilewitz et al. 1956). Only the total serum-vitamin-B12 was determined. This was done in either of the following two ways: (1) by diluting the serum 1 : 8 with distilled water, heating for 30 minutes at 100°C, and adding the heated mixture aseptically to the medium ; or (2) by liberating the vitamin B12 from the serum-proteins by acid pre-

Budapest

a

Results

ASSISTANT PHYSICIAN

patients with various malignant tumours exten. sively involving the liver were investigated. The malignancy and the hepatic metastases were diagnosed on the basis of clinical findings, biopsy at laparotomy, or necropsy findings. In most of these patients the liver was heavily infiltrated with tumour tissue. Mild to moderate jaundice was an accompanying sign in 8 patients. In 16 of 18 patients the serum-vitamin-B13 level was found to be raised (640-20,000 ,.g. per ml.) (see table). In cases 8 and 9 with malignant melanoma involving the liver the serum-vitamin-B12 level was moderately raised (800 and 820 pLg. per ml.). In case 10, however, with a like tumour, the serum-vitamin-BI2 level was excessively high (5800 {jg. per ml.). The highest serum-vitamin-B12 level (20,000 jijig. per ml.) was found in case 2, who had undergone total gastrectomy for cancer of the stomach. When the level was estimated several months after the gastrectomy, the liver was extensively infiltrated with metastases causing 18

M. RACHMILEWITZ M.D. Berlin PROFESSOR OF MEDICINE

THE

HEBREW

UNIVERSITY-HADASSAH MEDICAL JERUSALEM, ISRAEL

SCHOOL,

HIGH

serum-vitamin-B12 levels have been found in (Rachmilewitz et al. 1955, 1956) and in cirrhosis of the liver. In acute hepatitis occasionally the serum-vitamin-B12 level rose in the acute phase of the disease, when disintegration of liver-cells was most pronounced. It was therefore assumed that the injured liver-cells released into the blood-stream the vitamin-B12 stored in the liver. This assumption was supported by findings in dogs with acute liver necrosis induced by carbon tetrachloride. Extremely high serum-vitamin-B12 levels (up to fourteen times as high as the normal level) were found in these dogs as early as 1-2 hours after the intraportal administration of carbon tetrachloride (Stein et al. 1956). The interrelationship between liver damage and a raised serum-vitamin-B12 level prompted us to estimate the serum-vitamin-B12 levels of patients with neoplastic disease involving the liver. acute liver disease

was supported by a grant from the Stela Glezer Memorial Fund, Mexico City.

* This work

SERUM-VITAMIN-Bl2

jaundice. In case 16, with multiple myeloma, necropsy showed extensive amyloidosis of the liver causing flattening and displacement of the liver-cells by amyloid, and the serumvitamin-B12 level was raised at several examinations. In 2 patients with multiple myeloma not complicated by amyloid the serum -vitamin-B .2 level was normal. In case 15, a girl aged 19 with cancer of the ovary, the liver was heavily infiltrated with metastases, and

LEVELS IN PATIENTS WITH MALIGNANT TUMOURS

1117 in the liver the levels were raised (640-20,000 g. per ml.). These and previous findings indicate that this rise in serum-vitamin-B12 level is due to release of the stored vitamin from damaged liver-cells. The rise of serum-vitamin-B12 level may be used to help the diagnosis of metastases to the liver in cases of malism ancv.

histological examination revealed atrophy of the liverHer serum-vitamin-B12 cells adjacent to the tumour. level was 4800 t-Lt-Lg. per ml. In case 12, with hepatoma in

a

cirrhotic liver and

a

raised serum-vitamin-B12 level (4350 g. per ml.), the

found at necropsy to be infiltrated with case 11, with hepatoma and a normal serum-vitamin-B12 level (470 {g. per ml.), the tumour was limited to a circumscribed area, leaving the rest of the liver intact. In 19 control patients with malignant diseases involving various organs but without evidence of liver metastases the serum-vitamin-B12 levels were normal (100-550 t-Lt-Lg. per ml.) (see table).

entire liver

tumour

was

tissue; but in

REFERENCES

Beard, M. F.,

Pitney, (1954) Blood, 9, 789. Grossowicz, N., Aronovitch, J., Rachmilewitz, M. (1954) Proc. Soc. exp. Biol., N.Y. 87, 513. Killander, A. (1954) Nord. Med. 52, 1513. Kristensen, H. P. Ø. (1956) Ibid, 55, 85. Mollin, D. L., Ross, G. I. M. (1955) Brit. J. Hœmatol. 1, 155. Rachmilewitz, M., Aronovitch, J., Grossowicz, N. (1955) Harefuah, 49, 267. (1956) J. Lab. clin. Med. 48, 339. — Izak, G., Hochman, A., Aronovitch, J., Grossowicz, N. (1957) Blood (in the press). Stein. Y., Stein, O., Aronovitch, J., Grossowicz, N., Rachmilewitz, M. (1956) Bull. Res. Coun. Israel, 6E, 5. Wroblewski, F., La Due, J. S. (1955) Cancer, 8, 1155.

Discussion

These results show that invasion of the liver by a malignant growth is accompanied by a rise in the serumvitamin-B12 level. The invading tumour, by causing necrosis and/or displacement of liver-cells, allows vitamin B12 to escape from the liver into the blood. Damage of liver-cells by virus (Rachmilewitz et al. 1955, 1956, Kristensen 1956) or by carbon tetrachloride (Stein et al. 1956) similarly raises the serum -vitamin -B 12 level. In liver disease, whether of viral or of chemical origin, the serum-vitamin-B12 level increases rapidly but only temporarily (lasting only 1-2 weeks in hepatitis and a few days in liver injury from carbon tetrachloride) and then falls rapidly to normal levels. In cancer of the liver the process damaging the liver is more prolonged ; hence a persistent rise of serum-vitamin-B12 level is to be expected. Persistent rises were actually found in 3 patients (cases 5, 14, and 16) in whom estimations of serum-vitamin-B12 were repeated in the course of illness

—

—

W. R., Sanneman, E. H.

—

CHILDREN IN HOSPITAL G. F. VAUGHAN M.B. CHIEF

ASSISTANT,

Lond., M.R.C.P., D.P.M.

DEPARTMENT OF PSYCHOLOGICAL

GUY’S HOSPITAL ;

CONSULTANT

PSYCHIATRIST,

MEDICINE,

WOOD VALE

RECEPTION CENTRE

usually given some kind of explanation before they go into hospital. Are they fearful and anxious ?Mac Keith (1953) pointed

CHILDREN

are

by their parents

then less out that children may have varied, bizarre, and sometimes frightening ideas about the hospital. What they are told may be coloured by their parents’ own anxiety about an operation, which is often based on incomplete understanding of the situation and is likely to confuse the child-the opposite to what was intended. We assume that the nurses and doctors explain what is happening, and relieve these fears. Are we justified in this assumption ? Should a simple explanation be given to children soon after they are admitted ? The following investigation was undertaken with a small group of children to discover more about their attitudes towards admission and operation, and to see whether a simple introductory explanation would result in less emotional disturbance.

(see table).

That the neoplastic process per se is not responsible for the rise of serum-vitamin-B12 level is shown by finding normal levels in the controls with various malignant These tumours but no evidence of liver metastases. that determination of the serumfindings suggest vitamin-B12 may help the diagnosis of metastases to the liver in cases of malignancy. Raised levels should be interpreted as an indication that the liver is involved. Normal levels, however, do not rule out this possibility, because metastasising tumours not causing liver damage could be present in the liver without raising the serumvitamin-B12 level. Method Vitamin B12 is not the only substance released from liver-cells affected by tumour. Wroblewski and La Due The children were all admitted to the hospital for (1955) reported that the level of glutamic-oxalacetic five days for the same operation-correction of a strabistransaminase in the serum was raised in virus hepatitis, mus. Those living more than twenty-five miles from carbon-tetrachloride poisoning, and malignancy with liver Central London, and those with a history of previous metastases. However, whereas increased transaminase4operations, were not included. The parents were interactivity of the serum is found in destruction of variousviewed, and the cliild’s behaviour and personality before tissues, including heart-muscle, as in myocardial infarc:admission was assessed and classified under a number tion (Wroblewski and La Due 1955), raised serum-(of headings (Cameron 1955). All the children were tested vitamin-B12 levels are found only when the injured1briefly by a psychologist. tissue is liver. They were divided into two groups. Group A was The serum-vitamin-B12 level is also much raised in control" a consecutive series of 20 children who formed a myeloid leukaemia (Beard et al. 1954, Killander 1954, Mollin and Ross 1955, Rachmilewitz et al. 1957). AGE, SEX, AND INTELLECTUAL LEVELS OF THE TWO GROUPS OF 20 CHILDREN ADMITTED TO HOSPITAL FOR OPERATION Whether a mechanism common to liver disease and myeloid leukaemia is responsible or not for the striking rise in serum-vitamin-B12 levels in these two conditions remains to be elucidated. .

"

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Summary Serum-vitamin B12

-

determined microbiologically in patients with malignant disease. In 19 patients without metastases in the liver the serum-vitamin-B12 levels were normal (100-550 [jLg. per nil.), whereas in 16 of 18 patients with metastases levels

were

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