405
Clinico Chimica Acta, 66 (1976) 405-409 0 Elsevier Scientific Publishing Company,
Amsterdam
- Printed in The Netherlands
CCA 7546
ELEVATED SERUM ENZYMES IN PATIENTS AND THEIR CLINICAL SIGNIFICANCE
WITH WASP/BEE STING
PIN LIMa, I.K. TANb and P.H. FENG’ aDepartment of Medicine, University of Singapore, bSingapore General Hospital, Singapore, and ’ Toa Pay oh Hospital, Singapore (Singapore) (Received
August 19, 1975)
Seventeen patients who had been admitted to hospital for wasp/bee sting were studied. Mild pyrexia was encountered in 7 patients, rash/m-tic&a in 3, angioneurotic oedema in 2, oliguria in 2, microscopic haematuria and albuminuria in 3, transient hypotension in 1. However, there were frequent elevations of serum glutamic-oxaloacetic transaminase (9 out of 17 patients), serum creatine phosphokinase (14 out of 17 patients) and serum lactate dehydrogenase (8 out of 14 patients), indicating presence of damage to muscle fibres. This was confirmed by the histological findings of a muscle-biopsy from the most severe case. Elevation of serum glutamic-pyruvic transaminase was found in 6, and elevation of serum isocitrate dehydrogenase in 5 out of 14 patients, suggesting presence of liver damage. The above enzyme elevations appeared short-lived except in the clinically most severe patient (case 9) who developed acute tubular necrosis. All patients except the latter suffered no clinical sequelae and there was no correlation between their clinical condition and the presence or degree of elevations of serum enzymes. Introduction There have been many reports of serious complications of bee/wasp sting [l-6]. Despite these reports, however, it has been the general impression that grave clinical complications occur in only a small fraction of all cases of bee/ wasp sting. Even though cases that are admitted to hospitals tend to be selec-
* Requests for reprints should be addressed to: Professor Pin Lim. Department of Medicine, University of Singapore, Sepoy Lines, Singapore 3.
406
tively more serious, the majority of them do not develop clinically obvious sequelae [ 61. However, the more subtle biochemical changes and their relationship to clinical features have not been studied, and these aspects form the subject of the present study. Materials and methods Seventeen cases of bee/wasp sting were ~vestigated on admission to hospital. There were 11 males and 6 females, their ages ranged from 11 to 33 years. After a thorough clinical examination, venous blood was drawn within 2 hours of admission for the estimation of serum giutamic-oxaloacetic transaminase (serum GOT), serum creatinine phosphokinase (serum CPK), serum glutamicpyruvic transaminase (serum GPT), serum lactate dehydrogenase (serum SLD), serum isocitrate dehydrogenase (serum ICD) and serum leucine aminopeptidase (serum LAP). Determination of serum GOT and serum GPT were made by the calorimetric methods using 3,4~initrophenylhydrazine [ 73 , serum ED and serum LD by the methods of Ling [ 81, serum CPK by the method of Hughes [9], and serum LAP by the method of Goldbarg and Rutenburg [lo]. Normal ranges for these serum enzymes are: serum GOT 35--125 units; serum GPT 30-120 units; serum ICI) 15-480 units; serum CPK 0.3- -4.5 unit; serum LD 100-340 units; and serum LAP 70-200 units. Serum urea and potassium were measured by the Technicon Auto-analyser. Results Other than local swelling at the sites of stings, the commonest clinical finding, occurring in 7 patients, was a mild pyrexia of between 99.5”F and 101.5”F lasting 1 to 2 days. Widespread erythematous rash with urticaria was found in 3 patients and angioneurotic oedema in 2. One patient (case 4) had hypotension (80/60 mmHg) associated with urticaria, but he promptly responded to parenteral hydrocortisone. Case 3 had oliguria for only 2 days. In case 9, however, oliguria persisted, indicating the development of acute tubular necrosis. Cases 13 and 16 had proteinuria and haematuria but these urinary abnormalities did not persist. Myoglobinuria or haemoglobinuria was absent in all cases. No patients had jaundice, anaemia or reticulocytosis. Bleeding tendency was not encountered. Of the serum enzymes studied, GOT, CPK, LD, GPT and ICD showed frequent abno~alities. GOT was elevated in 9 and CPK in 14 of the total number of patients. LD, GPT and ICD, estimated in 14 patients were found to be elevated in 8, 6 and 5 patients, respectively, Three of the patients with raised GPT also had concomitant elevated ICD. Grossly high levels of all 5 enzymes were seen in the patient who developed acute tubular necrosis (case 9). No abnormality in LAP level was found in any of the subjects. The final outcome was complete clinical recovery in all patients except case 9 who finally developed chronic uraemia with hypertension. The great majority of patients were discharged clinically well from the ward within 3 days of admission. Repeat estimation of the serum enzymes in 5 patients (cases 1, 4, 6, 7, 8) at the time of discharge showed that the levels had either
I
+
+
+
Urticaria
Rash/
+ + +
+ +
+ +
Pyrexia
DATA
+
+
Oliguria
+
+
Microscopic haematuria and albuminuria
OF PATIENTS
* Wasp-sting. + Indicates presence of abnormality stated above.
M/19 M/26 F/19 M/33 M/25 M/15 M/26 F/25 M/18 + M/19 F/16 F/22 F/21 + F/21 M/19 M/11 M/18
1* 2* 3* 4* 5 6 I* 8 9* 10 11 12* 13 14 15* 16* 17*
Angioneurotic edema
Age
Sex/
AND BIOCHEMICAL
Case No.
CLINICAL
TABLE
114 100 88 100 85 82 125 103 7400 161 150 730 176 300 185 163 213
SGOT (Normal 35-125 units) 4.7 4.2 5.6 2.6 20 19.4 >20
SCPK (Normal 0.34.5 unit) 179 428 130 240 170 365 259 214 1230 520 625 890 410 635
units)
SLD (Normal 100-340
50 112 150 70 85 10 138 50 5300 114 350 800 150 100
SGPT (Normal 30-120 units)
240 950
269 147 215 162 242 54 54 216 12600 510 1110
SICD (Normal 15-190 units) 36 21 26 22 24 36 39 32 66-l 18 12 20 21 14 39 34 24 22
Blood urea (m%/lOOmI
4.1 3.5 3.8 3.8 3.7 3.5 4.0 3.6 4.5-7.1 4.2 4.0 4.1 4.1 4.1 4.0 3.6 3.1
Serum K (meQuiv./I
408
remained within the normal. In contrast, Except for case presence or degree of
normal ranges or, if initially high, had all returned to all the enzymes remained elevated for 40 days in case 9. 9, there was no correlation between clinical condition and elevations of serum enzymes.
Discussion Although cl~i~ally all patients except one suffered no serious consequences, raised levels of the serum enzymes CPK, GOT, LD, GPT and ICD were common. The majority of patients had raised values in at least 2 of these enzymes. These elevations were generally transient as indicated by the results of repeat estimations in 5 patients. In contrast, the only patient who developed serious clinical sequelae (case 9) had prolonged, grossly high levels of all the above enzymes. The elevations of GOT, CPK and LD and their frequent clustering in individual patients (10 patients had elevations of at least 2 of the 3 enzymes) suggest muscle injury. Rhabdomyolysis due to wasp sting had been described in 2 clinically severe cases with acute renal failure [13] , but frequent subclinical muscle injury as seen in the present study does not appear to have been previously reported. None of our patients had clinical features suggesting muscle injury. Tests for myoglobinuria were repeatedly negative even in the most severe case (case 9). It is probable that in our patients the injury was not associated with actual necrosis of the muscle fibres. Biopsy of the gastrocnemius of case 9 revealed essentially eosinophilic changes within the muscle fibres with no evidence of necrosis. Serum hydroxybutyrate dehydrogenase, estimated in the first ten patients of the present series, was found to be elevated in 3 (case 2, 388 units; case 9, 1160 units; case 10, 445 units; normal range: 125-350 units), raising the possibility of damage to the myocardium. However, Shilkin et al. [13] found no evidence of damage to cardiac or smooth muscle in one case. Although jaundice was not present clinically and no patient had hyperbilirubinaemia, raised serum GPT and serum ICD, especially in 3 patients (cases 9, 11, 12) in whom both abnormalities were found together, indicated liver injury. The absence of elevated serum LAP suggested that the injury was essentially hepato~ellul~. The basis of tissue injury is probably one of direct injury by mellitin [ll] or other cytotoxic substance(s) in the venom, Susceptibility of host tissue may be an important factor since in this series the degree of enzyme abnormalities could not be correlated with the number of stings received. Thus case ‘7 who had 62 sting marks showed only mild to moderate elevation of the enzymes, while case 9 with the most severe clinical features and biochemical abnormalities received only 30 stings. The varying nature of the venom from different species of the assailant insects may be important. Besides mellitin, which is a potent cytotoxic agent, bee venom is known to contain apamin and phosphorylase A which are liable to give rise to neurotoxicity and haemorrhage, respectively [ll] . Reports of haemolysis, haemo~hage and neurotoxicity in bee/wasp sting abound in the literature f2,4,5], but interestingly none of our patients exhibited these complications.
409
In terms of clinical prognosis, it would appear that transient, moderately raised levels of the enzymes do not imply or portend clinical severity while sustained, grossly elevated values appear to accompany overt, grave clinical sequelae. It is interesting, however, to note that of the 2 patients (cases 4 and 5) who had normal enzyme levels, case 4 developed features of anaphylactic reaction indicating hypersensitivity to the venom. Fatal caes due to hypersensitivity reaction have been well documented [ 1,121. Although there is evidence for the frequent occurrence of subclinical damage to muscle, liver and possibly myocardium, it is not certain whether subclinical injuries are indeed confined to these organs. The development of renal failure in some cases [ 3,5] could imply the occurrence of subclinical renal injury in a larger proportion of cases. It would have been of interest to determine, by isoenzyme studies, the contribution of renal damage to the elevated serum LD found in our patients. References 1 2 3 4 5 6 7 8 9 10 11 12 13
Schenken, J.R., Tamisiea, J. and Winter, F.D. (1953) Am. J. Clin. Pathol. 23.1216 Marshall, T.K. (1957) Practitioner 178, 712 Irvine, R0.H. (1962) N.Z. Med. J. 61,184 Day, J.M. (1962) Arch. Neural. 7,184 Tan, K.H., Chew, L.S. and Chao, T.C. (1966) Sing. Med. J. 7.122 Wang. H.B. (1970) J. Sing. Paed. Sot. 12,126 Varley, H. (1962) in Practical Clinical Biochemistry, 3rd edn., p. 217. William Heinemann Ling, A.M. (1969) in Development and Application of Calorimetric Method in Clinical Bi Ph.D. Thesis, p. 72, University of Singapore Hughes. B.P. (1962) Clin. Chim. Acta 7. 597 Goldbarg, J.A. and Rutenburg. A.M. (1958) Cancer 11.283 Habermann, E. (1972) Science 177,314 Benson, R.L. and Semenov, H. (1930) J. Allezy 1,105 Shilkin. K.B., Chen, B.T.M. and Khoo, O.T. (1972) Br. Med. J.. 156
:mistry.
Clinico Chimica Acta, 66 (1976) 405-409 0 Elsevier Scientific Publishing Company,
Amsterdam
- Printed in The Netherlands
CCA 7546
ELEVATED SERUM ENZYMES IN PATIENTS AND THEIR CLINICAL SIGNIFICANCE
WITH WASP/BEE STING
PIN LIMa, I.K. TANb and P.H. FENG’ aDepartment of Medicine, University of Singapore, bSingapore General Hospital, Singapore, and ’ Toa Pay oh Hospital, Singapore (Singapore) (Received
August 19, 1975)
Seventeen patients who had been admitted to hospital for wasp/bee sting were studied. Mild pyrexia was encountered in 7 patients, rash/m-tic&a in 3, angioneurotic oedema in 2, oliguria in 2, microscopic haematuria and albuminuria in 3, transient hypotension in 1. However, there were frequent elevations of serum glutamic-oxaloacetic transaminase (9 out of 17 patients), serum creatine phosphokinase (14 out of 17 patients) and serum lactate dehydrogenase (8 out of 14 patients), indicating presence of damage to muscle fibres. This was confirmed by the histological findings of a muscle-biopsy from the most severe case. Elevation of serum glutamic-pyruvic transaminase was found in 6, and elevation of serum isocitrate dehydrogenase in 5 out of 14 patients, suggesting presence of liver damage. The above enzyme elevations appeared short-lived except in the clinically most severe patient (case 9) who developed acute tubular necrosis. All patients except the latter suffered no clinical sequelae and there was no correlation between their clinical condition and the presence or degree of elevations of serum enzymes. Introduction There have been many reports of serious complications of bee/wasp sting [l-6]. Despite these reports, however, it has been the general impression that grave clinical complications occur in only a small fraction of all cases of bee/ wasp sting. Even though cases that are admitted to hospitals tend to be selec-
* Requests for reprints should be addressed to: Professor Pin Lim. Department of Medicine, University of Singapore, Sepoy Lines, Singapore 3.
406
tively more serious, the majority of them do not develop clinically obvious sequelae [ 61. However, the more subtle biochemical changes and their relationship to clinical features have not been studied, and these aspects form the subject of the present study. Materials and methods Seventeen cases of bee/wasp sting were ~vestigated on admission to hospital. There were 11 males and 6 females, their ages ranged from 11 to 33 years. After a thorough clinical examination, venous blood was drawn within 2 hours of admission for the estimation of serum giutamic-oxaloacetic transaminase (serum GOT), serum creatinine phosphokinase (serum CPK), serum glutamicpyruvic transaminase (serum GPT), serum lactate dehydrogenase (serum SLD), serum isocitrate dehydrogenase (serum ICD) and serum leucine aminopeptidase (serum LAP). Determination of serum GOT and serum GPT were made by the calorimetric methods using 3,4~initrophenylhydrazine [ 73 , serum ED and serum LD by the methods of Ling [ 81, serum CPK by the method of Hughes [9], and serum LAP by the method of Goldbarg and Rutenburg [lo]. Normal ranges for these serum enzymes are: serum GOT 35--125 units; serum GPT 30-120 units; serum ICI) 15-480 units; serum CPK 0.3- -4.5 unit; serum LD 100-340 units; and serum LAP 70-200 units. Serum urea and potassium were measured by the Technicon Auto-analyser. Results Other than local swelling at the sites of stings, the commonest clinical finding, occurring in 7 patients, was a mild pyrexia of between 99.5”F and 101.5”F lasting 1 to 2 days. Widespread erythematous rash with urticaria was found in 3 patients and angioneurotic oedema in 2. One patient (case 4) had hypotension (80/60 mmHg) associated with urticaria, but he promptly responded to parenteral hydrocortisone. Case 3 had oliguria for only 2 days. In case 9, however, oliguria persisted, indicating the development of acute tubular necrosis. Cases 13 and 16 had proteinuria and haematuria but these urinary abnormalities did not persist. Myoglobinuria or haemoglobinuria was absent in all cases. No patients had jaundice, anaemia or reticulocytosis. Bleeding tendency was not encountered. Of the serum enzymes studied, GOT, CPK, LD, GPT and ICD showed frequent abno~alities. GOT was elevated in 9 and CPK in 14 of the total number of patients. LD, GPT and ICD, estimated in 14 patients were found to be elevated in 8, 6 and 5 patients, respectively, Three of the patients with raised GPT also had concomitant elevated ICD. Grossly high levels of all 5 enzymes were seen in the patient who developed acute tubular necrosis (case 9). No abnormality in LAP level was found in any of the subjects. The final outcome was complete clinical recovery in all patients except case 9 who finally developed chronic uraemia with hypertension. The great majority of patients were discharged clinically well from the ward within 3 days of admission. Repeat estimation of the serum enzymes in 5 patients (cases 1, 4, 6, 7, 8) at the time of discharge showed that the levels had either
I
+
+
+
Urticaria
Rash/
+ + +
+ +
+ +
Pyrexia
DATA
+
+
Oliguria
+
+
Microscopic haematuria and albuminuria
OF PATIENTS
* Wasp-sting. + Indicates presence of abnormality stated above.
M/19 M/26 F/19 M/33 M/25 M/15 M/26 F/25 M/18 + M/19 F/16 F/22 F/21 + F/21 M/19 M/11 M/18
1* 2* 3* 4* 5 6 I* 8 9* 10 11 12* 13 14 15* 16* 17*
Angioneurotic edema
Age
Sex/
AND BIOCHEMICAL
Case No.
CLINICAL
TABLE
114 100 88 100 85 82 125 103 7400 161 150 730 176 300 185 163 213
SGOT (Normal 35-125 units) 4.7 4.2 5.6 2.6 20 19.4 >20
SCPK (Normal 0.34.5 unit) 179 428 130 240 170 365 259 214 1230 520 625 890 410 635
units)
SLD (Normal 100-340
50 112 150 70 85 10 138 50 5300 114 350 800 150 100
SGPT (Normal 30-120 units)
240 950
269 147 215 162 242 54 54 216 12600 510 1110
SICD (Normal 15-190 units) 36 21 26 22 24 36 39 32 66-l 18 12 20 21 14 39 34 24 22
Blood urea (m%/lOOmI
4.1 3.5 3.8 3.8 3.7 3.5 4.0 3.6 4.5-7.1 4.2 4.0 4.1 4.1 4.1 4.0 3.6 3.1
Serum K (meQuiv./I
408
remained within the normal. In contrast, Except for case presence or degree of
normal ranges or, if initially high, had all returned to all the enzymes remained elevated for 40 days in case 9. 9, there was no correlation between clinical condition and elevations of serum enzymes.
Discussion Although cl~i~ally all patients except one suffered no serious consequences, raised levels of the serum enzymes CPK, GOT, LD, GPT and ICD were common. The majority of patients had raised values in at least 2 of these enzymes. These elevations were generally transient as indicated by the results of repeat estimations in 5 patients. In contrast, the only patient who developed serious clinical sequelae (case 9) had prolonged, grossly high levels of all the above enzymes. The elevations of GOT, CPK and LD and their frequent clustering in individual patients (10 patients had elevations of at least 2 of the 3 enzymes) suggest muscle injury. Rhabdomyolysis due to wasp sting had been described in 2 clinically severe cases with acute renal failure [13] , but frequent subclinical muscle injury as seen in the present study does not appear to have been previously reported. None of our patients had clinical features suggesting muscle injury. Tests for myoglobinuria were repeatedly negative even in the most severe case (case 9). It is probable that in our patients the injury was not associated with actual necrosis of the muscle fibres. Biopsy of the gastrocnemius of case 9 revealed essentially eosinophilic changes within the muscle fibres with no evidence of necrosis. Serum hydroxybutyrate dehydrogenase, estimated in the first ten patients of the present series, was found to be elevated in 3 (case 2, 388 units; case 9, 1160 units; case 10, 445 units; normal range: 125-350 units), raising the possibility of damage to the myocardium. However, Shilkin et al. [13] found no evidence of damage to cardiac or smooth muscle in one case. Although jaundice was not present clinically and no patient had hyperbilirubinaemia, raised serum GPT and serum ICD, especially in 3 patients (cases 9, 11, 12) in whom both abnormalities were found together, indicated liver injury. The absence of elevated serum LAP suggested that the injury was essentially hepato~ellul~. The basis of tissue injury is probably one of direct injury by mellitin [ll] or other cytotoxic substance(s) in the venom, Susceptibility of host tissue may be an important factor since in this series the degree of enzyme abnormalities could not be correlated with the number of stings received. Thus case ‘7 who had 62 sting marks showed only mild to moderate elevation of the enzymes, while case 9 with the most severe clinical features and biochemical abnormalities received only 30 stings. The varying nature of the venom from different species of the assailant insects may be important. Besides mellitin, which is a potent cytotoxic agent, bee venom is known to contain apamin and phosphorylase A which are liable to give rise to neurotoxicity and haemorrhage, respectively [ll] . Reports of haemolysis, haemo~hage and neurotoxicity in bee/wasp sting abound in the literature f2,4,5], but interestingly none of our patients exhibited these complications.
409
In terms of clinical prognosis, it would appear that transient, moderately raised levels of the enzymes do not imply or portend clinical severity while sustained, grossly elevated values appear to accompany overt, grave clinical sequelae. It is interesting, however, to note that of the 2 patients (cases 4 and 5) who had normal enzyme levels, case 4 developed features of anaphylactic reaction indicating hypersensitivity to the venom. Fatal caes due to hypersensitivity reaction have been well documented [ 1,121. Although there is evidence for the frequent occurrence of subclinical damage to muscle, liver and possibly myocardium, it is not certain whether subclinical injuries are indeed confined to these organs. The development of renal failure in some cases [ 3,5] could imply the occurrence of subclinical renal injury in a larger proportion of cases. It would have been of interest to determine, by isoenzyme studies, the contribution of renal damage to the elevated serum LD found in our patients. References 1 2 3 4 5 6 7 8 9 10 11 12 13
Schenken, J.R., Tamisiea, J. and Winter, F.D. (1953) Am. J. Clin. Pathol. 23.1216 Marshall, T.K. (1957) Practitioner 178, 712 Irvine, R0.H. (1962) N.Z. Med. J. 61,184 Day, J.M. (1962) Arch. Neural. 7,184 Tan, K.H., Chew, L.S. and Chao, T.C. (1966) Sing. Med. J. 7.122 Wang. H.B. (1970) J. Sing. Paed. Sot. 12,126 Varley, H. (1962) in Practical Clinical Biochemistry, 3rd edn., p. 217. William Heinemann Ling, A.M. (1969) in Development and Application of Calorimetric Method in Clinical Bi Ph.D. Thesis, p. 72, University of Singapore Hughes. B.P. (1962) Clin. Chim. Acta 7. 597 Goldbarg, J.A. and Rutenburg. A.M. (1958) Cancer 11.283 Habermann, E. (1972) Science 177,314 Benson, R.L. and Semenov, H. (1930) J. Allezy 1,105 Shilkin. K.B., Chen, B.T.M. and Khoo, O.T. (1972) Br. Med. J.. 156
:mistry.
