Hypokalaemia in Acute Myeloid Leukaemia M. A. MIR, M.B., M.R.C.P., B. BRABIN, M.B., Ch.B., 0. T. TANG, M.B., M.R.C.P., M. J. LEYLAND, M.R.C.P., and I. W. DELAMORE, Ph.D., F.R.C.P.E., Manchester, England
Potassium balance studies were carried out in 32 consecutive patients with acute myeloid leukaemia and its variants. Serum K level fell below 3.5 meq/litre in 19 (59%) of these patients at some stage of their illness. There was no correlation between urinary and serum lysozyme (muramidase) concentrations and the low serum K level. In addition to the unexplained urinary K loss, there appear to be other factors contributing to the development of hypokalaemia.
UNEXPECTED HYPOKALAEMIA is a frequent and serious complication associated with acute myeloid leukaemia. The precise mechanism underlying this abnormality has remained obscure. Osserman and Lawlor (1) considered a possible relation between hypokalaemia, hyperkaluria, and the high concentration of urinary lysozyme (muramidase). Subsequently, Muggia and associates (2) carried out balance studies in three patients with hypokalaemia and attributed the electrolyte disturbance to failure of the kidney to conserve potassium. These authors suggested that lysozymuria might be responsible for renal tubular dysfunction causing renal wasting of K. This hypothesis does not explain the occurrence of hypokalaemia in patients with normal level of serum lysozyme. Pruzanski and Platts (3) found no correlation between hypokalaemia and the level of serum and urinary lysozyme. This study was undertaken to explore the relation between lysozyme and serum K and to investigate the disturbances leading to hypokalaemia. Patients and Methods
Thirty-two consecutive patients were admitted to the sixth Medical Research Council trial on acute myeloid (nonlymphoid) leukaemia. Cytotoxic therapy (daunorubicin and cytosine arabinoside) was given in 5-day courses with a minimum of 5 day's rest between the courses (4). Serum and urinary electrolytes, urea, creatinine, uric acid, and urinary proteins were estimated daily. The laboratory methods used were the same as reported elsewhere (5). Lysozyme concentration of urine and serum was determined by the turbidimetric method of Parry, Chandan, and Shahani (6). The dietary K values were obtained from the reference tables of McCance and Widdowson (7). Appropriate corrections were made for the food refused in each case. The average duration of stay in hospital was 11.6 days. Plasma aldosterone was estimated by radioimmunoassay (8). • From the University Department of Clinical Haematology, Manchester Royal Infirmary, Manchester, England.
54
Downloaded from https://annals.org by Tulane University user on 01/11/2019
Results
Hypokalaemia (serum K, < 3.5 meq/litre) developed in 19 (59%) patients at some stage of their illness. Potassium levels fell below 4 meq/litre in all but two cases (Patients 12 and 24) during the period of the study. Five (Patients 7, 9, 16, 22 and 26) had low serum K levels on admission before antibiotic or cytotoxic therapy had been started. There was no obvious cause for this except in Patient 22, who presented with osmbtic diuresis due to diabetes mellitus. The remaining 14 patients developed hypokalaemia during the course of their treatment (Table 1). No relation was observed between any drug and the fall in the serum K level. The low serum K state persisted in these patients during the period when no drugs were administered. RAISED LYSOZYME LEVELS AND HYPOKALAEMIA
Pretreatment serum lysozyme concentration was found to be raised (control, 3 through 13 /xg/ml) in 18 patients, and 9 of these developed hypokalaemia (Table 1). This association was statistically insignificant. Two (Patients 12 and 28), with a high level of serum lysozyme, remained normokalaemic throughout the period of the study. As expected, serum and urinary lysozyme levels were raised in all of the 11 patients with acute monocytic and myelomonocytic leukaemia. In the bigger group of 21 patients with acute myeloblastic leukaemia, only 7 patients had a raised serum lysozyme level. The incidence of hypokalaemia was approximately equal in both the groups. Urinary lysozyme concentration was raised (control, < 2 /Ag/ml) in 18 patients, and 10 of these developed hypokalaemia. The occurrence of hypokalaemia in patients with lysozymuria was not significant, because serum K levels also fell below 3.5 meq/litre in 9 of the remaining 14 patients (Table 1). Lysozymuria occurred in 16 of the 18 patients with raised serum lysozyme concentration. URINARY K DATA
The most striking feature was that all patients excreted inappropriately large quantities of K in relation to the low serum levels. Potassium losses were particularly heavy in 12 patients in whom the mean urinary excretion was more than the mean K intake (Table 1). Other patients with variable hyperkaluria excreted large quantities of K following cytotoxic therapy with a fall in blast cell count as judged from bone marrow and from peripheral blood. Of the 12 patients with hyperkaluria, only 7 had Annals of Internal Medicine 82:54-57,1975
Table 1. Potassium Ballance Data on 32 Patients with Acute Myc>loid Leukaemia Patierit
Mean K >/alues Intake
Serum K*
I.ysozyme
Urine
meq/d meq/litre Acute Myeloblasts leiukaemia 2 53 20 3.3 3 56 39 3.4 4 53 55 2.9 5 51 51 3.1 8 72 48 2.8 10 59 34 3.3 11 62 39 3.9 13 57 62 3.7 14 55 59 3.3 15 52 59 3.5 17 48 42 3.2 18 67 86 3.3 20 79 63 2.6 23 60 64 3.7 24 58 42 4.1 25 60 74 2.6 26 81 72 2.1 27 57 98 3.5 29 62 95 3.6 30 58 52 3.8 32 72 62 1.8 Acute monocytic and imyelomonocytic leukaemia 1 52 45 3.1 6 53 27 3.7 7 52 60 2.2 9 57 56 3.1 12 64 73 4.2 16 123 68 3.1 19 58 56 3.5 21 59 69 3.6 22 139 152 1.6 28 59 41 3.5 31 62 53 3.4
Urin 150 mg/day) during the period of the study, and in ten of these the urinary protein excretion exceeded 500 mg/day (Table 1). The proteinuria was intermittent, waxing after cytotoxic therapy and waning after the completion of a course.
OTHER STUDIES
Further studies were carried out in seven patients (Table 2 ) . Following an acid load (ammonium chloride, 0.1 g/kg body weight) urinary pH fell normally below 5.3 (9) in six patients. The urinary acidification was impaired in Patient 22, who had hypokalaemia for more than a week before the test. This patient had a low plasma bicarbonate concentration attributable to coexisting diabetes mellitus. A mild metabolic alkalosis due to hypokalaemia was present in the remaining six patients. In five of these (Patients 8, 13, 17, 31 and 32), who were normokalaemic on admission to hospital, the pretreatment arterial blood pH was observed to increase with the fall in the serum K level. Plasma aldosterone level was estimated in 4 cases (Patients 8, 26, 31, and 32). Moderately raised values were obtained in Patients 31 and 32, and in Patient 26 plasma aldosterone concentration was near the upper limit of normal range (normal resting value, 20 through 200 p g / m l ) . Additional evidence pointing to an increased Mir et a/. • Hypokalemia in Leukaemia
Downloaded from https://annals.org by Tulane University user on 01/11/2019
55
Table 2. Special Studies in 7 Patients With Acul» Myeloid Leulkaemia Patients 13
8 Plasma alderosterone, pg/ml* Urinary pH following acid load (see text) Plasma Cortisol, ng/100 ml\ Arterial blood pH Plasma bicarbonate, meq/litre % Serum K, meq/litre Urinary Na/K, meq/day
133 5.2 23 7.44 24 3.2 67/48
17
5.3 13.5 7.46 28 3.9 132/68
5.1 15.5 7.44 28 3.8 130/33
22 6.6 7.42 18 2.9 361/207
26
31
32
198 5 45.5 7.5 32 2.8 126/75
224 4.8 17.5 7.42 25 3.6 168/54
289 5 18 7.5 2 32 1.8 26/59
7.
* Normal resting value, 20 through 200 pg/ml (S
Potassium balance studies were carried out in 32 consecutive patients with acute myeloid leukaemia and its variants. Serum K level fell below 3.5 meq/litre in 19 (59%) of these patients at some stage of their illness. There was no correlation between urinary and serum lysozyme (muramidase) concentrations and the low serum K level. In addition to the unexplained urinary K loss, there appear to be other factors contributing to the development of hypokalaemia.
UNEXPECTED HYPOKALAEMIA is a frequent and serious complication associated with acute myeloid leukaemia. The precise mechanism underlying this abnormality has remained obscure. Osserman and Lawlor (1) considered a possible relation between hypokalaemia, hyperkaluria, and the high concentration of urinary lysozyme (muramidase). Subsequently, Muggia and associates (2) carried out balance studies in three patients with hypokalaemia and attributed the electrolyte disturbance to failure of the kidney to conserve potassium. These authors suggested that lysozymuria might be responsible for renal tubular dysfunction causing renal wasting of K. This hypothesis does not explain the occurrence of hypokalaemia in patients with normal level of serum lysozyme. Pruzanski and Platts (3) found no correlation between hypokalaemia and the level of serum and urinary lysozyme. This study was undertaken to explore the relation between lysozyme and serum K and to investigate the disturbances leading to hypokalaemia. Patients and Methods
Thirty-two consecutive patients were admitted to the sixth Medical Research Council trial on acute myeloid (nonlymphoid) leukaemia. Cytotoxic therapy (daunorubicin and cytosine arabinoside) was given in 5-day courses with a minimum of 5 day's rest between the courses (4). Serum and urinary electrolytes, urea, creatinine, uric acid, and urinary proteins were estimated daily. The laboratory methods used were the same as reported elsewhere (5). Lysozyme concentration of urine and serum was determined by the turbidimetric method of Parry, Chandan, and Shahani (6). The dietary K values were obtained from the reference tables of McCance and Widdowson (7). Appropriate corrections were made for the food refused in each case. The average duration of stay in hospital was 11.6 days. Plasma aldosterone was estimated by radioimmunoassay (8). • From the University Department of Clinical Haematology, Manchester Royal Infirmary, Manchester, England.
54
Downloaded from https://annals.org by Tulane University user on 01/11/2019
Results
Hypokalaemia (serum K, < 3.5 meq/litre) developed in 19 (59%) patients at some stage of their illness. Potassium levels fell below 4 meq/litre in all but two cases (Patients 12 and 24) during the period of the study. Five (Patients 7, 9, 16, 22 and 26) had low serum K levels on admission before antibiotic or cytotoxic therapy had been started. There was no obvious cause for this except in Patient 22, who presented with osmbtic diuresis due to diabetes mellitus. The remaining 14 patients developed hypokalaemia during the course of their treatment (Table 1). No relation was observed between any drug and the fall in the serum K level. The low serum K state persisted in these patients during the period when no drugs were administered. RAISED LYSOZYME LEVELS AND HYPOKALAEMIA
Pretreatment serum lysozyme concentration was found to be raised (control, 3 through 13 /xg/ml) in 18 patients, and 9 of these developed hypokalaemia (Table 1). This association was statistically insignificant. Two (Patients 12 and 28), with a high level of serum lysozyme, remained normokalaemic throughout the period of the study. As expected, serum and urinary lysozyme levels were raised in all of the 11 patients with acute monocytic and myelomonocytic leukaemia. In the bigger group of 21 patients with acute myeloblastic leukaemia, only 7 patients had a raised serum lysozyme level. The incidence of hypokalaemia was approximately equal in both the groups. Urinary lysozyme concentration was raised (control, < 2 /Ag/ml) in 18 patients, and 10 of these developed hypokalaemia. The occurrence of hypokalaemia in patients with lysozymuria was not significant, because serum K levels also fell below 3.5 meq/litre in 9 of the remaining 14 patients (Table 1). Lysozymuria occurred in 16 of the 18 patients with raised serum lysozyme concentration. URINARY K DATA
The most striking feature was that all patients excreted inappropriately large quantities of K in relation to the low serum levels. Potassium losses were particularly heavy in 12 patients in whom the mean urinary excretion was more than the mean K intake (Table 1). Other patients with variable hyperkaluria excreted large quantities of K following cytotoxic therapy with a fall in blast cell count as judged from bone marrow and from peripheral blood. Of the 12 patients with hyperkaluria, only 7 had Annals of Internal Medicine 82:54-57,1975
Table 1. Potassium Ballance Data on 32 Patients with Acute Myc>loid Leukaemia Patierit
Mean K >/alues Intake
Serum K*
I.ysozyme
Urine
meq/d meq/litre Acute Myeloblasts leiukaemia 2 53 20 3.3 3 56 39 3.4 4 53 55 2.9 5 51 51 3.1 8 72 48 2.8 10 59 34 3.3 11 62 39 3.9 13 57 62 3.7 14 55 59 3.3 15 52 59 3.5 17 48 42 3.2 18 67 86 3.3 20 79 63 2.6 23 60 64 3.7 24 58 42 4.1 25 60 74 2.6 26 81 72 2.1 27 57 98 3.5 29 62 95 3.6 30 58 52 3.8 32 72 62 1.8 Acute monocytic and imyelomonocytic leukaemia 1 52 45 3.1 6 53 27 3.7 7 52 60 2.2 9 57 56 3.1 12 64 73 4.2 16 123 68 3.1 19 58 56 3.5 21 59 69 3.6 22 139 152 1.6 28 59 41 3.5 31 62 53 3.4
Urin 150 mg/day) during the period of the study, and in ten of these the urinary protein excretion exceeded 500 mg/day (Table 1). The proteinuria was intermittent, waxing after cytotoxic therapy and waning after the completion of a course.
OTHER STUDIES
Further studies were carried out in seven patients (Table 2 ) . Following an acid load (ammonium chloride, 0.1 g/kg body weight) urinary pH fell normally below 5.3 (9) in six patients. The urinary acidification was impaired in Patient 22, who had hypokalaemia for more than a week before the test. This patient had a low plasma bicarbonate concentration attributable to coexisting diabetes mellitus. A mild metabolic alkalosis due to hypokalaemia was present in the remaining six patients. In five of these (Patients 8, 13, 17, 31 and 32), who were normokalaemic on admission to hospital, the pretreatment arterial blood pH was observed to increase with the fall in the serum K level. Plasma aldosterone level was estimated in 4 cases (Patients 8, 26, 31, and 32). Moderately raised values were obtained in Patients 31 and 32, and in Patient 26 plasma aldosterone concentration was near the upper limit of normal range (normal resting value, 20 through 200 p g / m l ) . Additional evidence pointing to an increased Mir et a/. • Hypokalemia in Leukaemia
Downloaded from https://annals.org by Tulane University user on 01/11/2019
55
Table 2. Special Studies in 7 Patients With Acul» Myeloid Leulkaemia Patients 13
8 Plasma alderosterone, pg/ml* Urinary pH following acid load (see text) Plasma Cortisol, ng/100 ml\ Arterial blood pH Plasma bicarbonate, meq/litre % Serum K, meq/litre Urinary Na/K, meq/day
133 5.2 23 7.44 24 3.2 67/48
17
5.3 13.5 7.46 28 3.9 132/68
5.1 15.5 7.44 28 3.8 130/33
22 6.6 7.42 18 2.9 361/207
26
31
32
198 5 45.5 7.5 32 2.8 126/75
224 4.8 17.5 7.42 25 3.6 168/54
289 5 18 7.5 2 32 1.8 26/59
7.
* Normal resting value, 20 through 200 pg/ml (S
