Acta Pzdiatr Scand 68: 129-132, 1979
CASE REPORT
THE ROLE OF ZINC IN TOTAL PARENTERAL NUTRITION N. PRINCIPI, A. GIUNTA and A. GERVASONI From the Department of Paediatrics (II) of Milano University Medical School, Milano, Italy
ABSTRACT. Principi, N., Giunta, A. and Gervasoni, A. (Department of Paediatrics (11) of Milano University Medical School, Milano, Italy). The role of zinc in total parenteral nutrition. Acta Paediatr Scand, 68: l29,1979.-Zinc deficiency was observed in an infant receiving total parenteral nutrition (TPN) for chronic untractable diarrhoea. Clinical findings included low zinc plasma levels, skin lesions and loss of all the advantages of TPN such as weight gain, serum proteins and albumin increase and normalization of intestinal mucosa. Oral administration of zinc sulphate was the decisive factor making possible both the improvement of clinical and laboratory findings and alimentation by natural route.
KEY WORDS: Zinc deficiency, total parenteral nutrition
Total parenteral nutrition (TPN) may ensure excellent results only if the infusion contains all the needed nutrients in appropriate amounts (5). A case we recently observed demonstrates the critical role of an adequate zinc supply.
MATERIALS AND METHODS The patient R. S. was born to healthy unrelated parents after a full term, uneventful pregnancy. He weighed 3.4 kg. Neonatal period was normal and he was fed cow’s milk formula. Diarrhoea, 6 to 15 times per day, began at one month of age. Dietary and antibiotic therapy was unsuccessful. At 2 months and 15 days of age he was admitted to our department. Physical examination revealed a poorly nourished infant, weighing 3.2 kg and measuring 56 cm; the circumference of his head was 36 cm. Repeated stool cultures revealed no pathogens. During the first 40 days a lactose-free diet with soya milk, peripheral intravenous infusions of glucose and aminoacids and antibiotics were given without effect on his diarrhoea. At the end of this period the body weight was 3.3 kg. TPN was then started. About 150 ml/kg of a prepared fat-free solution were administered daily through a silastic catheter placed in the superior vena cava. Total caloric intake was about 120 calories/kg/die, protein administration 3 glkgldie and zinc supply 40 pg/kg/die. Essential fatty acids were ensured with daily application of sunflower seed oil to the skin. Plasma, or when necessary fresh blood, was transfused once weekly at the dosage of 9-78287 I
20 ml/kg. A sharp and constant increase of body weight along with the cessation of the diarrhoea was observed. At the end of the first month of TPN the weight increase stopped and skin lesions appeared. They started as a moist eczematoid area in the nasolabial folds and progressed to crusting, followed by bullous or pustular lesions all over the face (Fig. l a ) and around the other natural orifices, eventually coalescing to form large erosive areas. Some days later a significant alopecia was also noticed. In this period an attempt of oral feeding with a lactose-free cow’s milk formula produced voluminous diarrhoea and a loss of weight in spite of the intravenous administration of the same volume of nutritive solution. On the Slst day of TPN oral administration of zinc sulphate, 25 mg/day, was started. Within 5 days a dramatic improvement of skin lesions (Fig. 1 b ) and a resumption of weight gain occurred. On the 56th day of TPN the dislodgement of the catheter from the cutdown site led to the discontinuation of TPN. A lactose-free cow’s milk formula was then given while zinc administration at the same dosage continued. Oral feeding was well tolerated: no diarrhoea appeared even though 14 days later zinc supply was discontinued. Skin lesions never recurred and the patient’s general condition gradually improved. Laborarory evaluation Samples of blood were collected before the beginning of TPN and several times during and after its cessation. In all samples serum total proteins and albumin, zinc and alkaline phosphatase activity were determined. Oral jejunal mucosal biopsies were performed at the beginning and on the 27th day of TPN, when the skin lesions appeared and when a good tolerance of oral feeding was obtained. A Crosby-Kugler capsule was used and the specimens stained with hematoxylin and eosin.
N . Principi et al.
130
Fig. I . ( a ) Skin lesions after one month of TPN when zinc plasma concentration was 27 pgldl. (b) Regression of skin lesions after zinc sulphate oral administration.
2 ) . The small bowel biopsy revealed a flat mucosa with hyperplastic crypts. In the first month of TPN the normalization of serum protein concentration and a significant improvement of the intestinal picture (Fig. 3 a ) were observed. When zinc plasma levels became
RESULTS Before the beginning of TPN serum total proteins and albumin were very low while alkaline phosphatase activity was normal. Zinc plasma level was a little below the normal range (Fig.
ALKALINE PHOSPHATASE (Wrnl)
~
a0
~
&
45
SERUM ALBUMIN
70
88
~
6
52
28
(g/dl)
100
40 18
~5 2
~
5
3 2 2 4 21
62
-
6
~6 2
29
32
&
40
92
64
66
34
34
pF--
\
_._. ._.__..._...._. .. -.... - - ..
LEVELS :%A
86
----
----.
(pg/dU
20 0
o
,
I
40
Actu Pzedicirr Scand 68
c
c
0
8
0
8
I
:
P4-w
50 60 70 eo 90 100 110 120 130 140 170200230 DAYS AFTER HOSPITAL I Z A T I 0 N
Fig. 2. Clinical course and biochemical parameters of the studied patient.
Zinc in total parenteral nutrition
13 I
Fig. 3. Histological picture of intestinal mucosa: ( a ) after some days of TPN ( X 150). ( b ) when zinc deficiency appeared ( ~ 1 7 0 ) (c) . after few days of oral zinc supply ( X 120).
markedly depressed a reduction both of serum protein concentration and of alkaline phosphatase activity was noticed (Fig. 2). In addition intestinal mucosal lesions returned similar to those seen when malnutrition was present (Fig. 36). With oral administration of zinc sulphate all the studied biochemical parameters returned to normal values. The last small bowel biopsy demonstrated only a slightly abnormal mucosa (Fig. 3c).
DISCUSSION This case clearly underlines the critical importance of an adequate zinc supply in conditioning TPN efficacy. Clinical and laboratory findings during TPN were as expected for as long as zinc plasma concentration remained near the normal range. When it decreased to a very low level and was accompanied by skin lesions an interruption of weight gain, a drop in serum protein concentration and a reappearance of a flat intestinal mucosa were manifest.
Zinc sulphate administration was the decisive factor making possible both the improvement of clinical and laboratory findings and the alimentation by natural route. The importance of zinc in nucleic acid metabolism and protein synthesis is well demonstrated in many experimental studies (2, 10, 12); in infants and children an inadequate zinc intake may retard growth, sexual development and wound healing (9, 13) and may induce anorexia, impaired taste perception, pica and lethargy (3, 4). However the best clinical example of zinc deficiency is acrodermatitis enteropathica (8), a disease in which both skin lesions and bowel alterations may be related to a reduced protein synthesis and cellular turnover due to a lack of this element (7). It is reasonable to suggest that the same metabolic impairment may have taken place in this patient leading, despite an adequate aminoacid intake, t o a reduction of serum protein concentration and a regression of intestinal mucosa to atrophy. A ( 10 Pd'dun S ( ofid 68
132
N . Principi el al.
Few data are available on minimum intravenous daily zinc requirement. It is however well known that if during TPN zinc is not added to the nutritive solution a deficiency syndrome may appear (1). The demonstration that in our patient zinc deficiency appeared despite an intake of 40 pglkgldie suggests that even this amount, usually recommended in guidelines for TPN (14), may be insufficient. This conclusion is in complete agreement with the data of Ricour et al. (11) and James & MacMahon (6) who demonstrated that during TPN the decline of zinc plasma level can be prevented only by providing term infants and small premature babies with 100 and 200 pgl kgldie respectively. It is however likely that intravenous zinc requirement may differ significantly from patient to patient according to individual body stores and the degree of anabolism of the first days of TPN. It is important therefore, when TPN is performed in infants and children with severe malnutrition, to frequently monitor zinc plasma level and eventually increase daily zinc supply if all the advantages of TPN are to be maintained. REFERENCES 1. Arakawa, T., Tamura, T., Igarashi, Y., Suzuki, H. &
Sandstead, H. H.: Zinc deficiency in two infants during total parenteral alimentation for diarrhea. Am J Clin Nutr, 29: 197, 1976. 2. Fosmire, G. J., Al-Ubaidi, Y. Y.& Sandstead, H. H.: Some effects of postnatal zinc deficiency on developing rat brain. Pediatr Res, 9: 89, 1975. 3. Hambidge, K. M., Hambidge, C., Jacobs, M. &
Actu Pzdiatr S w n d 68
Baum, J. D.: Low levels of zinc in hair, anorexia, poor growth and hypogeusia in children. Pediatr Res, 6: 868, 1972. 4. Hambidge, K. M. & Silverman, A.: Pica with rapid improvement after dietary zinc supplementation. Arch Dis Child, 48: 567, 1973. 5 . Heird, W. C. & Winters, R. W.: Total parenteral nutrition: the state of the art. J Pediatr, 86: 2, 1975. 6. James, B. E. & MacMahon, R. W.: Balance studies of nine elements during complete intravenous feeding of small premature infants. Aust Paediatr J, 12: 154, 1976. 7. Kelly, R., Davidson, G. P., Townley, R. R. W. & Campbell, P. E.: Reversible intestinal mucosal abnormality in acrodermatitis enteropathica. Arch Dis Child, 51: 219, 1976. 8. Moynahan, E. J.: Acrodermatitis enteropathica: a lethal inherited human zinc deficiency disorder. Lancet, 11: 339, 1974. 9. Pones, W. H . , Henzel, J. H., Rob, C. G. & Strain, W. H.: Acceleration of healing with zinc sulphate. Ann Surg, 165: 432, 1967. 10. Prasad, A. S. & Oberleas, D.: Thymidine kinase activity and incorporation of thymidine into DNA in zinc-deficient tissues. J Lab Clin Med, 83: 634, 1974. 1 1 . Ricour, C., Duhamel, J. F., Gros, J., Maziere, B. & Comar, D.: Oligo-elements chez I’enfant en nutrition parentkrale exclusive. Arch FranG Pkd, 34: 42, 1977. 12. Sandstead, H. H., Gillespie, D. D. & Brady, R. N.: Zinc deficiency: effect on brain of the suckling rat. Pediatr Res, 6: 119, 1972. 13. Sandstead, H. H., Prasad, A. S., Schulert, A. R., Farid, Z., Miale, A,, Bassilly, S. & Darby, W. J.: Human zinc deficiency, endocrine manifestations and response to treatment. Am J Clin Nutr, 20: 422, 1967. 14. Shils, M. E.: Guidelines for total parenteral nutrition. JAMA, 220: 1721, 1972. Submitted Febr. 28, 1978 Accepted June 25, 1978
(N. P.) Department of Paediatrics Istituti Clinici di Perfezionamento Via Commenda 9 20122 Milano Italy
CASE REPORT
THE ROLE OF ZINC IN TOTAL PARENTERAL NUTRITION N. PRINCIPI, A. GIUNTA and A. GERVASONI From the Department of Paediatrics (II) of Milano University Medical School, Milano, Italy
ABSTRACT. Principi, N., Giunta, A. and Gervasoni, A. (Department of Paediatrics (11) of Milano University Medical School, Milano, Italy). The role of zinc in total parenteral nutrition. Acta Paediatr Scand, 68: l29,1979.-Zinc deficiency was observed in an infant receiving total parenteral nutrition (TPN) for chronic untractable diarrhoea. Clinical findings included low zinc plasma levels, skin lesions and loss of all the advantages of TPN such as weight gain, serum proteins and albumin increase and normalization of intestinal mucosa. Oral administration of zinc sulphate was the decisive factor making possible both the improvement of clinical and laboratory findings and alimentation by natural route.
KEY WORDS: Zinc deficiency, total parenteral nutrition
Total parenteral nutrition (TPN) may ensure excellent results only if the infusion contains all the needed nutrients in appropriate amounts (5). A case we recently observed demonstrates the critical role of an adequate zinc supply.
MATERIALS AND METHODS The patient R. S. was born to healthy unrelated parents after a full term, uneventful pregnancy. He weighed 3.4 kg. Neonatal period was normal and he was fed cow’s milk formula. Diarrhoea, 6 to 15 times per day, began at one month of age. Dietary and antibiotic therapy was unsuccessful. At 2 months and 15 days of age he was admitted to our department. Physical examination revealed a poorly nourished infant, weighing 3.2 kg and measuring 56 cm; the circumference of his head was 36 cm. Repeated stool cultures revealed no pathogens. During the first 40 days a lactose-free diet with soya milk, peripheral intravenous infusions of glucose and aminoacids and antibiotics were given without effect on his diarrhoea. At the end of this period the body weight was 3.3 kg. TPN was then started. About 150 ml/kg of a prepared fat-free solution were administered daily through a silastic catheter placed in the superior vena cava. Total caloric intake was about 120 calories/kg/die, protein administration 3 glkgldie and zinc supply 40 pg/kg/die. Essential fatty acids were ensured with daily application of sunflower seed oil to the skin. Plasma, or when necessary fresh blood, was transfused once weekly at the dosage of 9-78287 I
20 ml/kg. A sharp and constant increase of body weight along with the cessation of the diarrhoea was observed. At the end of the first month of TPN the weight increase stopped and skin lesions appeared. They started as a moist eczematoid area in the nasolabial folds and progressed to crusting, followed by bullous or pustular lesions all over the face (Fig. l a ) and around the other natural orifices, eventually coalescing to form large erosive areas. Some days later a significant alopecia was also noticed. In this period an attempt of oral feeding with a lactose-free cow’s milk formula produced voluminous diarrhoea and a loss of weight in spite of the intravenous administration of the same volume of nutritive solution. On the Slst day of TPN oral administration of zinc sulphate, 25 mg/day, was started. Within 5 days a dramatic improvement of skin lesions (Fig. 1 b ) and a resumption of weight gain occurred. On the 56th day of TPN the dislodgement of the catheter from the cutdown site led to the discontinuation of TPN. A lactose-free cow’s milk formula was then given while zinc administration at the same dosage continued. Oral feeding was well tolerated: no diarrhoea appeared even though 14 days later zinc supply was discontinued. Skin lesions never recurred and the patient’s general condition gradually improved. Laborarory evaluation Samples of blood were collected before the beginning of TPN and several times during and after its cessation. In all samples serum total proteins and albumin, zinc and alkaline phosphatase activity were determined. Oral jejunal mucosal biopsies were performed at the beginning and on the 27th day of TPN, when the skin lesions appeared and when a good tolerance of oral feeding was obtained. A Crosby-Kugler capsule was used and the specimens stained with hematoxylin and eosin.
N . Principi et al.
130
Fig. I . ( a ) Skin lesions after one month of TPN when zinc plasma concentration was 27 pgldl. (b) Regression of skin lesions after zinc sulphate oral administration.
2 ) . The small bowel biopsy revealed a flat mucosa with hyperplastic crypts. In the first month of TPN the normalization of serum protein concentration and a significant improvement of the intestinal picture (Fig. 3 a ) were observed. When zinc plasma levels became
RESULTS Before the beginning of TPN serum total proteins and albumin were very low while alkaline phosphatase activity was normal. Zinc plasma level was a little below the normal range (Fig.
ALKALINE PHOSPHATASE (Wrnl)
~
a0
~
&
45
SERUM ALBUMIN
70
88
~
6
52
28
(g/dl)
100
40 18
~5 2
~
5
3 2 2 4 21
62
-
6
~6 2
29
32
&
40
92
64
66
34
34
pF--
\
_._. ._.__..._...._. .. -.... - - ..
LEVELS :%A
86
----
----.
(pg/dU
20 0
o
,
I
40
Actu Pzedicirr Scand 68
c
c
0
8
0
8
I
:
P4-w
50 60 70 eo 90 100 110 120 130 140 170200230 DAYS AFTER HOSPITAL I Z A T I 0 N
Fig. 2. Clinical course and biochemical parameters of the studied patient.
Zinc in total parenteral nutrition
13 I
Fig. 3. Histological picture of intestinal mucosa: ( a ) after some days of TPN ( X 150). ( b ) when zinc deficiency appeared ( ~ 1 7 0 ) (c) . after few days of oral zinc supply ( X 120).
markedly depressed a reduction both of serum protein concentration and of alkaline phosphatase activity was noticed (Fig. 2). In addition intestinal mucosal lesions returned similar to those seen when malnutrition was present (Fig. 36). With oral administration of zinc sulphate all the studied biochemical parameters returned to normal values. The last small bowel biopsy demonstrated only a slightly abnormal mucosa (Fig. 3c).
DISCUSSION This case clearly underlines the critical importance of an adequate zinc supply in conditioning TPN efficacy. Clinical and laboratory findings during TPN were as expected for as long as zinc plasma concentration remained near the normal range. When it decreased to a very low level and was accompanied by skin lesions an interruption of weight gain, a drop in serum protein concentration and a reappearance of a flat intestinal mucosa were manifest.
Zinc sulphate administration was the decisive factor making possible both the improvement of clinical and laboratory findings and the alimentation by natural route. The importance of zinc in nucleic acid metabolism and protein synthesis is well demonstrated in many experimental studies (2, 10, 12); in infants and children an inadequate zinc intake may retard growth, sexual development and wound healing (9, 13) and may induce anorexia, impaired taste perception, pica and lethargy (3, 4). However the best clinical example of zinc deficiency is acrodermatitis enteropathica (8), a disease in which both skin lesions and bowel alterations may be related to a reduced protein synthesis and cellular turnover due to a lack of this element (7). It is reasonable to suggest that the same metabolic impairment may have taken place in this patient leading, despite an adequate aminoacid intake, t o a reduction of serum protein concentration and a regression of intestinal mucosa to atrophy. A ( 10 Pd'dun S ( ofid 68
132
N . Principi el al.
Few data are available on minimum intravenous daily zinc requirement. It is however well known that if during TPN zinc is not added to the nutritive solution a deficiency syndrome may appear (1). The demonstration that in our patient zinc deficiency appeared despite an intake of 40 pglkgldie suggests that even this amount, usually recommended in guidelines for TPN (14), may be insufficient. This conclusion is in complete agreement with the data of Ricour et al. (11) and James & MacMahon (6) who demonstrated that during TPN the decline of zinc plasma level can be prevented only by providing term infants and small premature babies with 100 and 200 pgl kgldie respectively. It is however likely that intravenous zinc requirement may differ significantly from patient to patient according to individual body stores and the degree of anabolism of the first days of TPN. It is important therefore, when TPN is performed in infants and children with severe malnutrition, to frequently monitor zinc plasma level and eventually increase daily zinc supply if all the advantages of TPN are to be maintained. REFERENCES 1. Arakawa, T., Tamura, T., Igarashi, Y., Suzuki, H. &
Sandstead, H. H.: Zinc deficiency in two infants during total parenteral alimentation for diarrhea. Am J Clin Nutr, 29: 197, 1976. 2. Fosmire, G. J., Al-Ubaidi, Y. Y.& Sandstead, H. H.: Some effects of postnatal zinc deficiency on developing rat brain. Pediatr Res, 9: 89, 1975. 3. Hambidge, K. M., Hambidge, C., Jacobs, M. &
Actu Pzdiatr S w n d 68
Baum, J. D.: Low levels of zinc in hair, anorexia, poor growth and hypogeusia in children. Pediatr Res, 6: 868, 1972. 4. Hambidge, K. M. & Silverman, A.: Pica with rapid improvement after dietary zinc supplementation. Arch Dis Child, 48: 567, 1973. 5 . Heird, W. C. & Winters, R. W.: Total parenteral nutrition: the state of the art. J Pediatr, 86: 2, 1975. 6. James, B. E. & MacMahon, R. W.: Balance studies of nine elements during complete intravenous feeding of small premature infants. Aust Paediatr J, 12: 154, 1976. 7. Kelly, R., Davidson, G. P., Townley, R. R. W. & Campbell, P. E.: Reversible intestinal mucosal abnormality in acrodermatitis enteropathica. Arch Dis Child, 51: 219, 1976. 8. Moynahan, E. J.: Acrodermatitis enteropathica: a lethal inherited human zinc deficiency disorder. Lancet, 11: 339, 1974. 9. Pones, W. H . , Henzel, J. H., Rob, C. G. & Strain, W. H.: Acceleration of healing with zinc sulphate. Ann Surg, 165: 432, 1967. 10. Prasad, A. S. & Oberleas, D.: Thymidine kinase activity and incorporation of thymidine into DNA in zinc-deficient tissues. J Lab Clin Med, 83: 634, 1974. 1 1 . Ricour, C., Duhamel, J. F., Gros, J., Maziere, B. & Comar, D.: Oligo-elements chez I’enfant en nutrition parentkrale exclusive. Arch FranG Pkd, 34: 42, 1977. 12. Sandstead, H. H., Gillespie, D. D. & Brady, R. N.: Zinc deficiency: effect on brain of the suckling rat. Pediatr Res, 6: 119, 1972. 13. Sandstead, H. H., Prasad, A. S., Schulert, A. R., Farid, Z., Miale, A,, Bassilly, S. & Darby, W. J.: Human zinc deficiency, endocrine manifestations and response to treatment. Am J Clin Nutr, 20: 422, 1967. 14. Shils, M. E.: Guidelines for total parenteral nutrition. JAMA, 220: 1721, 1972. Submitted Febr. 28, 1978 Accepted June 25, 1978
(N. P.) Department of Paediatrics Istituti Clinici di Perfezionamento Via Commenda 9 20122 Milano Italy
