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Galactosaemia and major burn—a case report
Burns, 10, 135-1 39
135
Printed in Great Britain
Galactosaemia report
and major burn-a
case
P. Kumar Department
of Plastic Surgery, University
Hospital of South Manchester
Summary
The management of burns in an adult patient with galactosaemia is described and the problem of lactosecontaining drugs in this condition highlighted. The unique problem of hypokalaemia is discussed. Small amounts of lactose contained in various oral drugs which the patient received over a prolonged period caused proximal renal tubular dysfunction. This, combined with the tendency of potassium loss in major burns, resulted in severe hypokalaemia, in spite of large amounts of potassium supplements being given. This case history also supports the view that lactose restriction in patients with galactosaemia should be total and lifelong.
INTRODUCTION A MAJOR BURN produces marked changes in the metabolism of water and electrolytes. These have been well described (Moore, 1959; Sevitt, 1974). The interaction of a pre-existing metabolic disease can cause much confusion. Galactosaemia is a relatively rare disease of metabolism, in which lactose intake may produce renal tubular dysfunction. A major burn in such a patient can result in unexpected electrolyte changes. CASE REPORT A 16-year-old female sustained bums of 50 per cent of her body surface area when a paraffin room heater ignited her nylon shirt. The front and back ofthe trunk and parts of both upper and lower limbs were burnt, mostly to a deep dermal depth. She was known to suffer from transferase deficiency galactosaemia and had been on a lactose restricted diet since birth. She was mentally subnormal, physically small for her age and had not started menstruation. She arrived in the Bums Unit one hour after the
accident and was resuscitated with reconstituted dry human plasma, using the Muir and Barclay formula as a guideline. Multiple operations were performed under general anaesthesia to excise and graft the damaged skin, Early cover was provided by homografts and porcine heterograft. These were gradually replaced by autografts. She was fully healed by the 60th day. For the first two days after injury, the patient remained on galactose-free intravenous fluids only. Oral feeding started on the 3rd day with a lactose-free diet. She had supplementary naso-gastric tube feeding with Neutraxil and also received Ferrous Sulphate, Vitamin C, Multivitamin and Dihydrocodein tablets. Unknown to us, these all contain small amounts of lactose. On the 9th day, she became ill with vomiting, diarrhoea and abdominal distension. Neutraxil was stopped as soon as it was found to contain small amounts of galactose but the other drugs continued until the 21st day, when they too were discovered to contain lactose. The gastro-intestinal symptoms then improved. The total amount of lactose received during this period was 32.9 grams. Treatment with Vitamin C tablets continued until the 71st day, as we did not discover until then that this also contained lactose. The daily lactose intake in this form was 400mg (Fig. 3). She had intermittent mild gastro-intestinal symptoms during this period. The main problem in management was severe and persistent hypokalaemia (Fig. 1) in spite of Large oral supplements. We had to give frequent intravenous potassium for a long period and up to 300 m Eqv. per day (Fig. 2) in an effort to raise the serum potassium to within normal levels. In spite of the low serum potassium, the urinary concentration remained high. The serum sodium also remained low during this period and improved only in relation to the serum potassium. The urinary concentration of sodium remained high during this period. These changes are
136
Bums Vol. 1O/No. 2
DAYS SINCE BURN
Fig. 1. Changes in serum and urine concentration
of sodium and potassium. The lower limit of the normal range in serum levels, at our laboratory, is shown by solid horizontal line.
shown in Fig. 1. The serum inorganic phosphate concentration remained low (less than 1 mmol/l) until the 63rd post-bum day. The serum concentration of creatinine, urea and glucose remained within normal range. The urine showed presence of glucose and protein until the 55th post-bum day.
DISCUSSION This girl presented the usual problems of a severe burn with difficulties of resuscitation, skin cover, wound infection and nutrition. The pecu-
liar problems
were a persistently
low serum
Kumar: Galactosaemia-a
$
2.0
2 g
1.5
3 0
1.0
L a J
0.5
G g
0 13
case report
7
11
15
19
23
27
31 DAYS
Fig.
35
39
43
47
51
55
59
63
67
71
SINCE BURN
2. Daily lactose intake.
280-1
3 = i
240-
Y 2 z J
160-
f 2
60-
> d d
,
OJI, 13
7
(
(
,
(
,
,
,
,
11
15
19
23
27
31
35
39
DAYSSINCE
Fig.
3. Daily potassium
potassium and serum sodium and recurrent gastro-intestinal upsets. Large amounts of potassium are lost in burn patients. Moncrieff (1979) listed them as follows: i) Movement of potassium from cell to ECF and then excretion in urine. ii) Inadequate resuscitation, causing triggering of the aldosterone mechanism. iii) Greater secretion of potassium in the distal tubules secondary to increased excretion of sodium caused by high sodium load given during resuscitation. iv) Respiratory alkalosis seen in the early post-bum period increases potassium loss in urine. Initially plasma potasium remain normal, or even high (because of movement across cell membrane) but later, as the potassium from ECF returns into the cell, hypokalaemia occurs if adequate potassium supplement is not provided. When hypokalaemia occurs, the kidney tries to
(
43
,
(
,
,
,
,
,
47
51
55
59
65
67
71
BURN
intake.
conserve potassium and the urinary excretion of potassium falls, unless the kidney itself is at fault (Ypersele et al., 1979). In this girl the excretion of potassium remained high, in spite of very low serum levels (Fig. 1). Following a bum or other severe injury, sodium moves into the cell. The kidney tries to conserve sodium, so that urinary excretion of sodium is low. This changes after a few days with increased loss of sodium and water in urine but, in large burns, patients who are ill or have complications such as septicaemia, the retention of sodium persists longer (Flear, 1970; Sevitt, 1974). In this case, in spite of all these factors and a low serum concentration of sodium, urinary excretion of sodium was substantial. The urine contained glucose in varying amounts up to the 55th day, while blood glucose remained within normal limits. Early glycosuria may be due to post-traumatic glucose intolerance but its persistence for such a prolonged
138
Burns Vol. 1O/No. 2 6 galactose Lactose in intestine Galactose
glucose + galactose
)
+ ATP e+
Galactose-I-P UDP galactose
galactose-I-P
+ UDP glucose +
Epimerase
UDP glucose + PPi 4
4 w
+ ADP
Transferase
w
UDP galactose
+ glucose-l-P
UDP galactose
Pyrophosphorylase
)
glucose-l-P
+ UTP
Fig. 4. Steps of galactose metabolism.
Incidence Inheritance
= 1 : 55 000 = Autosomal
live births recessive
Clinical features 1) In neonatal period Vomiting Diarrhoea Lethargy Jaundice Hepatomegaly Renal tubular dysfunction High risk of sepsis 2) Later Mental and physical Cirrhosis Cataract Tubular dysfunction Amenorrhoea Fig. 5. A summary of
retardation
signs and symptoms in transferase deficiency galactosaemia.
period suggested tubular dysfunction. The urine also contained varying amounts of protein up to the 55th day. Retrospectively we examined the urine of the first 20 days, which had been kept frozen for another trial being undertaken in the Unit, and found it to contain significantly increased amounts of phosphate. the amino-acid chromatography showed significantly increased generalized amino-aciduria. This combination of amino-aciduria, phosphaturia, glycosuria, proteinuria, increased urinary excretion of sodium and potassium and low serum phosphate is a feature of proximal tubular dysfunction (Broyer, 1979). The cause of proximal tubular dysfunction in this case was galactosaemia. This is an inborn error of galactose metabolism. Most commonly it is due to absence or deficiency of galactose-Iphosphate uridyl transferase (Fig. 4). Overall
birth incidence is about 1 : 55 000 (Gitzelmann and Hanson, 1980). In this disease galactose-Iphosphate accumulates in the cells when the patient eats lactose or galactose. This causes damage to the liver, kidneys and brain, producing signs and symptoms which have been described by many investigators (Komrower et al., 1956; Nadler et al., 1969; Donnell et al., 1980). A summary of these is given in Fig. 5. On feeding lactose to patients with galactosaemia, amino-aciduria albuminuria and glycosuria appears (Komrower et al., 1956). In his study, Komrower observed that renal tubular upset does not involve sodium and potassium excretion but this was based on a few observations in a single case only. We think proximal tubular dysfunction occurred in this case, due to administration of lactose contained in various drugs over a long
Kumar: Galactosaemia-a
139
case report
period. The daily dose was very small but a cumulative effect over a long period may have resulted in intracellular build-up of galactose-Iphosphate. At present there is some controversy regarding complete restriction of lactose in the diet ofthese patients later in life. Komrower and Lee (1970) thought that it could be relaxed slightly when the child goes to school, whereas others think that restriction should be complete and life-long (Brandt, 1980). The renal tubular dysfunction was mild but, because of the low potassium pool due to the burn injury, hypokalaemia became very marked. As the patient recovered from the burn and the total potassium pool was restored, hypokalaemia disappeared. The recurrent mild gastro-intestinal upsets were due to lactose intake. Vomiting and diarrhoea occur in patients with galactosaemia when they take lactose. Acknowledgements
1 would like to thank Mr J Lendrum, Consultant Plastic Surgeon, University Hospital of South Manchester, for his permission to report this case. I am also grateful to Dr I. B. Sardharwalla, Director of the Willink Biochemical Genetics Unit, Pendlebury, Manchester, for his guidance on metabolic aspects. I also wish to express my thanks to Mr Mark Woolstencroft, Department of Medical Illustration, for preparation of figures and Miss Christine Whaley for secretarial help.
REFERENCES Brandt N. J. (1980) How long should Galactosaemia be treated? In: Burman D.., Holton J. B. and Pennock C. A. (eds) Inherited Disorders of Carbohydrate Metabolism. Lancaster, MTP Press Ltd, p. 103.
Correspondence
should be addressed 10:
Manchester M20 8LR.
Broyer M. (1979) Tubular Syndromes. In: Hamburger J., Crosnier J. and Grunfeld J. P. (eds) Nephrology. New York, Wiley, p. 19 1. Donnell G. N., Koch R., Fishler K. et al. (1980) Clinical Apects ofGalactosaemia. In: Burman D., Holton J. B., Pennock C. A. (eds) Inherited Disorders of Carbohydrate Metabolism. Lancaster, MTP Press Ltd, p. 103. Flear C. T. G. (1970) Electrolyte and Body Water Changes after Trauma. In: Sevitt S., Stoner H. B. (eds) The Pathology qf Trauma (symposium organized by The Royal College of Pathologists). London, BMA House, p. 16. Gitzelmann R. and Hansen R. G. (1980) Galactose Metabolism, Hereditary Defects and their clinical significance. In: Burman D., Holton J. B., Pennock C. A. (eds) Inherited Disorders of Carbohydrate Metabolism. Lancaster, MTP Press Ltd, p. 6 I. Komrower G. M.. Schwarz V.. Holzel A. et al. (1956) A clinical and biochemical study of Galactosaemia: Arch. Dis. Child. 31, 254. Komrower G. M. and Lee D. H. (1970) Longterm follow-UD of Galactosaemia. Arch. Dis. Child. 45. 372. Moncrieff J. A. (I 979) Replacement Therapy in iurns. In: Arts C. P., Moncrieff J. A., Pruitt B. A. (eds) Burns-A Team Approach. Philadelphia, Saunders &Co, p. 178. Moore F. D. (1959) Metabolic Care of Surgical Patient. Philadelphia, Saunders & Co, p. 307. Muir I. F. K. and Barclay T. L. (1974) Burns and their treatment, 2nd ed. London, Lloyd-Luke. Nadler H. L., lnouyc T. and Hasia D. Y.-Y. (1969) Classical Galactosaemia: A studv of 55 Cases. In: Hasia D. Y.-Y. (ed) Galactosaimia. Springfield, Charles C. Thomas, p. 127. Sevitt S. (1974) Reactions to Injury and Burns and their Clinical Importance. London, Heinemann, p. 74. Ypersele C. V., Bodart P. and Dardenne A. (1979) General Techniques in Clinical Nephrology. In: Hamburger J., Crosnier J., Grunfeld J. P. (eds) HephrologJ,. New York, Wiley, p. 120.
Paper accepted 12 March 1983.
Mr P. Kumar, Registrar in Plastic Surgery. Withington
Hospital, West Didsbury.
135
Printed in Great Britain
Galactosaemia report
and major burn-a
case
P. Kumar Department
of Plastic Surgery, University
Hospital of South Manchester
Summary
The management of burns in an adult patient with galactosaemia is described and the problem of lactosecontaining drugs in this condition highlighted. The unique problem of hypokalaemia is discussed. Small amounts of lactose contained in various oral drugs which the patient received over a prolonged period caused proximal renal tubular dysfunction. This, combined with the tendency of potassium loss in major burns, resulted in severe hypokalaemia, in spite of large amounts of potassium supplements being given. This case history also supports the view that lactose restriction in patients with galactosaemia should be total and lifelong.
INTRODUCTION A MAJOR BURN produces marked changes in the metabolism of water and electrolytes. These have been well described (Moore, 1959; Sevitt, 1974). The interaction of a pre-existing metabolic disease can cause much confusion. Galactosaemia is a relatively rare disease of metabolism, in which lactose intake may produce renal tubular dysfunction. A major burn in such a patient can result in unexpected electrolyte changes. CASE REPORT A 16-year-old female sustained bums of 50 per cent of her body surface area when a paraffin room heater ignited her nylon shirt. The front and back ofthe trunk and parts of both upper and lower limbs were burnt, mostly to a deep dermal depth. She was known to suffer from transferase deficiency galactosaemia and had been on a lactose restricted diet since birth. She was mentally subnormal, physically small for her age and had not started menstruation. She arrived in the Bums Unit one hour after the
accident and was resuscitated with reconstituted dry human plasma, using the Muir and Barclay formula as a guideline. Multiple operations were performed under general anaesthesia to excise and graft the damaged skin, Early cover was provided by homografts and porcine heterograft. These were gradually replaced by autografts. She was fully healed by the 60th day. For the first two days after injury, the patient remained on galactose-free intravenous fluids only. Oral feeding started on the 3rd day with a lactose-free diet. She had supplementary naso-gastric tube feeding with Neutraxil and also received Ferrous Sulphate, Vitamin C, Multivitamin and Dihydrocodein tablets. Unknown to us, these all contain small amounts of lactose. On the 9th day, she became ill with vomiting, diarrhoea and abdominal distension. Neutraxil was stopped as soon as it was found to contain small amounts of galactose but the other drugs continued until the 21st day, when they too were discovered to contain lactose. The gastro-intestinal symptoms then improved. The total amount of lactose received during this period was 32.9 grams. Treatment with Vitamin C tablets continued until the 71st day, as we did not discover until then that this also contained lactose. The daily lactose intake in this form was 400mg (Fig. 3). She had intermittent mild gastro-intestinal symptoms during this period. The main problem in management was severe and persistent hypokalaemia (Fig. 1) in spite of Large oral supplements. We had to give frequent intravenous potassium for a long period and up to 300 m Eqv. per day (Fig. 2) in an effort to raise the serum potassium to within normal levels. In spite of the low serum potassium, the urinary concentration remained high. The serum sodium also remained low during this period and improved only in relation to the serum potassium. The urinary concentration of sodium remained high during this period. These changes are
136
Bums Vol. 1O/No. 2
DAYS SINCE BURN
Fig. 1. Changes in serum and urine concentration
of sodium and potassium. The lower limit of the normal range in serum levels, at our laboratory, is shown by solid horizontal line.
shown in Fig. 1. The serum inorganic phosphate concentration remained low (less than 1 mmol/l) until the 63rd post-bum day. The serum concentration of creatinine, urea and glucose remained within normal range. The urine showed presence of glucose and protein until the 55th post-bum day.
DISCUSSION This girl presented the usual problems of a severe burn with difficulties of resuscitation, skin cover, wound infection and nutrition. The pecu-
liar problems
were a persistently
low serum
Kumar: Galactosaemia-a
$
2.0
2 g
1.5
3 0
1.0
L a J
0.5
G g
0 13
case report
7
11
15
19
23
27
31 DAYS
Fig.
35
39
43
47
51
55
59
63
67
71
SINCE BURN
2. Daily lactose intake.
280-1
3 = i
240-
Y 2 z J
160-
f 2
60-
> d d
,
OJI, 13
7
(
(
,
(
,
,
,
,
11
15
19
23
27
31
35
39
DAYSSINCE
Fig.
3. Daily potassium
potassium and serum sodium and recurrent gastro-intestinal upsets. Large amounts of potassium are lost in burn patients. Moncrieff (1979) listed them as follows: i) Movement of potassium from cell to ECF and then excretion in urine. ii) Inadequate resuscitation, causing triggering of the aldosterone mechanism. iii) Greater secretion of potassium in the distal tubules secondary to increased excretion of sodium caused by high sodium load given during resuscitation. iv) Respiratory alkalosis seen in the early post-bum period increases potassium loss in urine. Initially plasma potasium remain normal, or even high (because of movement across cell membrane) but later, as the potassium from ECF returns into the cell, hypokalaemia occurs if adequate potassium supplement is not provided. When hypokalaemia occurs, the kidney tries to
(
43
,
(
,
,
,
,
,
47
51
55
59
65
67
71
BURN
intake.
conserve potassium and the urinary excretion of potassium falls, unless the kidney itself is at fault (Ypersele et al., 1979). In this girl the excretion of potassium remained high, in spite of very low serum levels (Fig. 1). Following a bum or other severe injury, sodium moves into the cell. The kidney tries to conserve sodium, so that urinary excretion of sodium is low. This changes after a few days with increased loss of sodium and water in urine but, in large burns, patients who are ill or have complications such as septicaemia, the retention of sodium persists longer (Flear, 1970; Sevitt, 1974). In this case, in spite of all these factors and a low serum concentration of sodium, urinary excretion of sodium was substantial. The urine contained glucose in varying amounts up to the 55th day, while blood glucose remained within normal limits. Early glycosuria may be due to post-traumatic glucose intolerance but its persistence for such a prolonged
138
Burns Vol. 1O/No. 2 6 galactose Lactose in intestine Galactose
glucose + galactose
)
+ ATP e+
Galactose-I-P UDP galactose
galactose-I-P
+ UDP glucose +
Epimerase
UDP glucose + PPi 4
4 w
+ ADP
Transferase
w
UDP galactose
+ glucose-l-P
UDP galactose
Pyrophosphorylase
)
glucose-l-P
+ UTP
Fig. 4. Steps of galactose metabolism.
Incidence Inheritance
= 1 : 55 000 = Autosomal
live births recessive
Clinical features 1) In neonatal period Vomiting Diarrhoea Lethargy Jaundice Hepatomegaly Renal tubular dysfunction High risk of sepsis 2) Later Mental and physical Cirrhosis Cataract Tubular dysfunction Amenorrhoea Fig. 5. A summary of
retardation
signs and symptoms in transferase deficiency galactosaemia.
period suggested tubular dysfunction. The urine also contained varying amounts of protein up to the 55th day. Retrospectively we examined the urine of the first 20 days, which had been kept frozen for another trial being undertaken in the Unit, and found it to contain significantly increased amounts of phosphate. the amino-acid chromatography showed significantly increased generalized amino-aciduria. This combination of amino-aciduria, phosphaturia, glycosuria, proteinuria, increased urinary excretion of sodium and potassium and low serum phosphate is a feature of proximal tubular dysfunction (Broyer, 1979). The cause of proximal tubular dysfunction in this case was galactosaemia. This is an inborn error of galactose metabolism. Most commonly it is due to absence or deficiency of galactose-Iphosphate uridyl transferase (Fig. 4). Overall
birth incidence is about 1 : 55 000 (Gitzelmann and Hanson, 1980). In this disease galactose-Iphosphate accumulates in the cells when the patient eats lactose or galactose. This causes damage to the liver, kidneys and brain, producing signs and symptoms which have been described by many investigators (Komrower et al., 1956; Nadler et al., 1969; Donnell et al., 1980). A summary of these is given in Fig. 5. On feeding lactose to patients with galactosaemia, amino-aciduria albuminuria and glycosuria appears (Komrower et al., 1956). In his study, Komrower observed that renal tubular upset does not involve sodium and potassium excretion but this was based on a few observations in a single case only. We think proximal tubular dysfunction occurred in this case, due to administration of lactose contained in various drugs over a long
Kumar: Galactosaemia-a
139
case report
period. The daily dose was very small but a cumulative effect over a long period may have resulted in intracellular build-up of galactose-Iphosphate. At present there is some controversy regarding complete restriction of lactose in the diet ofthese patients later in life. Komrower and Lee (1970) thought that it could be relaxed slightly when the child goes to school, whereas others think that restriction should be complete and life-long (Brandt, 1980). The renal tubular dysfunction was mild but, because of the low potassium pool due to the burn injury, hypokalaemia became very marked. As the patient recovered from the burn and the total potassium pool was restored, hypokalaemia disappeared. The recurrent mild gastro-intestinal upsets were due to lactose intake. Vomiting and diarrhoea occur in patients with galactosaemia when they take lactose. Acknowledgements
1 would like to thank Mr J Lendrum, Consultant Plastic Surgeon, University Hospital of South Manchester, for his permission to report this case. I am also grateful to Dr I. B. Sardharwalla, Director of the Willink Biochemical Genetics Unit, Pendlebury, Manchester, for his guidance on metabolic aspects. I also wish to express my thanks to Mr Mark Woolstencroft, Department of Medical Illustration, for preparation of figures and Miss Christine Whaley for secretarial help.
REFERENCES Brandt N. J. (1980) How long should Galactosaemia be treated? In: Burman D.., Holton J. B. and Pennock C. A. (eds) Inherited Disorders of Carbohydrate Metabolism. Lancaster, MTP Press Ltd, p. 103.
Correspondence
should be addressed 10:
Manchester M20 8LR.
Broyer M. (1979) Tubular Syndromes. In: Hamburger J., Crosnier J. and Grunfeld J. P. (eds) Nephrology. New York, Wiley, p. 19 1. Donnell G. N., Koch R., Fishler K. et al. (1980) Clinical Apects ofGalactosaemia. In: Burman D., Holton J. B., Pennock C. A. (eds) Inherited Disorders of Carbohydrate Metabolism. Lancaster, MTP Press Ltd, p. 103. Flear C. T. G. (1970) Electrolyte and Body Water Changes after Trauma. In: Sevitt S., Stoner H. B. (eds) The Pathology qf Trauma (symposium organized by The Royal College of Pathologists). London, BMA House, p. 16. Gitzelmann R. and Hansen R. G. (1980) Galactose Metabolism, Hereditary Defects and their clinical significance. In: Burman D., Holton J. B., Pennock C. A. (eds) Inherited Disorders of Carbohydrate Metabolism. Lancaster, MTP Press Ltd, p. 6 I. Komrower G. M.. Schwarz V.. Holzel A. et al. (1956) A clinical and biochemical study of Galactosaemia: Arch. Dis. Child. 31, 254. Komrower G. M. and Lee D. H. (1970) Longterm follow-UD of Galactosaemia. Arch. Dis. Child. 45. 372. Moncrieff J. A. (I 979) Replacement Therapy in iurns. In: Arts C. P., Moncrieff J. A., Pruitt B. A. (eds) Burns-A Team Approach. Philadelphia, Saunders &Co, p. 178. Moore F. D. (1959) Metabolic Care of Surgical Patient. Philadelphia, Saunders & Co, p. 307. Muir I. F. K. and Barclay T. L. (1974) Burns and their treatment, 2nd ed. London, Lloyd-Luke. Nadler H. L., lnouyc T. and Hasia D. Y.-Y. (1969) Classical Galactosaemia: A studv of 55 Cases. In: Hasia D. Y.-Y. (ed) Galactosaimia. Springfield, Charles C. Thomas, p. 127. Sevitt S. (1974) Reactions to Injury and Burns and their Clinical Importance. London, Heinemann, p. 74. Ypersele C. V., Bodart P. and Dardenne A. (1979) General Techniques in Clinical Nephrology. In: Hamburger J., Crosnier J., Grunfeld J. P. (eds) HephrologJ,. New York, Wiley, p. 120.
Paper accepted 12 March 1983.
Mr P. Kumar, Registrar in Plastic Surgery. Withington
Hospital, West Didsbury.