- Email: [email protected]
ACUTE RESPONSE OF PLASMA 1,25-DIHYDROXYVITAMIN D TO PARATHYROID HORMONE
362
perience; every patient taking cyanamide presents the characteristic hepatic alteration. Thus we seem to be dealing with a predictable lesion developing in alcoholics taking this drug. A more extensive study is needed to confirm this point, and, we are now trying to reproduce the hepatic lesion experimentally. Alcohol consumption may be necessary for the development of the cellular change: alcohol could bring about SER hyperplasia and the cyanamide could then cause the breakdown of modified SER, together with mitochondria, resulting in the characteristic "inclusions". The lack of the SER-supported enzymes would account for the storage of an abnormal gly-
cogen.’
Fig. I-Periportal hepatocytes bearing inclusion. and eosin; reduced (HsEmatoxylm
to4 I of x 400)
.
The anti-alcoholic reaction induced by cyanamide and/or disulfiram in chronic alcoholics could also be explained in this way. The breakdown of SER membranes would cause the loss of the supported enzymes, resulting in an inhibition of the complete catabolism of alcohol and in the accumulation of acetaldehyde. There is general agreement that cyanamide and disulfiram inhibit one or more of the enzymes which are required to oxidise acetaldehyde.4-6 Department of Pathology, University of Navarra, Pamplona, Spain
J. J. VÁZQUEZ S. CERVERA
ACUTE RESPONSE OF PLASMA 1,25-DIHYDROXYVITAMIN D TO PARATHYROID HORMONE et al. have reported that intravenous infuparathyroid hormone extract (PTE) in two doses of 2 IU/kg, given 8 h apart in healthy volunteers produced an 80% increase of plasma 1,25-dihydroxyvitamin D (1,25[OH],D) 24 and 16 h after the first and second infusion, respectively. Using a different protocol we have found that significantly increased plasma levels of 1,25(OH)2D were elicted by a single PTE infusion, and that this effect was apparent as early as 2 h after the infusion. After informed parental consent we stud-
SIR,-Eisman
sion of
Fig. 2-Electronmicrograph showing inclusion (x6750). The typical lesion is seen in the hepatocytes and consists of well-demarcated cytoplasmic areas (fig. 1), resembling Lafora’s bodies observed in the livers in myoclonic epilepsy.2.3 The bodies are composed of jj—glycogen granules, myelin-like lamellar whorled structures, lipid droplets, and a few filaments (fig.2). The glycogen was more resistant to salivary hydrolysis than that of normal liver.’ Smooth endoplasmic reticulum (SER) was almost completely absent. The lesion was periportal in cases 1, 4, 5, and 6; the whole lobule was affected in cases 2 and 3; in case 7, with alcoholic cirrhosis, the damaged hepatocytes were located at the periphery of the nodules. Necropsy of case 1 (cause of death, lung carcinoma) showed that hepatocytes were the only inclusionbearing cells. No Lafora’s bodies were seen in nerve cells of the brain. This hepatic lesion seems to be induced by drugs used to discourage alcohol intake. Four of the seven patients were on cyanamide only; one was taking cyanamide and disulfiram; of the remaining two, one had been on oral disulfiram for a very long time and the other was taking a lot of other drugs besides disulfiram. In patients taking cyanamide only, hepatic involvement correlates well with duration of treatment. Moreover, in our ex2. Austin
J, Sakai M. Disorders of glycogen and related macromolecules in the system. In: Handbook of clinical neurology: vol XXVII. Amsterdam: North-Holland, 1967: 169-219. 3. Ramon Y, Cajal S, Blanes A, Martinez A, Saenz E, Guitierrez M. Lafora’s disease An ultra-structural and histochcmical study. Acta Neuropathol (Berlin) 1974, 30: 189-96. nervous
ied three children 5-11 years of age with different disorders of calcium metabolism: osteopetrosis (A), suspected hypoparathyroidism (B), and hypophosphataemic rickets (C). After an hour’s rest PTE (Eli Lilly) at a dose of 8 U.S.P. units/kg bodyweight in 30 ml 5% glucose solution was infused over 10 min. Blood-samples were collected 1 h before the PTE infusion and 10, 20, 30, 60, 90, and 120 min afterwards for determination of plasma cyclic AMP and 1,25(OH)2D. Urine was collected over the 12 h period before the PTE infusion, and thereafter all spontaneously voided urine was collected over two subsequent periods of about 2 h duration, and the urine specimens were analysed for cyclic AMP. EFFECT OF PTE ON PLASMA
1,25-(oH)2D
The PTH infusion resulted in an immediate and brisk rise of cyclic AMP in plasma with peak values after 10 min. All patients also responded with a marked increase in urinary cyclic AMP. The effect of the PTE infusion on the plasma level of 1,25(OH)2D is shown in the table. All patients responded with 4. Smith JA, Wolfrod JA, Weber M, McLean D. Use of citrate calcium carbimide (Temposil) in treatment of chronic alcoholism. JAMA 1957; 165: 2181-83. 5. Levy MS, Livingstone BL, Collins DM. A clinical comparison of disulfiram and calcium carbimide. Am J Psychiat 1967; 123: 1018-22. 6. Ferguson JKW. A new drug for alcoholism treatment. I. A new drug for the treatment alcoholism. Can Med Assoc J 1956; 74: 793-97. 7. Eisman JA, Wark JD, Prince RL, Moseley JM. Modulation of plasma 1,25-dihydrocy vitamin D in man by stimulation and suppression tests. Lancet 1979; ii: 931-33.
363 a substantial increase ranging from 32 to 62% above the basal levels. Animal work and in-vitro studies show that parathyroid hormone stimulates the conversion of 25-OHD to the biologically active 1,25(OH)2D in the kidneys.$·9 Eisman et al. have shown the same effect of bovine parathyroid hormone in man and suggested that investigation of 1,25(OH)2D productive capacity may prove of interest in the study of renal tubular disorders.’ Our experience indicates that the same information can be obtained by the less elaborate protocol of a standard PTE infusion test, and that the study of 25-OHD-1-hydroxylase response to the infusion might be a useful adjunct in the investigation of parathyroid/vitamin-D/calcium metabolism.
Department of Pædiatrics, University of Bergen, N-5016 Bergen, Norway
DAGFINN AARSKOG LAGE AKSNES
PROBLEMS WITH HAIR ZINC AS AN INDICATOR OF BODY ZINC STATUS
SiR,—The physiological significance of the
trace element of hair has yet to be defined. Values below the "normal" range are assumed to be due to lower circulating levels of trace elements. However, the level of trace elements in hair depends on the availability of trace elements for incorporation into the follicle and on the growth of the hair fibre, which is when hair is susceptible to trace element concentrations. If this relation changes in protein-calorie malnutrition (PCM) hair trace element concentrations will not have the significance they have in the normal state, and we already know that hair growth diminishes in severe malnutrition. Bradfield et al.’ found significant increases in shaft diameters between admission and recovery hair samples from the same Peruvian Indian children with classical kwashiorkor, suggesting that the amount of hair being produced per follicle had been drastically reduced during PCM. Sims2 confirmed these findings in Black children in South Africa and found that linear hair growth was halved during kwashiorkor. He calculated that during kwashiorkor hair fibre production was only 10% of normal. Because the amount of hair fibre extruded per unit time depends upon both the fibre thickness and the linear growth rate, decreased growth will affect the availability/growth relation whether hair trace element content is expressed as L919 hair, ;’.g/m hair fibre, or ;’.g/unit time. Hambidge et a1.3 have reported lower hair zinc values in mild to moderate malnutirition, but "normal"4,5 even abnormally highhair zinc values have been reported in kwashiorkor. Perhaps the explanation for these apparently inconsistent findings is that, as malnutrition becomes more severe and/or of longer duration, there are points where the body’s loss of nitrogen is diminished by slower hair growth, in terms of both volume and linear rate. If follicle availability does not decrease at the same rate the "normal" values found in kwashiorkor may be the result of
content
-
8. Haussler MR, McCain TA. Basic and clinical concepts related to vitamin D metabolism and action. N Engl J Med 1977; 297: 974-83. 9. DeLuca HF. Vitamin D: Metabolism and function (Monog Endocrinol vol XII). Berlin: Springer Verlag, 1979: 1-80. 1. Bradfield RB, Poresky B, Cordano A. Hair diameter changes during proteincalorie malnutrition. In: Proceedings of 2nd Pacific Science Congress
(Tokyo, Japan). 1966: 319-20. 2. Sims RT. Hair growth in kwashiorkor. Arch Dis Child 1967; 42: 397-400. 3. Hambidge KM, Walravens PA, Brown RM, Webster J, White S, Anthony M, Roth ML. Zinc nutrition of preschool children in the Denver Head Start
Program. Am J Clin Nutr 1976; 29: 734-38. 4. Hambidge KM. Zinc deficiency in children. In:
Hoekstra WG, ed. Trace elemetabolism in animals: vol 2. London: Butterworths, 1974: 171-83. 5. Bradfield RB, Yee T, Baertl JM. Hair zinc levels of Andean Indian children during protein-calorie malnutrition. Am J Clin Nutr 1969; 22: 1349-53. 6. Erten J, Arcasoy A, Caudar AO, Cin S. Hair zinc levels in healthy and malnourished children. Am J Clin Nutr 1978; 31: 1172-74. ment
lower-than-normal levels of available zinc which are incorporated into the hair in normal amounts due to slower-than normal formation and growth of the fibre. Until we understand the factors that make these growth set-points operational, the diagnostic value of hair trace element concentrations during severe malnutrition will remain uncertain. This controversy apart, the findings of Hambidge et a1.3-namely, low hair and plasma zinc levels in the lower height percentiles of predominantly Hispanic-American Colorado preschool children of low income families participating in Operation Head Start-could be explained by genetic factors. In an attempt to clarify this we have studied 90 HispanicAmerican four-year-old children participating in the same federal programme in Tulare County, in California’s San
Joaquin Valley. The children came from a stable population of farmworkers. All had been born in the valley, and almost all the parents had been born in the United States. All the children had completed at least six months in the programme, which furnishes day care and meals for children of low-income working parents. Informed consent was obtained by Operation Head Start through its Parents’ Council. Hair samples were collected, treated, and analysed.’ The children were weighed, in their underpants, on beam scales controlled with calibrated weights and levelled daily. Vertical heights were measured8 and weight/height and height/age were calculated from U.S. Public Health Service standards.
The results, expressed as mean +SD (and range) were: hair zinc 131±40 (69-219) :’.g/g; weight/height 98±8 (78-122; and height/age 97±3 (90-110). When we compared hair zinc and height by linear regression across the narrow range of values, we found that less than 1% of the variance could be explained by the regression. The same was true for hair zinc and height/age. These data confirm the finding that normally growing Hispanic-American children have normal hair zinc values and suggest that the low hair zinc values reported in the lower height percentiles of Hispanic-American preschool children3 are more likely to be related to poor growth than to genetic factors. Department of Nutritional Sciences, University of California, Berkeley, California, U.S.A.
ROBERT B. BRADFIELD*
Department of Pediatrics, University of Colorado Medical Center, Denver, Colorado
K. MICHAEL HAMBIDGE
*Present address: International Nutrition Associates, 36 El California 94563, U.S.A.
Toyonal, Orinda,
TRYPSIN CLEARANCE AND PANCREATIC DISEASE
SiR,—Dr Lake-Bakaar and his colleagues (Oct. 27, p. 878) have raised the interesting possibility that measurement of urinary trypsin/creatinine clearance ratio (TCCR) may be of value in distinguishing between chronic pancreatitis and carcinoma of the pancreas. However, they seemed to be uncertain of the underlying mechanism of the raised TCCR in acute pancreatitis and pancreatic cancer. We have compared the amylase/creatinine clearance ratio (ACCR) with the &bgr;2-microglobulin/creatinin&bgr;’ clearance ratio (BCCR).9 &bgr;2-microglobulin (&bgr;2-MG) is a low-molecular-weight protein (11 500) with more than 99% resorption by renal tubules. In acute pancreatitis serum j3-MG levels remain unchanged, so that a parallel ACCR and BCCR in acute pan-
7.
Hambidge KM, Hambidge C, Jacobs M, Baum JB. Low levels of zinc in hair, anorexia, poor growth and hypogeusia in children. Pediat Res 1972; 6:
868-74. 8. Owen GM. The assessment and recording of measurements of growth of children. Pediatrics 1973; 51: 461-65. 9. Playforth MJ, Rashid SA, Cooper EH, McMahon MJ. Increased renal clearance of amylase—a non-specific response to acute illness. Gut 1979; 20:
A929.
perience; every patient taking cyanamide presents the characteristic hepatic alteration. Thus we seem to be dealing with a predictable lesion developing in alcoholics taking this drug. A more extensive study is needed to confirm this point, and, we are now trying to reproduce the hepatic lesion experimentally. Alcohol consumption may be necessary for the development of the cellular change: alcohol could bring about SER hyperplasia and the cyanamide could then cause the breakdown of modified SER, together with mitochondria, resulting in the characteristic "inclusions". The lack of the SER-supported enzymes would account for the storage of an abnormal gly-
cogen.’
Fig. I-Periportal hepatocytes bearing inclusion. and eosin; reduced (HsEmatoxylm
to4 I of x 400)
.
The anti-alcoholic reaction induced by cyanamide and/or disulfiram in chronic alcoholics could also be explained in this way. The breakdown of SER membranes would cause the loss of the supported enzymes, resulting in an inhibition of the complete catabolism of alcohol and in the accumulation of acetaldehyde. There is general agreement that cyanamide and disulfiram inhibit one or more of the enzymes which are required to oxidise acetaldehyde.4-6 Department of Pathology, University of Navarra, Pamplona, Spain
J. J. VÁZQUEZ S. CERVERA
ACUTE RESPONSE OF PLASMA 1,25-DIHYDROXYVITAMIN D TO PARATHYROID HORMONE et al. have reported that intravenous infuparathyroid hormone extract (PTE) in two doses of 2 IU/kg, given 8 h apart in healthy volunteers produced an 80% increase of plasma 1,25-dihydroxyvitamin D (1,25[OH],D) 24 and 16 h after the first and second infusion, respectively. Using a different protocol we have found that significantly increased plasma levels of 1,25(OH)2D were elicted by a single PTE infusion, and that this effect was apparent as early as 2 h after the infusion. After informed parental consent we stud-
SIR,-Eisman
sion of
Fig. 2-Electronmicrograph showing inclusion (x6750). The typical lesion is seen in the hepatocytes and consists of well-demarcated cytoplasmic areas (fig. 1), resembling Lafora’s bodies observed in the livers in myoclonic epilepsy.2.3 The bodies are composed of jj—glycogen granules, myelin-like lamellar whorled structures, lipid droplets, and a few filaments (fig.2). The glycogen was more resistant to salivary hydrolysis than that of normal liver.’ Smooth endoplasmic reticulum (SER) was almost completely absent. The lesion was periportal in cases 1, 4, 5, and 6; the whole lobule was affected in cases 2 and 3; in case 7, with alcoholic cirrhosis, the damaged hepatocytes were located at the periphery of the nodules. Necropsy of case 1 (cause of death, lung carcinoma) showed that hepatocytes were the only inclusionbearing cells. No Lafora’s bodies were seen in nerve cells of the brain. This hepatic lesion seems to be induced by drugs used to discourage alcohol intake. Four of the seven patients were on cyanamide only; one was taking cyanamide and disulfiram; of the remaining two, one had been on oral disulfiram for a very long time and the other was taking a lot of other drugs besides disulfiram. In patients taking cyanamide only, hepatic involvement correlates well with duration of treatment. Moreover, in our ex2. Austin
J, Sakai M. Disorders of glycogen and related macromolecules in the system. In: Handbook of clinical neurology: vol XXVII. Amsterdam: North-Holland, 1967: 169-219. 3. Ramon Y, Cajal S, Blanes A, Martinez A, Saenz E, Guitierrez M. Lafora’s disease An ultra-structural and histochcmical study. Acta Neuropathol (Berlin) 1974, 30: 189-96. nervous
ied three children 5-11 years of age with different disorders of calcium metabolism: osteopetrosis (A), suspected hypoparathyroidism (B), and hypophosphataemic rickets (C). After an hour’s rest PTE (Eli Lilly) at a dose of 8 U.S.P. units/kg bodyweight in 30 ml 5% glucose solution was infused over 10 min. Blood-samples were collected 1 h before the PTE infusion and 10, 20, 30, 60, 90, and 120 min afterwards for determination of plasma cyclic AMP and 1,25(OH)2D. Urine was collected over the 12 h period before the PTE infusion, and thereafter all spontaneously voided urine was collected over two subsequent periods of about 2 h duration, and the urine specimens were analysed for cyclic AMP. EFFECT OF PTE ON PLASMA
1,25-(oH)2D
The PTH infusion resulted in an immediate and brisk rise of cyclic AMP in plasma with peak values after 10 min. All patients also responded with a marked increase in urinary cyclic AMP. The effect of the PTE infusion on the plasma level of 1,25(OH)2D is shown in the table. All patients responded with 4. Smith JA, Wolfrod JA, Weber M, McLean D. Use of citrate calcium carbimide (Temposil) in treatment of chronic alcoholism. JAMA 1957; 165: 2181-83. 5. Levy MS, Livingstone BL, Collins DM. A clinical comparison of disulfiram and calcium carbimide. Am J Psychiat 1967; 123: 1018-22. 6. Ferguson JKW. A new drug for alcoholism treatment. I. A new drug for the treatment alcoholism. Can Med Assoc J 1956; 74: 793-97. 7. Eisman JA, Wark JD, Prince RL, Moseley JM. Modulation of plasma 1,25-dihydrocy vitamin D in man by stimulation and suppression tests. Lancet 1979; ii: 931-33.
363 a substantial increase ranging from 32 to 62% above the basal levels. Animal work and in-vitro studies show that parathyroid hormone stimulates the conversion of 25-OHD to the biologically active 1,25(OH)2D in the kidneys.$·9 Eisman et al. have shown the same effect of bovine parathyroid hormone in man and suggested that investigation of 1,25(OH)2D productive capacity may prove of interest in the study of renal tubular disorders.’ Our experience indicates that the same information can be obtained by the less elaborate protocol of a standard PTE infusion test, and that the study of 25-OHD-1-hydroxylase response to the infusion might be a useful adjunct in the investigation of parathyroid/vitamin-D/calcium metabolism.
Department of Pædiatrics, University of Bergen, N-5016 Bergen, Norway
DAGFINN AARSKOG LAGE AKSNES
PROBLEMS WITH HAIR ZINC AS AN INDICATOR OF BODY ZINC STATUS
SiR,—The physiological significance of the
trace element of hair has yet to be defined. Values below the "normal" range are assumed to be due to lower circulating levels of trace elements. However, the level of trace elements in hair depends on the availability of trace elements for incorporation into the follicle and on the growth of the hair fibre, which is when hair is susceptible to trace element concentrations. If this relation changes in protein-calorie malnutrition (PCM) hair trace element concentrations will not have the significance they have in the normal state, and we already know that hair growth diminishes in severe malnutrition. Bradfield et al.’ found significant increases in shaft diameters between admission and recovery hair samples from the same Peruvian Indian children with classical kwashiorkor, suggesting that the amount of hair being produced per follicle had been drastically reduced during PCM. Sims2 confirmed these findings in Black children in South Africa and found that linear hair growth was halved during kwashiorkor. He calculated that during kwashiorkor hair fibre production was only 10% of normal. Because the amount of hair fibre extruded per unit time depends upon both the fibre thickness and the linear growth rate, decreased growth will affect the availability/growth relation whether hair trace element content is expressed as L919 hair, ;’.g/m hair fibre, or ;’.g/unit time. Hambidge et a1.3 have reported lower hair zinc values in mild to moderate malnutirition, but "normal"4,5 even abnormally highhair zinc values have been reported in kwashiorkor. Perhaps the explanation for these apparently inconsistent findings is that, as malnutrition becomes more severe and/or of longer duration, there are points where the body’s loss of nitrogen is diminished by slower hair growth, in terms of both volume and linear rate. If follicle availability does not decrease at the same rate the "normal" values found in kwashiorkor may be the result of
content
-
8. Haussler MR, McCain TA. Basic and clinical concepts related to vitamin D metabolism and action. N Engl J Med 1977; 297: 974-83. 9. DeLuca HF. Vitamin D: Metabolism and function (Monog Endocrinol vol XII). Berlin: Springer Verlag, 1979: 1-80. 1. Bradfield RB, Poresky B, Cordano A. Hair diameter changes during proteincalorie malnutrition. In: Proceedings of 2nd Pacific Science Congress
(Tokyo, Japan). 1966: 319-20. 2. Sims RT. Hair growth in kwashiorkor. Arch Dis Child 1967; 42: 397-400. 3. Hambidge KM, Walravens PA, Brown RM, Webster J, White S, Anthony M, Roth ML. Zinc nutrition of preschool children in the Denver Head Start
Program. Am J Clin Nutr 1976; 29: 734-38. 4. Hambidge KM. Zinc deficiency in children. In:
Hoekstra WG, ed. Trace elemetabolism in animals: vol 2. London: Butterworths, 1974: 171-83. 5. Bradfield RB, Yee T, Baertl JM. Hair zinc levels of Andean Indian children during protein-calorie malnutrition. Am J Clin Nutr 1969; 22: 1349-53. 6. Erten J, Arcasoy A, Caudar AO, Cin S. Hair zinc levels in healthy and malnourished children. Am J Clin Nutr 1978; 31: 1172-74. ment
lower-than-normal levels of available zinc which are incorporated into the hair in normal amounts due to slower-than normal formation and growth of the fibre. Until we understand the factors that make these growth set-points operational, the diagnostic value of hair trace element concentrations during severe malnutrition will remain uncertain. This controversy apart, the findings of Hambidge et a1.3-namely, low hair and plasma zinc levels in the lower height percentiles of predominantly Hispanic-American Colorado preschool children of low income families participating in Operation Head Start-could be explained by genetic factors. In an attempt to clarify this we have studied 90 HispanicAmerican four-year-old children participating in the same federal programme in Tulare County, in California’s San
Joaquin Valley. The children came from a stable population of farmworkers. All had been born in the valley, and almost all the parents had been born in the United States. All the children had completed at least six months in the programme, which furnishes day care and meals for children of low-income working parents. Informed consent was obtained by Operation Head Start through its Parents’ Council. Hair samples were collected, treated, and analysed.’ The children were weighed, in their underpants, on beam scales controlled with calibrated weights and levelled daily. Vertical heights were measured8 and weight/height and height/age were calculated from U.S. Public Health Service standards.
The results, expressed as mean +SD (and range) were: hair zinc 131±40 (69-219) :’.g/g; weight/height 98±8 (78-122; and height/age 97±3 (90-110). When we compared hair zinc and height by linear regression across the narrow range of values, we found that less than 1% of the variance could be explained by the regression. The same was true for hair zinc and height/age. These data confirm the finding that normally growing Hispanic-American children have normal hair zinc values and suggest that the low hair zinc values reported in the lower height percentiles of Hispanic-American preschool children3 are more likely to be related to poor growth than to genetic factors. Department of Nutritional Sciences, University of California, Berkeley, California, U.S.A.
ROBERT B. BRADFIELD*
Department of Pediatrics, University of Colorado Medical Center, Denver, Colorado
K. MICHAEL HAMBIDGE
*Present address: International Nutrition Associates, 36 El California 94563, U.S.A.
Toyonal, Orinda,
TRYPSIN CLEARANCE AND PANCREATIC DISEASE
SiR,—Dr Lake-Bakaar and his colleagues (Oct. 27, p. 878) have raised the interesting possibility that measurement of urinary trypsin/creatinine clearance ratio (TCCR) may be of value in distinguishing between chronic pancreatitis and carcinoma of the pancreas. However, they seemed to be uncertain of the underlying mechanism of the raised TCCR in acute pancreatitis and pancreatic cancer. We have compared the amylase/creatinine clearance ratio (ACCR) with the &bgr;2-microglobulin/creatinin&bgr;’ clearance ratio (BCCR).9 &bgr;2-microglobulin (&bgr;2-MG) is a low-molecular-weight protein (11 500) with more than 99% resorption by renal tubules. In acute pancreatitis serum j3-MG levels remain unchanged, so that a parallel ACCR and BCCR in acute pan-
7.
Hambidge KM, Hambidge C, Jacobs M, Baum JB. Low levels of zinc in hair, anorexia, poor growth and hypogeusia in children. Pediat Res 1972; 6:
868-74. 8. Owen GM. The assessment and recording of measurements of growth of children. Pediatrics 1973; 51: 461-65. 9. Playforth MJ, Rashid SA, Cooper EH, McMahon MJ. Increased renal clearance of amylase—a non-specific response to acute illness. Gut 1979; 20:
A929.