to note that the incidence of NTD is decreasing and varies geographically in the United States and elsewhere. Finally, although differences in vitamin use between affected and control groups were found only in the Atlanta study, data on vitamin use were more accurate and complete in the more recent study of Mills et al., whose design also minimized recall bias. The results of Mills et a1.l also differ from those reported in the United Kingdom by Smithells et al.,233 whose nonrandomized clinical trial of the effect of periconceptional multivitamin supplementation on NTD recurrence showed that supplements protected against recurrence, and of others.6 In interpreting the results of the latter s t ~ d i e s one , ~ ~must ~ ~ ~consider that the incidence of NTD is much higher in the United Kingdom than in the United States; genetic factors as well as the extent of vitamin fortification of the food supply are also likely to be quite different in the two countries. In summary, findings from epidemiologic studies and clinical trials designed to detect a relationship between multivitamin supplementation and NTD have been discordant and controversial, and therefore continue to challenge investigators in this field. As stressed in the preceding re vie^,^ the hypothesis that periconceptional use of multivitamin supplements decreases the incidence of NTD must now be tested by a
prospective, randomized clinical trial that addresses possible geog raphidgeneti c variation. Complete and accurate data on dietary intake and nutritional status, in addition to information on use of multivitamin supplements, should be obtained in future studies. 1. Mills JL, Rhoads GG, Simpson JL, et al. The absence of a relation between the periconceptional use of vitamins and neural tube defects. N Engl J Med 1989;321:430-5 2. Smithells RW, Sheppard S, Schorah CJ, et al. Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch Dis Child 1981;56:911-8 3. Smithells RW, Sheppard S, Wild J, Schorah CJ. Prevention of neural tube defect recurrences in Yorkshire: final report [letter]. Lancet 1989;2:4989 4. Mulinare J, Corder0 JF, Erickson JD, Berry RJ. Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 1988;260: 3141-5 5. Evidence for an association between periconceptional use of multivitamins and neural tube defects. Nutr Rev 1990;48:23-5 6. Dobbing J, ed. Prevention of spina bifida and other neural tube defects. London: Academic Press, 1983
Note Added in Proof: Another retrospective study showing benefits of vitamin supplementation during pregnancy has recently been published (Milunsky A, et al. Multivitamin folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989; 2822847-52). Results of a prospective study are still awaited.
ZINC AND COPPER WASTAGE DURING ACUTE DIARRHEA An episode of acute infectious dehydrating diarrhea in infants can cause nutritional deficits in the trace elements zinc and copper.
In 1959 Scrimshaw, Taylor, and Gordon’ pointed out the synergistic relationship between malnutrition and infection. Poor nutrition increases the severity of infection, and infection impairs the nutritional status of the individual. The importance of infantile diarrheal disease has long been appre-
ciated as a major pediatric public health problem.2 Only recently has increased attention been given to the unique role of episodic gastroenteritides in the etiology of m a l n u t r i t i ~ n . ~In. ~the pre-1960 literature considered by Scrimshaw et aI.,l issues of human nutrition regarding the trace metals NUTRITION REVIEWSIVOL 48, NO llJANUARY 1990 19
zinc and copper were unknown. It has only been since the 1960s that deficiencies of zinc5 and copper6 in humans have been recognized. Several reports have examined the nutritional status of young children with chronic diarrhea, but information on the more typical acute diarrheal diatheses has been lacking. Careful metabolic-balance studies by Castillo-Duran et al.7 have clarified and quantified the impact that an episode of infectious diarrhea can have on the trace-element economy of the sick child. The subjects of the study were 14 boys ranging in age from three to 14 months (mean, 6.4 months); they had been admitted to a Chilean pediatric hospital with an acute episode of dehydrating diarrhea of from two to 15 days’ duration (mean, five days) for which antibiotic treatment was not indicated. All patients received intravenous fluids to correct electrolyte and acidbase disturbances during the first 24-48 h of hospitalization. Simultaneously, at 8-12 h after admission, oral feeding with a formula of diluted cow’s milk and sucrose was instituted. For comparison, a control group of 12 male infants ranging in age from four to 12 months (mean, 7.0months) was studied in a parallel fashion. Patients in the control group were recovering in the same hospital from respiratory diseases such as asthma or pneumonia. Both groups had comparable birth weights and nutritional status, with a mean adequacy of weightfor-age values of 80% (affected) and 82% (control). Metabolic balance studies were performed in a similar fashion in both groups. With affected infants, the balance study was performed during the first 48 h after admission (period no. 1); with seven randomly selected infants, the study was repeated on days 6 and 7, when they were consuming the formula described earlier. Specimens for balance studies were collected from the controls on days 5-10, about two or three days prior to anticipated discharge. These children consumed undiluted cow’s milk formula with added sucrose. Urine was separated from stool by 20 NUTRITION REVlEWSlVOL 48, NO llJANUARY 1990
plastic, trace metal-free collectors. BriIliant-blue fecal markers were used to indicate the commencement and termination of the 48-h collection period. Plasma samples were also collected at the end of each metabolic-balance study. Analyses of trace minerals in dietary formulas, feces, urine, and plasma were performed by atomic absorption spectrophotometry. Because of differences in appetite and intestinal tolerance of foods at different stages of recovery and between the groups with intestinal and respiratory (controls) infections, the intakes of trace elements differed in each balance situation. In period no. 1 , affected children consumed 6.3 t 2.7 p g of copper/kg per day, whereas in period no. 2, this rose to 28.0 ? 11.0 pg/kg per day. The fecal losses were 55.7 ? 21.2 and 50.1 t 47.0 pg/kg per day in the respective periods. Urinary copper excretion was negligible ( ~ 0 .pg/kg 3 per day), and net copper balance values for children with diarrhea were -49.6 t 21.9 pg/kg per day and - 21.5 t 46.7pg/kg per day in periods 1 and 2, respectively. The control infants consumed 50.0 t 10.8pg of copper/kg per day in their balance period and had a fecal loss of 28.2 ? 6.7 pg/kg per day. Urinary losses were equally small, giving a net retention of +21.0 ? 11.7pg/kg per day. In the affected group (but not in the controls) during both periods, a significant correlation between fecal weight and fecal copper losses was observed (r = 0.72,p < 0.0001). Patients with diarrhea had an oral intake of zinc of 51.4 t 23.3pg/kg per day in balance period no. l and 254.1 k 87.4 pg/kg per day in the second period. As with copper, renal losses of zinc were ~ 0 . pg/kg 3 per day. Fecal losses were 159.4 t 59.9 pglkg per day in period no. 1 and 49.6 t 20.4 pg/kg per day in period no. 2. These values provided a negative zinc balance of -108.0 k 67.5 pg/kg per day in the postadmission period and +49.6 ? 20.4pg/kg per day in the predischarge period. The control group consumed 453.0 k 71.3 p g of zinc/kg per day, excreted 47.4 k 6.4 pg/kg per day, and had an overall positive balance of +405.3 ? 60.8 pg/kg per day.
Fecal weight and fecal zinc losses correlated significantly in the affected children (r = 0.81, p < 0.001) but not in the controls. A negative correlation between plasma zinc levels and fecal zinc excretion was seen in the children with diarrhea ( r = -0.74, p < 0.001). Thus, Castillo-Duran et at.’ confirmed once again-with two additional nutrients (zinc and copper) and with a specific infectious entity (acute diarrhea)-the cardinal features of the interaction between infection and malnutrition. These authors provide a mechanism for loss, i.e., wastage from the gastrointestinal tract. This loss probably derives both from the malabsorption of dietary minerals and excessive losses of endogenous sources of the metals, at least in the early period after admission to the hospital. In infants, who are growing at a rapid rate, the normal state for metabolic balance of all nutrients is in the direction of net accretion. The Chilean invest igators have put specific quantitative numbers on the expected deficits in copper and zinc retention. Since the normal state for the growing infant is net retention, possibly the most appropriate expression of the deficit would be the net difference between the metal lost from the body and that which would be gained by a normal child of the same age. Calculated in that way, the nutritional deficit for copper in the postadmission period would combine the 49.6 pgikg per day lost and the 21 kg/kg retained daily by the controls. This gives a net deficit of 70 pgikg per day. (In fact, this calculation may slightly overestimate the true deficit since the control group is not a perfect control. Since they are malnourished and convalescent, a more-positivethan-normal nutrient balance might be expected, as compared with healthy age-matched controls.) With similar assumptions and calculations for zinc, i.e., combining the amount retained by controls with the amount lost by affected subjects, the average postadmission nutritional deficit for this mineral would be 513.3 pg/kg per day. Here again, the caveat of the exag-
gerated retention in the control group must be considered. Clear indication that the pathophysiologic abnormalities of diarrhea are involved in the process of intestinal loss of trace metals can be found in the fact that the amount of watery fecal substances is a direct predictor of the quantity of each mineral lost. The interaction with circulating levels of metal ions, often used as nutritional indexes of trace mineral status, is more complex. Copper levels often increase during infection as a result of stimulation of the hepatic production of ceruloplasmin.8 At admission the mean plasma levels of copper were 63.2 k 14.4 pg/dL for the group with diarrhea; this value is significantly lower than the 90.7 k 19.5 pg/dL observed after the second balance period. Both of these copper concentrations are significantly lower than that of 117.1 -+ 18.0 pg/kg per day in the comparison group. The increase in plasma copper through the recovery from diarrhea may represent the sealing of the intestinal copper leak. Circulating levels of zinc often decline during acute infections because of an internal redistribution of the metal to the liver.8 This mechanism would be a convenient explanation for the marked difference in plasma zinc from the first period (57.7 k 19.0 p,g/dL) to the second (101.4 ? 20.7 pg/dL) were it not for the strong correlation between plasma zinc and fecal zinc losses demonstrated by the balance data. Some mediation of lowered circulating zinc levels must be attributed to fecal wastages of the mineral. Thus, a reasonable explanation of the observed effects on plasma zinc during acute gastroenteritis would be the reduced retention of zinc during diarrhea and the redistributional influence of infection. Fortunately, recent public health measures such as oral rehydration therapy have shifted our focus in infantile diarrhea somewhat from strict issues of mortality to concerns about nutritional recovery and ~ e l l - b e i n g . With ~ , ~ the conceptual framework of a synergistic interaction of nutrition and infection having been developed
NUTRITION REVIEWSIVOL 48, NO 1NANUARY 1990 21
three decades ago,' it has been the work of subsequent investigators to give an empiric context to this idea. It should be recognized that the Chilean findings raise-but do not answer-questions of whether recovery regimens should contain supplemental amounts of copper and zinc. However, the work of Castillo-Duran et al.7 has opened the way for additional investigation into the dietary management of acute diarrhea.
4.
5.
6.
7. Scrimshaw NS, Taylor CE, Gordon JE. Interaction of nutrition and infection. Am J Med Sci 1959;237: 367-403 Gordon JE, Chitkara ID, Wyon JB: Weanling diarrhea. Am J Med Sci 1963;245:345-77 National Academy of Sciences. Management of
8.
the diarrheal diseases at the community level. Washington, DC: National Academy Press, 1981 National Academy of Sciences. Nutritional management of acute diarrhea in infants and children. Washington, DC: National Academy Press, 1985 Prasad AS, Miale A, Farid Z, Sandstead HH, Schubert AR. Zinc metabolism in patients with the syndrome of iron-deficiency anemia, hepatosplenomegaly, dwarfism, and hypogonadism. J Lab Clin Med 1963;61:537-49 Cordano A, Graham GG. Copper deficiency complicating severe chronic intestinal malabsorption. Pediatrics 1966;38:596-604 Castillo-Duran C, Vial P, Uauy R. Trace mineral balance during acute diarrhea in infants. J Pediatr 1988; 1 13 1452- 7 Kampschmidt RF, Upchurch HF, Eddington CL, Pulliam LA. Multiple biological activities of partially purified leukocytic endogenous mediator. Am J Physiol 1973;224:530-3
USEOFETHYLESTERSOFTRYPTOPHANTOBYPASSTHE ABSORPTION DEFECT IN HARTNUP DISEASE Oral administration of tryptophan ethyl ester bypassed the absorptive defect in a severe case of Hartnup disease in a young child. After treatment, growth resumed and symptoms were alleviated.
The supplying of an amino acid as its methyl or ethyl ester has proved experimentally useful to increase its passage across a biologic membrane.' The increased passage is due to the fact that the ester is more soluble in lipid than is the amino acid itself. In particular, administration of the dimethyl ester of cystine has allowed simulation of the very high cystine levels seen in various cells in cystinosis. Such esters are subject to intracellular, and particularly intralysosomal, esterase action, which regenerates the native amino acid. In Hartnup disease, a congenital disorder, a considerable group of dipolar (neutral) amino acids show subnormal 22 NUTRITION REVIEWSIVOL 48, NO 1IJANUARY 1990
renal and intestinal absorption.*z3 Although the disorder may be entirely asymptomatic, some patients suffer an episodic, pellagralike illness with dermatitis, diarrhea, ataxia, and occasionally severe neuropsychiatric symptoms. The pellagralike character of some of the symptoms have called attention to a possibly important contribution of tryptophan deficiency; however, the disease tends to present as a multifactorial p r ~ b l e mAlthough .~ treatment with nicotinamide may permit synthesis of nicotinamide adenine dinucleotide (NAD), it does not directly provide a substrate for protein and serotonin synthesis. Jonas and Butler4 have investigated the
prospective, randomized clinical trial that addresses possible geog raphidgeneti c variation. Complete and accurate data on dietary intake and nutritional status, in addition to information on use of multivitamin supplements, should be obtained in future studies. 1. Mills JL, Rhoads GG, Simpson JL, et al. The absence of a relation between the periconceptional use of vitamins and neural tube defects. N Engl J Med 1989;321:430-5 2. Smithells RW, Sheppard S, Schorah CJ, et al. Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch Dis Child 1981;56:911-8 3. Smithells RW, Sheppard S, Wild J, Schorah CJ. Prevention of neural tube defect recurrences in Yorkshire: final report [letter]. Lancet 1989;2:4989 4. Mulinare J, Corder0 JF, Erickson JD, Berry RJ. Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 1988;260: 3141-5 5. Evidence for an association between periconceptional use of multivitamins and neural tube defects. Nutr Rev 1990;48:23-5 6. Dobbing J, ed. Prevention of spina bifida and other neural tube defects. London: Academic Press, 1983
Note Added in Proof: Another retrospective study showing benefits of vitamin supplementation during pregnancy has recently been published (Milunsky A, et al. Multivitamin folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989; 2822847-52). Results of a prospective study are still awaited.
ZINC AND COPPER WASTAGE DURING ACUTE DIARRHEA An episode of acute infectious dehydrating diarrhea in infants can cause nutritional deficits in the trace elements zinc and copper.
In 1959 Scrimshaw, Taylor, and Gordon’ pointed out the synergistic relationship between malnutrition and infection. Poor nutrition increases the severity of infection, and infection impairs the nutritional status of the individual. The importance of infantile diarrheal disease has long been appre-
ciated as a major pediatric public health problem.2 Only recently has increased attention been given to the unique role of episodic gastroenteritides in the etiology of m a l n u t r i t i ~ n . ~In. ~the pre-1960 literature considered by Scrimshaw et aI.,l issues of human nutrition regarding the trace metals NUTRITION REVIEWSIVOL 48, NO llJANUARY 1990 19
zinc and copper were unknown. It has only been since the 1960s that deficiencies of zinc5 and copper6 in humans have been recognized. Several reports have examined the nutritional status of young children with chronic diarrhea, but information on the more typical acute diarrheal diatheses has been lacking. Careful metabolic-balance studies by Castillo-Duran et al.7 have clarified and quantified the impact that an episode of infectious diarrhea can have on the trace-element economy of the sick child. The subjects of the study were 14 boys ranging in age from three to 14 months (mean, 6.4 months); they had been admitted to a Chilean pediatric hospital with an acute episode of dehydrating diarrhea of from two to 15 days’ duration (mean, five days) for which antibiotic treatment was not indicated. All patients received intravenous fluids to correct electrolyte and acidbase disturbances during the first 24-48 h of hospitalization. Simultaneously, at 8-12 h after admission, oral feeding with a formula of diluted cow’s milk and sucrose was instituted. For comparison, a control group of 12 male infants ranging in age from four to 12 months (mean, 7.0months) was studied in a parallel fashion. Patients in the control group were recovering in the same hospital from respiratory diseases such as asthma or pneumonia. Both groups had comparable birth weights and nutritional status, with a mean adequacy of weightfor-age values of 80% (affected) and 82% (control). Metabolic balance studies were performed in a similar fashion in both groups. With affected infants, the balance study was performed during the first 48 h after admission (period no. 1); with seven randomly selected infants, the study was repeated on days 6 and 7, when they were consuming the formula described earlier. Specimens for balance studies were collected from the controls on days 5-10, about two or three days prior to anticipated discharge. These children consumed undiluted cow’s milk formula with added sucrose. Urine was separated from stool by 20 NUTRITION REVlEWSlVOL 48, NO llJANUARY 1990
plastic, trace metal-free collectors. BriIliant-blue fecal markers were used to indicate the commencement and termination of the 48-h collection period. Plasma samples were also collected at the end of each metabolic-balance study. Analyses of trace minerals in dietary formulas, feces, urine, and plasma were performed by atomic absorption spectrophotometry. Because of differences in appetite and intestinal tolerance of foods at different stages of recovery and between the groups with intestinal and respiratory (controls) infections, the intakes of trace elements differed in each balance situation. In period no. 1 , affected children consumed 6.3 t 2.7 p g of copper/kg per day, whereas in period no. 2, this rose to 28.0 ? 11.0 pg/kg per day. The fecal losses were 55.7 ? 21.2 and 50.1 t 47.0 pg/kg per day in the respective periods. Urinary copper excretion was negligible ( ~ 0 .pg/kg 3 per day), and net copper balance values for children with diarrhea were -49.6 t 21.9 pg/kg per day and - 21.5 t 46.7pg/kg per day in periods 1 and 2, respectively. The control infants consumed 50.0 t 10.8pg of copper/kg per day in their balance period and had a fecal loss of 28.2 ? 6.7 pg/kg per day. Urinary losses were equally small, giving a net retention of +21.0 ? 11.7pg/kg per day. In the affected group (but not in the controls) during both periods, a significant correlation between fecal weight and fecal copper losses was observed (r = 0.72,p < 0.0001). Patients with diarrhea had an oral intake of zinc of 51.4 t 23.3pg/kg per day in balance period no. l and 254.1 k 87.4 pg/kg per day in the second period. As with copper, renal losses of zinc were ~ 0 . pg/kg 3 per day. Fecal losses were 159.4 t 59.9 pglkg per day in period no. 1 and 49.6 t 20.4 pg/kg per day in period no. 2. These values provided a negative zinc balance of -108.0 k 67.5 pg/kg per day in the postadmission period and +49.6 ? 20.4pg/kg per day in the predischarge period. The control group consumed 453.0 k 71.3 p g of zinc/kg per day, excreted 47.4 k 6.4 pg/kg per day, and had an overall positive balance of +405.3 ? 60.8 pg/kg per day.
Fecal weight and fecal zinc losses correlated significantly in the affected children (r = 0.81, p < 0.001) but not in the controls. A negative correlation between plasma zinc levels and fecal zinc excretion was seen in the children with diarrhea ( r = -0.74, p < 0.001). Thus, Castillo-Duran et at.’ confirmed once again-with two additional nutrients (zinc and copper) and with a specific infectious entity (acute diarrhea)-the cardinal features of the interaction between infection and malnutrition. These authors provide a mechanism for loss, i.e., wastage from the gastrointestinal tract. This loss probably derives both from the malabsorption of dietary minerals and excessive losses of endogenous sources of the metals, at least in the early period after admission to the hospital. In infants, who are growing at a rapid rate, the normal state for metabolic balance of all nutrients is in the direction of net accretion. The Chilean invest igators have put specific quantitative numbers on the expected deficits in copper and zinc retention. Since the normal state for the growing infant is net retention, possibly the most appropriate expression of the deficit would be the net difference between the metal lost from the body and that which would be gained by a normal child of the same age. Calculated in that way, the nutritional deficit for copper in the postadmission period would combine the 49.6 pgikg per day lost and the 21 kg/kg retained daily by the controls. This gives a net deficit of 70 pgikg per day. (In fact, this calculation may slightly overestimate the true deficit since the control group is not a perfect control. Since they are malnourished and convalescent, a more-positivethan-normal nutrient balance might be expected, as compared with healthy age-matched controls.) With similar assumptions and calculations for zinc, i.e., combining the amount retained by controls with the amount lost by affected subjects, the average postadmission nutritional deficit for this mineral would be 513.3 pg/kg per day. Here again, the caveat of the exag-
gerated retention in the control group must be considered. Clear indication that the pathophysiologic abnormalities of diarrhea are involved in the process of intestinal loss of trace metals can be found in the fact that the amount of watery fecal substances is a direct predictor of the quantity of each mineral lost. The interaction with circulating levels of metal ions, often used as nutritional indexes of trace mineral status, is more complex. Copper levels often increase during infection as a result of stimulation of the hepatic production of ceruloplasmin.8 At admission the mean plasma levels of copper were 63.2 k 14.4 pg/dL for the group with diarrhea; this value is significantly lower than the 90.7 k 19.5 pg/dL observed after the second balance period. Both of these copper concentrations are significantly lower than that of 117.1 -+ 18.0 pg/kg per day in the comparison group. The increase in plasma copper through the recovery from diarrhea may represent the sealing of the intestinal copper leak. Circulating levels of zinc often decline during acute infections because of an internal redistribution of the metal to the liver.8 This mechanism would be a convenient explanation for the marked difference in plasma zinc from the first period (57.7 k 19.0 p,g/dL) to the second (101.4 ? 20.7 pg/dL) were it not for the strong correlation between plasma zinc and fecal zinc losses demonstrated by the balance data. Some mediation of lowered circulating zinc levels must be attributed to fecal wastages of the mineral. Thus, a reasonable explanation of the observed effects on plasma zinc during acute gastroenteritis would be the reduced retention of zinc during diarrhea and the redistributional influence of infection. Fortunately, recent public health measures such as oral rehydration therapy have shifted our focus in infantile diarrhea somewhat from strict issues of mortality to concerns about nutritional recovery and ~ e l l - b e i n g . With ~ , ~ the conceptual framework of a synergistic interaction of nutrition and infection having been developed
NUTRITION REVIEWSIVOL 48, NO 1NANUARY 1990 21
three decades ago,' it has been the work of subsequent investigators to give an empiric context to this idea. It should be recognized that the Chilean findings raise-but do not answer-questions of whether recovery regimens should contain supplemental amounts of copper and zinc. However, the work of Castillo-Duran et al.7 has opened the way for additional investigation into the dietary management of acute diarrhea.
4.
5.
6.
7. Scrimshaw NS, Taylor CE, Gordon JE. Interaction of nutrition and infection. Am J Med Sci 1959;237: 367-403 Gordon JE, Chitkara ID, Wyon JB: Weanling diarrhea. Am J Med Sci 1963;245:345-77 National Academy of Sciences. Management of
8.
the diarrheal diseases at the community level. Washington, DC: National Academy Press, 1981 National Academy of Sciences. Nutritional management of acute diarrhea in infants and children. Washington, DC: National Academy Press, 1985 Prasad AS, Miale A, Farid Z, Sandstead HH, Schubert AR. Zinc metabolism in patients with the syndrome of iron-deficiency anemia, hepatosplenomegaly, dwarfism, and hypogonadism. J Lab Clin Med 1963;61:537-49 Cordano A, Graham GG. Copper deficiency complicating severe chronic intestinal malabsorption. Pediatrics 1966;38:596-604 Castillo-Duran C, Vial P, Uauy R. Trace mineral balance during acute diarrhea in infants. J Pediatr 1988; 1 13 1452- 7 Kampschmidt RF, Upchurch HF, Eddington CL, Pulliam LA. Multiple biological activities of partially purified leukocytic endogenous mediator. Am J Physiol 1973;224:530-3
USEOFETHYLESTERSOFTRYPTOPHANTOBYPASSTHE ABSORPTION DEFECT IN HARTNUP DISEASE Oral administration of tryptophan ethyl ester bypassed the absorptive defect in a severe case of Hartnup disease in a young child. After treatment, growth resumed and symptoms were alleviated.
The supplying of an amino acid as its methyl or ethyl ester has proved experimentally useful to increase its passage across a biologic membrane.' The increased passage is due to the fact that the ester is more soluble in lipid than is the amino acid itself. In particular, administration of the dimethyl ester of cystine has allowed simulation of the very high cystine levels seen in various cells in cystinosis. Such esters are subject to intracellular, and particularly intralysosomal, esterase action, which regenerates the native amino acid. In Hartnup disease, a congenital disorder, a considerable group of dipolar (neutral) amino acids show subnormal 22 NUTRITION REVIEWSIVOL 48, NO 1IJANUARY 1990
renal and intestinal absorption.*z3 Although the disorder may be entirely asymptomatic, some patients suffer an episodic, pellagralike illness with dermatitis, diarrhea, ataxia, and occasionally severe neuropsychiatric symptoms. The pellagralike character of some of the symptoms have called attention to a possibly important contribution of tryptophan deficiency; however, the disease tends to present as a multifactorial p r ~ b l e mAlthough .~ treatment with nicotinamide may permit synthesis of nicotinamide adenine dinucleotide (NAD), it does not directly provide a substrate for protein and serotonin synthesis. Jonas and Butler4 have investigated the
