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CORRELATION OF SERUM-VITAMIN B12 LEVELS AND URINARY FOLIC ACID IN NUTRITIONAL MEGALOBLASTIC ANÆMIA
61 been recorded. Haemoptysis as a presenting symptom does not seem to have been observed, although in the last five years in the department of thoracic surgery at this hospital three patients with retrosternal goitre have presented with haemoptysis out of a total of fifteen
treated.
Case-reports was referred with a provisional of bronchial carcinoma. Over the previous nine months he -had lost 2 st. in weight, and for two months he had experienced haemoptysis daily, about two tablespoonfuls in quantity and bright red, unmixed with sputum. Examination showed a fit man for his age, although he had obviously lost weight. His thyroid gland appeared normal, and trachea central. Dilated veins were present over the upper chest and arms. No other abnormality was detected
Case 1.-A man,
aged 67,
diagnosis ..
on
physical
examination.
Investigations.-No tubercle bacilli were seen in the sputum. Radiographs of the chest showed a large mass in the upper mediastinum, displacing the trachea to the right and the oesophagus to the left. Screening did not reveal any movement of the mass on swallowing. Diaphragmatic movement was normal, and the lung fields were emphysematous. No
and sometimes oedema, as the alternative return to the heart.
flow finds an troublesome venous bleeding occurs. The increased venous pressure is probably also responsible for the haemoptysis. The trachea derives its blood-supply from the inferior thyroid artery (Johnston and Whillis 1944) and is drained by the inferior thyroid veins, in which venous engorgement takes place as a result of compression. Rupture of a tracheal vein would be associated with bleeding relieved by a drop in the venous pressure-i.e., it would be fairly brisk, unmixed with sputum, and copious. venous
At
operation
Summary due to retrosternal goitre is described. Three cases are noted. A mechanism for the production of this symptom is suggested.
Haemoptysis
I am indebted to Mr. W. F. Nicholson for permission to publish his cases and for helpful advice, and to Mr. A. Graham Bryce for permission to publish one of his cases. REFERENCES
Higgins, C. C. (1927) Arch. Surg. 15, 895. Johnston, T. B., Whillis, J. (1944) Gray’s Anatomy. London ; p. 1257. Pemberton, J. de J. (1921) Arch. Surg. 2, 1. Rundle, F. F. (1951) Joll’s Diseases of the Thyroid Gland. London ; p. 104. Sauerbruch, F., Felix, W. (1927) Schweiz. med. Wschr. 57, 859.
evidence of bronchial carcinoma. Bronchoscopy normal larynx. The trachea was deviated to the right slightly, and its left wall was indented. At operation a colloid goitre was found extending from the right lower pole into the upper mediastinum. It enveloped the trachea, except its posterior aspect, and descended to the CORRELATION OF SERUM-VITAMIN B12 level of the aortic arch. After removal of the goitre the patient has had no recurrence of symptoms. LEVELS AND URINARY FOLIC ACID IN Case 2.-A man, aged 72, complained of dyspnoea on NUTRITIONAL MEGALOBLASTIC ANÆMIA exertion and of haemoptysis. Eleven years previously he had had an adenoma of the thyroid removed. Eight years later P. W. G. TASKER he noted that he was dyspnoeic on exertion and when lying M.B. Lond. down. Six months ago his voice became weak, and in the From the Medical last two months he had haemoptysis on two occasions, the Institute for Research, Kuala Lumpur, Malaya blood being bright red, but he could not estimate how much. NUTRITIONAL megaloblastic anaemia and the closely Investigations.-Radiographs of the chest showed a large related megaloblastic anaemia, of pregnancy are consuperior mediastinal tumour displacing the oesophagus formost workers to be caused primarily by a sidered far to the and to the left. The trachea was by wards displaced left and laterally compressed. deficiency of folic acid, and at present folic acid is At operation the place of the right lobe of the thyroid was regarded as the treatment of choice (Davidson 1948, found to be taken by a large adenoma extending into the Spies et al. 1948, Wilkinson 1948). thorax and passing behind the trachea. After his operation Vitamin B12 is also therapeutically active in some of the patient has had no recurrence of symptoms. these patients in India (Patel and Kocher 1950, Chaudhuri Case 3.-A female shop-assistant, aged 48, was referred in 1951, Das Gupta et al. 1953), as I have found it in some June, 1950, with a provisional diagnosis of bronchiectasis. of my patients in Malaya. Low serum-vitamin B12 She complained of hæmoptysis lasting seven days in 1949. levels have been found in patients with pernicious The blood was dark red and came into the back of her mouth anaemia and with other types of megaloblastic anaemia "as if it had come from her windpipe." Six months later and (Mollin and Ross 1952, 1954, Unglaub et al. 1954) ; thereafter at two-monthly intervals the hæmoptysis recurredlow levels have been found among the patients similar a cupful of blood each time and unmixed with sputum. seen here. Examination showed a healthy woman with a midline Details of the interrelationship between folic acid suprasternal swelling which was ill defined and did not move on swallowing. and vitamin B12 in the aetiology of megaloblastic anæmia Investigations.-Tubercle bacilli were not seen in the are still largely unknown ; but that a relationship sputum. Radiographs of the chest showed a soft-tissue exists is well established (Vilter et al. 1950, Girdwood swelling in the left side of the thoracic inlet. No evidence of 1952a and b). I report here a correlation found between pulmonary tuberculosis. Screening showed that the swelling the serum-vitamin B12 level and the urinary excretion moved on and was continuous with the cervical
radiographic showed
a
swallowing thyroid swelling. The
of folic acid after
From these three cases it will be noted that the blood was unmixed with sputum. In two cases the haemoptysis was considerable, and one patient could not estimate the quantity. Since these goitres lie behind the sternum, there is an increase in local pressure on the surrounding structures. The veins are obstructed before the arteries and became engorged. The inferior thyroid vessels, together with the internal jugular, innominate, and superior vena cava, depending on the extent of the goitre, take part in this congestion. This increased venous pressure manifests itself clinically as distended cutaneous veins of the neck and upper part of the arms,
The 29 patients studied came from the lower-income groups served by the General Hospital, Kuala Lumpur, Malaya, most of them being Indian and Chinese labourers and artisans. They all had gross nutritional megaloblastic anaemia, proved in each case by marrow biopsy. Clinical sprue was not seen by me in this population. and four representative patients with severe megaloblastic anaemia gave normal vitamin-A absorption curves and normal radiological intestinal patterns. Nearly all the patients had a haemoglobin concentration of 5 g. or less per 100 ml., and had received no previous treatment except iron. None of them had severe pyrexia, but some had a slightly raised temperature not associated with any clinical infection, as is sometimes seen in severe megaloblastic anaemia. There was no gross eedema or other clinical evidence of disease, apart from that related
trachea was pushed over to the right. Bronchoscopy showed no abnormality. At operation a retrosternal enlargement of the thyroid extending from the left lobe was found. No recurrence of symptoms followed the operation. .
Discussion
a
loading
dose.
Material
62 to anaemia, and malnutrition. A few patients excluded when it was found that they had a urinary output of less than 300 ml. in six hours during the determination of the urinary excretion of folic acid, because a urinary flow as small as this affects the output of folic acid.
directly
SERUM-VITAMIN
were
B12
LEVELS
AND
EXCRETION
AFTER A LOADING DOSE OF
5
OF
FOLIC ACID’
MG.
Methods The serum-vitamin Bl2 levels were kindly estimated by Dr. G. I. M. Ross and Dr. D. L. Mollin at the Post-
graduate Medical School, London, using Euglena gracilis the test organism (Ross 1952). Urinary folic acid was estimated as recommended by Girdwood (1953a and b) ; the test organism was S’treptococcus lactis R (Gradwohl and Kouri 1948). A twelve-tube assay technique was used, and the tests were planned for statistical accuracy as suggested by Wood (1953). A loading dose of 5 mg. of folic acid was given subcutaneously, and the amount excreted in the urine in the following six hours was assayed. Folic acid 15 mg. was then given each day parenterally for the next five days to ensure tissue saturation. Forty-eight hours after the last dose the second loading dose of folic acid (5 mg.) was given orally and the subsequent six-hours urinary excretion was assayed as before. as
Results
The normal range for total serum-vitamin B12 is given by Mollin and Ross (1952) as 100-720 µµg. (mean Of the present 29 patients with 358 µµg.) per ml. megaloblastic anaemia 11 had low levels. A normal range of urinary excretion of folic acid was established for 15 patients with normoblastic irondeficiency nutritional anaemia of comparable severity. The subcutaneous loading dose gave a mean excretion of 2.02 mg. (standard deviation 0.236) and the oral loading dose 1.63 mg. (standard deviation 0.238). In the patients with megaloblastic anaemia the excretion of folic acid was below normal after the subcutaneous loading dose in 8, and after the oral loading dose in 11. The accompanying figure shows the relationship between the urinary folic acid and the serum-vitamin B12 +",no
29 patients, compared
with the normal ranges, after the subcutaneous
dose. As the excretion of folic acid decreased,
loading
so the serumvitamin B12 level fell,
)
although both remained within normal 7
_
_
1
_
these had severe mega,loblastic anaemia. Only when urinary folic acid reached values below normal did the serum-vitamin B12 level also drop This regression was highly to a pathological value. Correlation between serum-vitamin 8’2 level and urinary excretion of folic acid during six hours after loading dose of 5 mg.
though patients
significant (0.001
When a small dose of folic acid is given subcutaneously it may go to the tissues or be excreted in the urine. If
proportion of folic acid going to the tissues increases the body becomes more depleted of folic acid, the amount excreted in the urine will be inversely proportional to the degree of folic-acid deficiency. In that case the vitamin-B12 deficiency only develops when the folic-acid deficiency has become severe. In pernicious anaemia, which is regarded as primarily a vitamin-B12 deficiency, the excretion of folic acid is decreased (Spray and Witts 1952), as in the present cases. Since pernicious anaemia also responds to folicacid therapy, it can be assumed that there is a folic-acid deficiency conditioned by the vitamin-B12 deficiency. This appears to be the opposite of the hypothesis given above for these nutritional megaloblastic anaemias. Spray and Witts (1952) suggest that a vitamin-B12 deficiency may lead to a conditioned retention of folio acid in the tissues, accounting for this low excretion. Nieweg et al. (1954) found that, in non-pernicious megaloblastic anaemia, folic-acid levels tended to be normal when the vitamin-B12 level was low, and vice versa ; in about half their pernicious-anaemia patients both vitamins were at low levels. They also, like Spray and Witts, believe that a vitamin-B12 deficiency can influence the storage of folic acid. In the present investigation the excretion of folic acid was normal while the serum-vitamin B12level was normal, in spite of the fact that the patients had severe megaloblastic anaemia. This supports the suggestion of Spray and Witts that the excretion of folic acid does not measure the tissue depletion but, rather, follows the the as
-
vitamin-B12 deficiency. Finally, it is possible that a vitamin-B12 deficiency may develop independently of an already established folic-acid deficiency. Between these two vitamins it is still not known which
deficiency develops first-which is the horse and which the cart-but certainly a deficiency of both can be present in this type of megaloblastic anaemia as observed in Malaya. Summary A close correlation was found between the serumvitamin B12 level and the urinary excretion of folic acid after a subcutaneous loading dose of 5 mg.in patients with severe megaloblastic anæmia.
63 When the serum-vitamin B12 level excretion of folic acid was low also. I for
was
low, the
indebted to Dr. D. L. Mollin and Dr. R. H. Girwood helpful criticism. am
REFERENCES
Chaudhuri, S. (1951) Brit. med J. ii, 825. Das Gupta, C. R., Chatterjea, J. B., Basu, P. (1953) Ibid, ii, 645 Davidson, L. S. P. (1948) Edinb. med. J. 55, 400. Girdwood, R. H. (1952a) Blood, 7, 77. (1952b) Brit. J. Nutr. 6, 315. (1953a) Lancet, ii, 53. (1953b) Brit. med. J. ii, 741. Gradwohl, R. B. H., Kouri, P. (1948) Clinical Laboratory Methods and Diagnosis. 4th ed., St. Louis. Mollin, D. L., Ross, G. I. M. (1952) J. clin. Path. 5, 129. (1954) Proc. R. Soc. Med. 47, 428. Nieweg, H. O., Faber, J. G., De Vries, J. A., Kroese, W. F. (1954) J. Lab. clin. Med. 44, 118. Patel, J. C., Kocher, B. R. (1950) Brit. med. J. i, 924. Ross, G. I. M. (1952) J. clin. Path. 5, 250. Spies, T. D., García Lopez, G., Stone, R. E., Milanes, F., Lopez Toca, R., Aramburu, T. (1948) Lancet, i, 239. Spray, G. H., Witts, L. J. (1952) Brit. med. J. ii, 62. Unglaub, W. G., Rosenthal, H. L., Goldsmith, G. A. (1954) J. Lab. clin. Med. 43, 143. Vilter. R. W., Horrigan, D., Mueller, J. F., Jarrold, T., Vilter, C. F. Hawkins, V., Seaman, A. (1950) Blood, 5, 695. Wilkinson, J. F. (1948) Brit. med. J. i, 822. Wood, E. C. (1953) Analyst, 78, 451. —
—
—
—
—
CHRONIC HYPOPOTASSÆMIA OF RENAL
ORIGIN E. G. SAYERS M.B. N.Z., F.R.C.P., F.R.A.C.P., D.T.M.
&
H.
SENIOR PHYSICIAN
K. E. D. EYRE M.B. N.Z., M.R.A.C.P. MEDICAL REGISTRAR
AUCKLAND HOSPITAL,
M.B.,
F. H. SIMS N.Z., Ph.D. Edin.
M.Se.
CHEMICAL PATHOLOGIST
AUCKLAND,
NEW ZEALAND
MUSCULAR weakness or paralysis due to low serumpotassium levels is well recognised, and the causes of low serum-potassium levels are numerous. When renal disease causes disordered potassium metabolism, there is usually potassium retention with high serum-potassium levels affecting mainly the heart and skeletal muscles. Within recent years, however, reports have been published of renal disease causing excessive urinary excretion of potassium, low serum-potassium levels, and paralysis. Brown et al. (1944) reported three patients with hypopotassaemia due to renal disease ; Kjerulf-Jensen et al. (1951) reported a woman with persistently low serumpotassium levels which may have been renal in origin; Davidsen et al. (1951) recorded a case of chronic potassium deficiency probably due to renal disease ; and Earle et al. (1951) made prolonged observations on a Chinese with renal
hypopotasssemia. We present here with this
syndrome, damage.
observations on another patient who is unusual in having remarkably
our
little renal
Clinical Record The patient was seen by one of us (E. G. S.) in consultation on Sept. 8, 1952, because of generalised weakness and sudden attacks of paralysis during the previous few months. She was a married European woman aged 37, and had been in her usual good health until half-way through her third and latest pregnancy. About this time she began to have undue fatigue, which became progressively worse up to the time of her delivery. This third pregnancy, like her previous two pregnancies, was abnormal. Her first pregnancy was ectopic, necessitating the removal of her right fallopian tube on April 20, 1947. Her blood-pressure then was 160/100 mm. Hg and her urine was normal. She became pregnant again in 1948, when her bloodpressure and urine were normal. Because of slight albuminuria and
hypertension (blood-pressure 165/110
mm.
Hg)
in the
last few weeks of pregnancy, labour was induced surgically two weeks before the expected date of delivery. The puer-
was normal, and two weeks post partum her bloodpressure had returned to normal. Her third pregnancy began in 1951, the last menstrual’ period starting on June 16. She had no albuminuria then, but her blood-pressure was 165/100 mm. Hg and remained about this level during the first trimester, fell to about 145/85 mm. Hg in the middle trimester, and rose to about 165/95 Labour was induced on mm. Hg in the last two months. March 14, 1952, a week before the expected date of deliveryIt was during the latter half of this pregnancy that the patient developed excessive fatigue. She felt well on discharge from hospital, but after a week at, home she again became very tired. After two months her milk began to diminish, and the baby took an hour over each feed. On May 14, 1952, after feeding the baby she suddenly collapsed on the bed and could scarcely move an arm or a leg. She regained her strength in three days. After this episode she continued to be very tired after slight exertion. After a further interval she developed attacks of weakness of the legs in which she would suddenly drop to the ground and have great difficulty in getting up again. There was no disturbance of consciousness in these attacks, and she described them as a feeling as if someone had struck her behind the knees, causing her legs to buckle up under her. The first such attack came on about three days after her collapse after feeding the baby. On this evening she unexpectedly dropped to the floor, and her husband had to help her to bed. Similar episodes took place about once a week thereafter at any hour of the day. In July, 1952, the weakness in her arms became worse, causing clumsiness, and she often dropped things. She would test the power in her legs by raising herself on tiptoe and then take one foot off the ground. Often her legs were too weak to support her. As time went by, although these recurrent paralyses became no more frequent, they were more severe and lasted longer. In August, 1952, she had two severe episodes and was severely paralysed for several days. The last attack before seeing, E. G. S. was on Aug. 28, 1952, and on this occasion, after having afternoon tea, she stood up, but on stepping forward she fell to the floor and could not get up. She was carried to bed and remained there for five days. For the first two days she could not move her legs and could barely lift her It was eight days before she could walk without arms. assistance.
perium
.
In all the attacks only the skeletal musculature was affected and there were no symptoms of weakness in the muscles supplied by the cranial nerves. The legs were often affected alone and were always more paralysed than the arms. There had been no respiratory distress. The only symptom of abnormal sensation was occasional tingling and numbness of the hands. Her previous history revealed npthing of significance The family other than the abnormal pregnancies.
history
unimportant. interrogation brought to light the following
was
Routine
points : In the preceding twelve months the patient frequency of micturition, nocturia, polyuria,
had developed and increased
thirst. For several months she had noticed a rather unusual visual defect. When reading, she could see clearly only the central portion of one line, the rest of the page being blurred. This disability was so great that she had given up reading.
On admission to the Auckland Public Hospital for investigation on Sept. 11, 1952, physical examination gave the following results : She was intelligent and cooperative but languid. Careful examination of the nervous system revealed only generalised skeletal muscular weakness, greatest in the legs. No changes. in sensory appreciation were detected, and all her superficial and deep reflexes were brisk and her plantar responses flexor. Her optic fundi were normal ; she had normal visual acuity, and her visual fields were full. Her gait was shuffling and unsteady, and after walking about twenty-five yards she became exhausted and had to support herself by holding on to the wall. Her blood-pressure was 165/100 mm. Hg, the cardiovascular system being otherwise normal. The respiratory and alimentary systems were normal. A catheter specimen of urine contained a faint trace of albumin, an occasional epithelial cell, and one leucocyte per high power field.
The urine
was
sterile
on
culture.
treated.
Case-reports was referred with a provisional of bronchial carcinoma. Over the previous nine months he -had lost 2 st. in weight, and for two months he had experienced haemoptysis daily, about two tablespoonfuls in quantity and bright red, unmixed with sputum. Examination showed a fit man for his age, although he had obviously lost weight. His thyroid gland appeared normal, and trachea central. Dilated veins were present over the upper chest and arms. No other abnormality was detected
Case 1.-A man,
aged 67,
diagnosis ..
on
physical
examination.
Investigations.-No tubercle bacilli were seen in the sputum. Radiographs of the chest showed a large mass in the upper mediastinum, displacing the trachea to the right and the oesophagus to the left. Screening did not reveal any movement of the mass on swallowing. Diaphragmatic movement was normal, and the lung fields were emphysematous. No
and sometimes oedema, as the alternative return to the heart.
flow finds an troublesome venous bleeding occurs. The increased venous pressure is probably also responsible for the haemoptysis. The trachea derives its blood-supply from the inferior thyroid artery (Johnston and Whillis 1944) and is drained by the inferior thyroid veins, in which venous engorgement takes place as a result of compression. Rupture of a tracheal vein would be associated with bleeding relieved by a drop in the venous pressure-i.e., it would be fairly brisk, unmixed with sputum, and copious. venous
At
operation
Summary due to retrosternal goitre is described. Three cases are noted. A mechanism for the production of this symptom is suggested.
Haemoptysis
I am indebted to Mr. W. F. Nicholson for permission to publish his cases and for helpful advice, and to Mr. A. Graham Bryce for permission to publish one of his cases. REFERENCES
Higgins, C. C. (1927) Arch. Surg. 15, 895. Johnston, T. B., Whillis, J. (1944) Gray’s Anatomy. London ; p. 1257. Pemberton, J. de J. (1921) Arch. Surg. 2, 1. Rundle, F. F. (1951) Joll’s Diseases of the Thyroid Gland. London ; p. 104. Sauerbruch, F., Felix, W. (1927) Schweiz. med. Wschr. 57, 859.
evidence of bronchial carcinoma. Bronchoscopy normal larynx. The trachea was deviated to the right slightly, and its left wall was indented. At operation a colloid goitre was found extending from the right lower pole into the upper mediastinum. It enveloped the trachea, except its posterior aspect, and descended to the CORRELATION OF SERUM-VITAMIN B12 level of the aortic arch. After removal of the goitre the patient has had no recurrence of symptoms. LEVELS AND URINARY FOLIC ACID IN Case 2.-A man, aged 72, complained of dyspnoea on NUTRITIONAL MEGALOBLASTIC ANÆMIA exertion and of haemoptysis. Eleven years previously he had had an adenoma of the thyroid removed. Eight years later P. W. G. TASKER he noted that he was dyspnoeic on exertion and when lying M.B. Lond. down. Six months ago his voice became weak, and in the From the Medical last two months he had haemoptysis on two occasions, the Institute for Research, Kuala Lumpur, Malaya blood being bright red, but he could not estimate how much. NUTRITIONAL megaloblastic anaemia and the closely Investigations.-Radiographs of the chest showed a large related megaloblastic anaemia, of pregnancy are consuperior mediastinal tumour displacing the oesophagus formost workers to be caused primarily by a sidered far to the and to the left. The trachea was by wards displaced left and laterally compressed. deficiency of folic acid, and at present folic acid is At operation the place of the right lobe of the thyroid was regarded as the treatment of choice (Davidson 1948, found to be taken by a large adenoma extending into the Spies et al. 1948, Wilkinson 1948). thorax and passing behind the trachea. After his operation Vitamin B12 is also therapeutically active in some of the patient has had no recurrence of symptoms. these patients in India (Patel and Kocher 1950, Chaudhuri Case 3.-A female shop-assistant, aged 48, was referred in 1951, Das Gupta et al. 1953), as I have found it in some June, 1950, with a provisional diagnosis of bronchiectasis. of my patients in Malaya. Low serum-vitamin B12 She complained of hæmoptysis lasting seven days in 1949. levels have been found in patients with pernicious The blood was dark red and came into the back of her mouth anaemia and with other types of megaloblastic anaemia "as if it had come from her windpipe." Six months later and (Mollin and Ross 1952, 1954, Unglaub et al. 1954) ; thereafter at two-monthly intervals the hæmoptysis recurredlow levels have been found among the patients similar a cupful of blood each time and unmixed with sputum. seen here. Examination showed a healthy woman with a midline Details of the interrelationship between folic acid suprasternal swelling which was ill defined and did not move on swallowing. and vitamin B12 in the aetiology of megaloblastic anæmia Investigations.-Tubercle bacilli were not seen in the are still largely unknown ; but that a relationship sputum. Radiographs of the chest showed a soft-tissue exists is well established (Vilter et al. 1950, Girdwood swelling in the left side of the thoracic inlet. No evidence of 1952a and b). I report here a correlation found between pulmonary tuberculosis. Screening showed that the swelling the serum-vitamin B12 level and the urinary excretion moved on and was continuous with the cervical
radiographic showed
a
swallowing thyroid swelling. The
of folic acid after
From these three cases it will be noted that the blood was unmixed with sputum. In two cases the haemoptysis was considerable, and one patient could not estimate the quantity. Since these goitres lie behind the sternum, there is an increase in local pressure on the surrounding structures. The veins are obstructed before the arteries and became engorged. The inferior thyroid vessels, together with the internal jugular, innominate, and superior vena cava, depending on the extent of the goitre, take part in this congestion. This increased venous pressure manifests itself clinically as distended cutaneous veins of the neck and upper part of the arms,
The 29 patients studied came from the lower-income groups served by the General Hospital, Kuala Lumpur, Malaya, most of them being Indian and Chinese labourers and artisans. They all had gross nutritional megaloblastic anaemia, proved in each case by marrow biopsy. Clinical sprue was not seen by me in this population. and four representative patients with severe megaloblastic anaemia gave normal vitamin-A absorption curves and normal radiological intestinal patterns. Nearly all the patients had a haemoglobin concentration of 5 g. or less per 100 ml., and had received no previous treatment except iron. None of them had severe pyrexia, but some had a slightly raised temperature not associated with any clinical infection, as is sometimes seen in severe megaloblastic anaemia. There was no gross eedema or other clinical evidence of disease, apart from that related
trachea was pushed over to the right. Bronchoscopy showed no abnormality. At operation a retrosternal enlargement of the thyroid extending from the left lobe was found. No recurrence of symptoms followed the operation. .
Discussion
a
loading
dose.
Material
62 to anaemia, and malnutrition. A few patients excluded when it was found that they had a urinary output of less than 300 ml. in six hours during the determination of the urinary excretion of folic acid, because a urinary flow as small as this affects the output of folic acid.
directly
SERUM-VITAMIN
were
B12
LEVELS
AND
EXCRETION
AFTER A LOADING DOSE OF
5
OF
FOLIC ACID’
MG.
Methods The serum-vitamin Bl2 levels were kindly estimated by Dr. G. I. M. Ross and Dr. D. L. Mollin at the Post-
graduate Medical School, London, using Euglena gracilis the test organism (Ross 1952). Urinary folic acid was estimated as recommended by Girdwood (1953a and b) ; the test organism was S’treptococcus lactis R (Gradwohl and Kouri 1948). A twelve-tube assay technique was used, and the tests were planned for statistical accuracy as suggested by Wood (1953). A loading dose of 5 mg. of folic acid was given subcutaneously, and the amount excreted in the urine in the following six hours was assayed. Folic acid 15 mg. was then given each day parenterally for the next five days to ensure tissue saturation. Forty-eight hours after the last dose the second loading dose of folic acid (5 mg.) was given orally and the subsequent six-hours urinary excretion was assayed as before. as
Results
The normal range for total serum-vitamin B12 is given by Mollin and Ross (1952) as 100-720 µµg. (mean Of the present 29 patients with 358 µµg.) per ml. megaloblastic anaemia 11 had low levels. A normal range of urinary excretion of folic acid was established for 15 patients with normoblastic irondeficiency nutritional anaemia of comparable severity. The subcutaneous loading dose gave a mean excretion of 2.02 mg. (standard deviation 0.236) and the oral loading dose 1.63 mg. (standard deviation 0.238). In the patients with megaloblastic anaemia the excretion of folic acid was below normal after the subcutaneous loading dose in 8, and after the oral loading dose in 11. The accompanying figure shows the relationship between the urinary folic acid and the serum-vitamin B12 +",no
29 patients, compared
with the normal ranges, after the subcutaneous
dose. As the excretion of folic acid decreased,
loading
so the serumvitamin B12 level fell,
)
although both remained within normal 7
_
_
1
_
these had severe mega,loblastic anaemia. Only when urinary folic acid reached values below normal did the serum-vitamin B12 level also drop This regression was highly to a pathological value. Correlation between serum-vitamin 8’2 level and urinary excretion of folic acid during six hours after loading dose of 5 mg.
though patients
significant (0.001
When a small dose of folic acid is given subcutaneously it may go to the tissues or be excreted in the urine. If
proportion of folic acid going to the tissues increases the body becomes more depleted of folic acid, the amount excreted in the urine will be inversely proportional to the degree of folic-acid deficiency. In that case the vitamin-B12 deficiency only develops when the folic-acid deficiency has become severe. In pernicious anaemia, which is regarded as primarily a vitamin-B12 deficiency, the excretion of folic acid is decreased (Spray and Witts 1952), as in the present cases. Since pernicious anaemia also responds to folicacid therapy, it can be assumed that there is a folic-acid deficiency conditioned by the vitamin-B12 deficiency. This appears to be the opposite of the hypothesis given above for these nutritional megaloblastic anaemias. Spray and Witts (1952) suggest that a vitamin-B12 deficiency may lead to a conditioned retention of folio acid in the tissues, accounting for this low excretion. Nieweg et al. (1954) found that, in non-pernicious megaloblastic anaemia, folic-acid levels tended to be normal when the vitamin-B12 level was low, and vice versa ; in about half their pernicious-anaemia patients both vitamins were at low levels. They also, like Spray and Witts, believe that a vitamin-B12 deficiency can influence the storage of folic acid. In the present investigation the excretion of folic acid was normal while the serum-vitamin B12level was normal, in spite of the fact that the patients had severe megaloblastic anaemia. This supports the suggestion of Spray and Witts that the excretion of folic acid does not measure the tissue depletion but, rather, follows the the as
-
vitamin-B12 deficiency. Finally, it is possible that a vitamin-B12 deficiency may develop independently of an already established folic-acid deficiency. Between these two vitamins it is still not known which
deficiency develops first-which is the horse and which the cart-but certainly a deficiency of both can be present in this type of megaloblastic anaemia as observed in Malaya. Summary A close correlation was found between the serumvitamin B12 level and the urinary excretion of folic acid after a subcutaneous loading dose of 5 mg.in patients with severe megaloblastic anæmia.
63 When the serum-vitamin B12 level excretion of folic acid was low also. I for
was
low, the
indebted to Dr. D. L. Mollin and Dr. R. H. Girwood helpful criticism. am
REFERENCES
Chaudhuri, S. (1951) Brit. med J. ii, 825. Das Gupta, C. R., Chatterjea, J. B., Basu, P. (1953) Ibid, ii, 645 Davidson, L. S. P. (1948) Edinb. med. J. 55, 400. Girdwood, R. H. (1952a) Blood, 7, 77. (1952b) Brit. J. Nutr. 6, 315. (1953a) Lancet, ii, 53. (1953b) Brit. med. J. ii, 741. Gradwohl, R. B. H., Kouri, P. (1948) Clinical Laboratory Methods and Diagnosis. 4th ed., St. Louis. Mollin, D. L., Ross, G. I. M. (1952) J. clin. Path. 5, 129. (1954) Proc. R. Soc. Med. 47, 428. Nieweg, H. O., Faber, J. G., De Vries, J. A., Kroese, W. F. (1954) J. Lab. clin. Med. 44, 118. Patel, J. C., Kocher, B. R. (1950) Brit. med. J. i, 924. Ross, G. I. M. (1952) J. clin. Path. 5, 250. Spies, T. D., García Lopez, G., Stone, R. E., Milanes, F., Lopez Toca, R., Aramburu, T. (1948) Lancet, i, 239. Spray, G. H., Witts, L. J. (1952) Brit. med. J. ii, 62. Unglaub, W. G., Rosenthal, H. L., Goldsmith, G. A. (1954) J. Lab. clin. Med. 43, 143. Vilter. R. W., Horrigan, D., Mueller, J. F., Jarrold, T., Vilter, C. F. Hawkins, V., Seaman, A. (1950) Blood, 5, 695. Wilkinson, J. F. (1948) Brit. med. J. i, 822. Wood, E. C. (1953) Analyst, 78, 451. —
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CHRONIC HYPOPOTASSÆMIA OF RENAL
ORIGIN E. G. SAYERS M.B. N.Z., F.R.C.P., F.R.A.C.P., D.T.M.
&
H.
SENIOR PHYSICIAN
K. E. D. EYRE M.B. N.Z., M.R.A.C.P. MEDICAL REGISTRAR
AUCKLAND HOSPITAL,
M.B.,
F. H. SIMS N.Z., Ph.D. Edin.
M.Se.
CHEMICAL PATHOLOGIST
AUCKLAND,
NEW ZEALAND
MUSCULAR weakness or paralysis due to low serumpotassium levels is well recognised, and the causes of low serum-potassium levels are numerous. When renal disease causes disordered potassium metabolism, there is usually potassium retention with high serum-potassium levels affecting mainly the heart and skeletal muscles. Within recent years, however, reports have been published of renal disease causing excessive urinary excretion of potassium, low serum-potassium levels, and paralysis. Brown et al. (1944) reported three patients with hypopotassaemia due to renal disease ; Kjerulf-Jensen et al. (1951) reported a woman with persistently low serumpotassium levels which may have been renal in origin; Davidsen et al. (1951) recorded a case of chronic potassium deficiency probably due to renal disease ; and Earle et al. (1951) made prolonged observations on a Chinese with renal
hypopotasssemia. We present here with this
syndrome, damage.
observations on another patient who is unusual in having remarkably
our
little renal
Clinical Record The patient was seen by one of us (E. G. S.) in consultation on Sept. 8, 1952, because of generalised weakness and sudden attacks of paralysis during the previous few months. She was a married European woman aged 37, and had been in her usual good health until half-way through her third and latest pregnancy. About this time she began to have undue fatigue, which became progressively worse up to the time of her delivery. This third pregnancy, like her previous two pregnancies, was abnormal. Her first pregnancy was ectopic, necessitating the removal of her right fallopian tube on April 20, 1947. Her blood-pressure then was 160/100 mm. Hg and her urine was normal. She became pregnant again in 1948, when her bloodpressure and urine were normal. Because of slight albuminuria and
hypertension (blood-pressure 165/110
mm.
Hg)
in the
last few weeks of pregnancy, labour was induced surgically two weeks before the expected date of delivery. The puer-
was normal, and two weeks post partum her bloodpressure had returned to normal. Her third pregnancy began in 1951, the last menstrual’ period starting on June 16. She had no albuminuria then, but her blood-pressure was 165/100 mm. Hg and remained about this level during the first trimester, fell to about 145/85 mm. Hg in the middle trimester, and rose to about 165/95 Labour was induced on mm. Hg in the last two months. March 14, 1952, a week before the expected date of deliveryIt was during the latter half of this pregnancy that the patient developed excessive fatigue. She felt well on discharge from hospital, but after a week at, home she again became very tired. After two months her milk began to diminish, and the baby took an hour over each feed. On May 14, 1952, after feeding the baby she suddenly collapsed on the bed and could scarcely move an arm or a leg. She regained her strength in three days. After this episode she continued to be very tired after slight exertion. After a further interval she developed attacks of weakness of the legs in which she would suddenly drop to the ground and have great difficulty in getting up again. There was no disturbance of consciousness in these attacks, and she described them as a feeling as if someone had struck her behind the knees, causing her legs to buckle up under her. The first such attack came on about three days after her collapse after feeding the baby. On this evening she unexpectedly dropped to the floor, and her husband had to help her to bed. Similar episodes took place about once a week thereafter at any hour of the day. In July, 1952, the weakness in her arms became worse, causing clumsiness, and she often dropped things. She would test the power in her legs by raising herself on tiptoe and then take one foot off the ground. Often her legs were too weak to support her. As time went by, although these recurrent paralyses became no more frequent, they were more severe and lasted longer. In August, 1952, she had two severe episodes and was severely paralysed for several days. The last attack before seeing, E. G. S. was on Aug. 28, 1952, and on this occasion, after having afternoon tea, she stood up, but on stepping forward she fell to the floor and could not get up. She was carried to bed and remained there for five days. For the first two days she could not move her legs and could barely lift her It was eight days before she could walk without arms. assistance.
perium
.
In all the attacks only the skeletal musculature was affected and there were no symptoms of weakness in the muscles supplied by the cranial nerves. The legs were often affected alone and were always more paralysed than the arms. There had been no respiratory distress. The only symptom of abnormal sensation was occasional tingling and numbness of the hands. Her previous history revealed npthing of significance The family other than the abnormal pregnancies.
history
unimportant. interrogation brought to light the following
was
Routine
points : In the preceding twelve months the patient frequency of micturition, nocturia, polyuria,
had developed and increased
thirst. For several months she had noticed a rather unusual visual defect. When reading, she could see clearly only the central portion of one line, the rest of the page being blurred. This disability was so great that she had given up reading.
On admission to the Auckland Public Hospital for investigation on Sept. 11, 1952, physical examination gave the following results : She was intelligent and cooperative but languid. Careful examination of the nervous system revealed only generalised skeletal muscular weakness, greatest in the legs. No changes. in sensory appreciation were detected, and all her superficial and deep reflexes were brisk and her plantar responses flexor. Her optic fundi were normal ; she had normal visual acuity, and her visual fields were full. Her gait was shuffling and unsteady, and after walking about twenty-five yards she became exhausted and had to support herself by holding on to the wall. Her blood-pressure was 165/100 mm. Hg, the cardiovascular system being otherwise normal. The respiratory and alimentary systems were normal. A catheter specimen of urine contained a faint trace of albumin, an occasional epithelial cell, and one leucocyte per high power field.
The urine
was
sterile
on
culture.