Am J Clin Nutr

Effects of resistant starch on the colon in healthy volunteers: possible implications for cancer prevention.

Hylla S. Gostner A. Dusel G. Anger H. Bartram HP. Christl SU. Kasper H. Scheppach W.
Department of Medicine, University of Wurzburg, Germany.
Recent evidence suggests that resistant starch (RS) is the single most important substrate for bacterial carbohydrate fermentation in the human colon. During two 4-wk periods. 12 healthy volunteers consumed a controlled basal diet enriched with either amylomaize starch (55.2 +/- 3.5 g RS/d; high-RS diet) or available cornstarch (7.7 +/- 0.3 g RS/d; low-RS diet). Approximately 90% of the RS consumed disappeared during intestinal passage; increased fermentation was verified by elevated breath-hydrogen excretion. During the high-RS diet, fecal wet and dry weight increased 49% and 56%, respectively (P < or = 0.005), whereas stool water content did not change significantly. Fecal concentrations and daily excretion of short-chain fatty acids were not different in the two study periods. During the high-RS diet, bacterial beta-glucosidase activity decreased by 26% (P < or = 0.05). Fecal concentrations of total and secondary bile acids were significantly lower during the high-RS than during the low-RS period [a decrease of 30% (P < or = 0.05) and 32% (P < or = 0.01), respectively, in total and secondary bile acids] whereas concentrations of primary bile acids were unaffected by RS consumption. During the high-RS diet, fecal concentrations of total neutral sterols decreased by 30% (P < or = 0.005) and fecal concentrations of 4-cholesten-3-one decreased by 36% (P < or = 0.05). These data suggest that RS has potentially important effects on bacterial metabolism in the human colon that may be relevant for cancer prevention.

Twenty-four-hour energy balance in Crohn disease patients: metabolic implications of steroid treatment.

Mingrone G. Benedetti G. Capristo E. De Gaetano A. Greco AV. Tataranni PA. Gasbarrini G.
Istituto di Medicina Interna, Universita Cattolica del Sacro Cuore, Rome, Italy. iclcm@rm.unicatt.it
Several hypotheses have been proposed to explain the nutritional deficiencies seen in Crohn disease patients, including inadequate food intake, decreased assimilation and increased loss of nutrients, and increased energy expenditure. To assess the effect of steroid therapy on body composition, energy expenditure, and fuel selection in Crohn disease, we compared 12 patients (6 men and 6 women) with biopsy-proven ileal Crohn disease with 11 healthy volunteers (6 men and 5 women). Five patients [Crohn's disease activity index (CDAI) = 98.4 +/- 3.78] took no medication and seven patients (CDAI = 283.9 +/- 22.5) were administered 29 +/- 18 mg prednisone/d. Body composition was evaluated by isotopic dilution and bioelectrical impedance analysis, and 24-h energy expenditure and basal metabolic rate were measured in a respiratory chamber. Fat-free mass was not significantly different among groups, whereas fat mass was lower in patients than in control subjects. Energy intake was higher in treated patients than in both untreated patients (P = 0.004) and control subjects (P = 0.005). Fecal losses were not significantly different between untreated patients and control subjects, but were higher (and proportional to the CDAI) in treated patients than in control subjects (P = 0.001). Metabolizable energy was not significantly different among groups, whereas energy balance was significantly higher in treated patients than in both control subjects (P = 0.0057) and untreated patients (P = 0.018). Nitrogen balance was mildly negative in treated patients compared with both control subjects and untreated patients, but not significantly so. In conclusion, prednisone treatment in Crohn disease patients stimulates food intake, promoting an overall positive energy balance despite large fecal nutrient losses.

Moderation of lactulose-induced diarrhea by psyllium: effects on motility and fermentation.

Washington N. Harris M. Mussellwhite A. Spiller RC.
Division of Gastroenterology and Department of Surgery, Queen's Medical Centre, Nottingham, United Kingdom. neena.washington@nottingham.ac.uk
Psyllium has been reported to inhibit lactulose-induced colonic mass movements and to benefit patients with irritable bowel syndrome, improving both constipation and diarrhea. Our aim was to define how psyllium modified the whole-gut transit of a radiolabeled lactulose-containing test meal by using gamma scintigraphy. Eight subjects participated in a randomized crossover study comparing gastric emptying and small bowel and colonic transit after consumption of 20 mL lactulose three times daily with or without 3.5 g psyllium three times daily. Psyllium significantly delayed gastric emptying: the time to 50% emptying increased from a control value of 69 +/- 9 to 87 +/- 11 min (mean +/- SEM; P < 0.05, n = 8). Small bowel transit was unaltered. However, progression through the colon was delayed with an increase in the percentage of the dose at 24 h in the ascending (control group: 2 +/- 3%, psyllium group: 11 +/- 8%; P < 0.02) and transverse colon (control group: 5 +/- 12%, psyllium group: 21 +/- 14%) with correspondingly less in the descending colon. Although the time for 50% of the isotope to reach the colon was not significantly different with psyllium, psyllium significantly delayed the rise in breath-hydrogen concentrations, which reached 50% of their peak at 217 +/- 34 min compared with control values of 155 +/- 27 min (P < 0.05). Psyllium delays gastric emptying, probably by increasing meal viscosity, and reduces the acceleration of colon transit, possibly by delaying the production of gaseous fermentation products.

Limited effect of consumption of uncooked (RS2) or retrograded (RS3) resistant starch on putative risk factors for colon cancer in healthy men.

Heijnen ML. van Amelsvoort JM. Deurenberg P. Beynen AC.
Department of Human Nutrition, Wageningen Agricultural University, The Netherlands. marie-louise.heijnen@rivm.nl
To investigate whether resistant starch (RS) affects putative risk factors for colon cancer, 24 healthy men consumed a daily RS supplement for 4 wk in addition to their habitual diet in a single-blind, randomized, balanced multiple crossover trial. During the first week, all subjects consumed the control supplement containing glucose. Subsequently, each subject consumed, in random order, a supplement with RS2 (uncooked high-amylose cornstarch), RS3 (extruded and retrograded high-amylose cornstarch), and glucose, each for 1 wk. The RS2 and RS3 supplements provided 32 g RS/d. Lithium was added to the supplements to measure compliance. Feces, 24-h urine, and breath samples, as well as a 24-h food-consumption recall were obtained weekly from each subject. Compliance as measured by urinary lithium recovery was satisfactory. The mean composition of the background diet did not differ between the various supplementation periods. Breath-hydrogen excretion, stool weight, and fecal starch excretion were significantly higher during RS than during glucose supplementation, but did not differ during RS2 and RS3 supplementation. There were no significant differences in fecal dry weight, pH, or short-chain fatty acid concentrations, nor in the pH, bile acid concentrations, cytotoxicity, or osmolality of fecal water. It is concluded that in healthy men, supplementing the habitual diet for 1 wk with 32 g RS2 or RS3/d compared with glucose had no effect on putative risk factors for colon cancer, except for increasing stool weight and colonic fermentative activity. There were no significant differences between the effects of RS2 and RS3 on the indexes studied.

Reversal of low bone density with a gluten-free diet in children and adolescents with celiac disease.

Year 1998
Mora S. Barera G. Ricotti A. Weber G. Bianchi C. Chiumello G.
Department of Pediatrics, Scientific Institute H San Raffaele, University of Milan, Italy. s.mora@.hsr.it
Osteoporosis is a common finding in adult celiac disease patients; however, there are still few data regarding children and adolescents. In the present study we measured the bone mineral density (BMD) in children and adolescents at diagnosis of celiac disease and after approximately 1 y of a gluten-free diet. BMD was measured at the lumbar spine and in the whole skeleton by dual-energy X-ray absorptiometry in 44 celiac disease patients aged 2.58-20.42 y at diagnosis. BMD was also measured in a subset of 25 patients after 1.4 +/- 0.04 y of a gluten-free diet. BMD was compared with that of 177 healthy control subjects aged 1.52-20.99 y. Lumbar spine and whole-body BMD values at diagnosis of celiac disease were significantly lower than in control subjects (P = 0.015 and P = 0.0001, respectively) after differences in age and anthropomorphic variables were controlled for. The subjects studied after the gluten-free diet had BMD values not significantly different from those of control subjects. In conclusion, children and adolescents with celiac disease have remarkably reduced lumbar spine and whole-body bone density. A gluten-free diet promotes a rapid increase of BMD that leads to a complete recovery of bone mineralization. These results emphasize the need for an early diagnosis and treatment in patients with celiac disease to obtain an adequate peak bone mass at the end of puberty.

Nutritional status of newly diagnosed celiac disease patients before and after the institution of a celiac disease diet--association with the grade of mucosal villous atrophy.

Year 1998
Kemppainen TA. Kosma VM. Janatuinen EK. Julkunen RJ. Pikkarainen PH. Uusitupa MI.
Department of Clinical Nutrition, University of Kuopio, Finland.
No systematic studies have been carried out on the association of nutritional status with the severity of mucosal villous atrophy in newly diagnosed celiac disease patients. We examined the nutritional status of 40 adult patients with newly diagnosed celiac disease classified according to the grade of villous atrophy: partial, subtotal, and total. Nutritional status was determined by food records as well as by anthropometric and biochemical measurements. Anthropometric results did not differ among the three atrophy groups, but serum ferritin and erythrocyte folate were lower in patients with total villous atrophy than in the other groups. Most of the abnormal biochemical values were normalized during 1 y of a gluten-free diet; villous atrophy healed concomitantly. To conclude, patients with total mucosal villous atrophy at diagnosis had low erythrocyte folate and serum ferritin values, but no other major differences were found in nutritional status among celiac disease patients with different grades of villous atrophy.

Role of irritable bowel syndrome in subjective lactose intolerance.

Year 1998
Vesa TH. Seppo LM. Marteau PR. Sahi T. Korpela R.
Department of Biochemistry and Food Chemistry, University of Turku, Finland.
It has been suggested that the symptoms of irritable bowel syndrome (IBS) may be wrongly attributed to lactose intolerance. We examined the relations among IBS, demographic factors, living habits, and lactose intolerance. On the basis of a lactose tolerance test with ethanol, 101 of the 427 healthy subjects studied were lactose maldigesters and 326 were lactose digesters. IBS was diagnosed by means of the Bowel Disease Questionnaire, according to the Rome criteria. The use of dairy products and symptoms experienced after their consumption were recorded. IBS was found in 15% of both the lactose maldigesters and lactose digesters. One-third of the subjects reported intolerance to dairy products containing < or = 20 g lactose. About half of this third were lactose maldigesters and about half were lactose digesters. As explanations for this subjective lactose intolerance, the logistic regression model estimated lactose maldigestion (odds ratio: 10.3; 95% CI: 5.2, 20.4), IBS (4.6; 2.1, 10.1), experience of symptoms other than gastrointestinal ones (2.3; 1.2, 4.5), and female sex (2.1; 1.1, 4.0). Characteristics common to both subjective lactose intolerance and IBS were female sex and the experience of abdominal pain in childhood (P < 0.01). Age, regularity of meals, and the amount of physical activity were not associated with either subjective lactose intolerance or IBS. Of the subjects with IBS, the percentage of lactose maldigesters was the same as in the whole study group (24%) but the number who reported lactose intolerance was higher (60% compared with 27%, P < 0.001). We showed a strong relation among subjective lactose intolerance, IBS, the experience of abdominal pain in childhood, and female sex.

Biochemical assessment of the nutritional status of cystic fibrosis patients treated with pancreatic enzyme extracts.

Year 1998
Benabdeslam H. Garcia I. Bellon G. Gilly R. Revol A.
Laboratoire de Biochimie B et d'Immunologie, UF Lipides-Glucides, Centre Hospitalier Lyon Sud, France.
We examined the protein and fat nutritional status of 65 cystic fibrosis patients aged 4-26 y (x +/- SD: 11.2 +/- 5.6 y). Patients were treated with pancreatic enzyme extracts to improve nutrient absorption; in addition, most patients were supplemented with vitamins A and E. Results were compared with those in a control group of 39 subjects aged 5-29 y (x: 14.3 +/- 5.6 y) with no digestive diseases or nutritional deficiencies. Protein determination showed low albumin concentrations in 42% of the cystic fibrosis patients and decreased blood concentrations of retinol binding protein in 12% of the patients. Lipoprotein components were characterized by decreased cholesterol concentrations in 25% of the cystic fibrosis group. Also, mean concentrations of apolipoprotein A-I were significantly lower in the cystic fibrosis group than in control subjects. The results of fatty acid status, expressed in relative (%) and absolute (mg/L) values, showed concentrations of essential fatty acids, represented by linoleic and arachidonic acids, to be significantly decreased in cystic fibrosis patients; this decrease was markedly significant for fatty acid status expressed in absolute values, especially in the cholesteryl ester subfraction. Serum retinol and alpha-tocopherol concentrations were lowered by 8% and 46% in cystic fibrosis patients and control subjects, respectively: retinol, 1.80 +/- 0.50 and 2.37 +/- 0.60 micromol/L, P < 0.001, and alpha-tocopherol, 18.1 +/- 8.7 and 25.7 +/- 5.0 micromol/L, P < 0.001. In conclusion, despite regular treatment with pancreatic enzyme replacements, neither protein nor fat malnutrition in cystic fibrosis patients was completely corrected.

Comprehensive nutritional status in patients with long-standing Crohn disease currently in remission.

Year 1998
Geerling BJ. Badart-Smook A. Stockbrugger RW. Brummer RJ.
Department of Gastroenterology, University Hospital Maastricht, The Netherlands. bgee@sint.azm.nl
Malnutrition is observed frequently and is an important complication in patients with Crohn disease (CD). The pathophysiology of malnutrition in this disorder is complex. To obtain a comprehensive picture of nutritional status in patients with long-standing CD that was clinically in remission, we assessed four measures of nutritional status in 32 patients (18 women and 14 men) and 32 matched healthy control subjects: 1) body composition, 2) dietary intake, 3) biochemical indexes of nutrition, and 4) and muscle strength (as a functional index). Mean daily intakes of fiber and phosphorus were significantly lower in CD patients than in control subjects. Serum concentrations of several nutrients (beta-carotene, vitamin C, vitamin E, selenium, and zinc) and activity of the enzyme glutathione peroxidase were also significantly lower in CD patients, as were antioxidant status and serum concentrations of magnesium and vitamin D. Percentage body fat and hamstring muscle strength were significantly lower in male CD patients than in control subjects, whereas muscle strength of the quadriceps was preserved. In conclusion, this study showed a variety of nutritional and functional deficiencies in patients with long-standing CD in remission, especially in male patients with a high lifetime prednisone dose. A comprehensive nutritional assessment seems superior to the assessment of a single dimension of nutritional status.

Growth, morbidity, and mortality of children in Dhaka after treatment for severe malnutrition: a prospective study.

Year 1998
Khanum S. Ashworth A. Huttly SR.
Centre for Human Nutrition, and Maternal and Child Epidemiology Unit, London School of Hygiene and Tropical Medicine, United Kingdom.
Over 1300 severely malnourished children (< 60% of US National Center for Health Statistics weight-for-height, with edema, or both) are admitted each year to the Children's Nutrition Unit in Dhaka. Fatality during treatment is low and recovery is rapid. Our aim was to determine whether this initial success is sustained when children return home. A previous attempt to address this question was frustrated by the difficulty in tracing children after discharge because most are from slum settlements and families move frequently. This prospective study with fortnightly monitoring was therefore undertaken. The main outcomes of interest were anthropometric status, relapse, morbidity, and mortality. Children (n = 437) who had been treated for severe malnutrition when aged 12-59 mo and had reached the discharge criterion of 80% of weight-for-height, were followed for the next 12 mo. During follow-up, 7.5% were lost without trace, 0.6% relapsed, and 2.3% died. Morbidity was high, with a mean of seven episodes of diarrhea during the year. Outpatient visits for diarrhea occurred for 67% of children, and 58% had pneumonia (10% had pneumonia three times). After 12 mo, mean weight-for-height was 91% (-0.92 z score) but mean height-for-age remained at 84% (-4.14 z score). Weight gain, but not height gain, tended to be lower in children who experienced more diarrhea. Fever and cough were not associated with either weight or height gain. The high prevalence of illness highlights the need for continued accessible health care and for interventions to reduce disease acquisition.

Physiologic function of the Wilson disease gene product, ATP7B.

Year 1998
Bingham MJ. Ong TJ. Summer KH. Middleton RB. McArdle HJ.
Department of Child Health, Ninewells Hospital and Medical School, University of Dundee, United Kingdom.
The genes responsible for Wilson disease and Menkes syndrome have been cloned and identified as copper ATPases. These enzymes form part of a large family of transporters, the P-type ATPases. Although copper ATPases share strong structural similarities with these other pumps, comparatively little is known about their physiologic function. In this review, we examine data relating to the Wilson disease protein, ATP7B, in the liver. We present evidence suggesting that ATP7B is located intracellularly, together with data suggesting that, at least in part, ATP7B may also be found on the canalicular membrane. We also examine the form of copper that the transporter recognizes. We then review data on the Long-Evans Cinnamon rat, a model for Wilson disease, and discuss what effect the Wilson disease mutation has on copper transport. Finally, we conclude that, although we have made major advances in our understanding of copper metabolism in the liver, there are still many questions awaiting answers.

Functional analysis of copper homeostasis in cell culture models: a new perspective on internal copper transport.

Year 1998
Harris ED. Qian Y. Tiffany-Castiglioni E. Lacy AR. Reddy MC.
Department of Biochemistry and Biophysics and the Faculty of Nutrition, Texas A&M University, College Station 77843-2128, USA. eharris@bioch.tamu.edu
The movement of copper ions across membrane barriers of vital organs and tissues is a priority topic in nutrition and one for which there continues to be little understanding of the mechanism. Reports of membrane-bound, copper-transporting adenosine triphosphatases (Cu-ATPases) selective for copper ions have brought new focus to the problem and prompted fresh ideas. Using a cell culture model approach, we attempted to learn whether transport into and out of cells depends on a Cu-ATPase. Measurement of transport kinetics in fibroblasts, brain glial cells, neuroblastoma cells, and placental cells showed differences in the rates of copper uptake and response to sulfhydryl reagents. BeWo cells, a human choriocarcinoma placental cell line, behaved as did Menkes fibroblasts by avidly absorbing copper but not releasing copper to the immediate environment. Further tests showed that BeWo cells did not express the transcript for the membrane-bound Cu-ATPase that has been identified with Menkes syndrome. Transcript induction, however, was achieved by growing BeWo cells on porous filters that allowed apical and basolateral surfaces to form. With transcript expression, the cells showed a capacity to release copper into the medium. BeWo cells also synthesized a form of ceruloplasmin whose structure differed from that of the plasma protein and hence may be a product of a different gene. BeWo cells may also express the gene for Wilson disease, thus linking Menkes and Wilson proteins to maternal delivery of copper. We constructed a model in which both ATPases work in concert in a vesicle-based transport mechanism. The vesicle model may help us understand the transport of copper across the placenta and all cells in general.

Clinical conditions altering copper metabolism in humans.

Year 1998
Beshgetoor D. Hambidge M.
Section of Pediatric Nutrition and Center for Human Nutrition, University of Colorado School of Medicine, Denver, USA.
Overt copper deficiency is not believed to be a widespread public health concern for most population groups. However, a variety of case studies suggest that under certain circumstances, clinical conditions may predispose individuals to the risk of copper deficiency or copper excess. Acquired copper deficiency has been documented in conditions predisposing to inadequate copper intakes, in prematurity, in malabsorption syndromes, and in conditions predisposing to excessive copper losses. In contrast, increases in copper concentrations have been reported in response to stress, inflammation, and infection; in Parkinson disease and diabetes mellitus; and in conditions involving an obstruction to bile flow.

Role of copper in Indian childhood cirrhosis.

Year 1998
Tanner MS.
Department of Paediatrics, University of Sheffield, United Kingdom. m.s.tanner@sheffield.ac.uk
Of the cirrhoses that affect Indian children, Indian childhood cirrhosis (ICC) is a discrete clinical and histologic entity in which large amounts of copper are deposited in the liver. The evidence linking copper deposition to increased dietary copper intake in infancy was reviewed. Prevention of this feeding pattern prevents ICC, and the disease has now largely disappeared from many parts of India. Penicillamine, if given before the terminal clinical stage of ICC, reduces mortality from 92% to 53%. Long-term survivors show a sequence of histologic resolution, resulting either in inactive micronodular cirrhosis or in virtually normal histologic appearance. Twenty-nine treated ICC patients reexamined at 8.8 y of age (range: 6.3-13 y), 5-12 y after diagnosis, were well and had normal results from liver function tests. Clinical and epidemiologic evidence show that there must be excessive copper ingestion for ICC to develop, but the lack of an animal model, the inconstant relation between liver copper concentrations and liver damage, and the rarity of liver disease in adults suggests that other etiologic factors contribute. Two mechanisms are discussed: 1) that copper may be acting in synergy with a hepatotoxin, or 2) that there may be a genetic predisposition to copper-associated liver damage, as suggested recently for Tyrollean childhood cirrhosis. Although ICC is now rare, sporadic cases of an ICC-like disorder in infants continue to occur. There should be a greater awareness among pediatricians of this disease to enable early diagnosis. Penicillamine should be used early and adverse prognostic factors recognized as indications for early transplantation and unregulated water supplies should not be used to prepare infant feeds.

Idiopathic copper toxicosis.

Year 1998
Muller T. Muller W. Feichtinger H.
Department of Pediatrics, University of Innsbruck, Austria. th.mueller@tirol.com
Liver diseases of infancy and childhood are generally rare and within the spectrum of these disorders, only a few subtypes are related to abnormal hepatic copper accumulation. Idiopathic copper toxicosis has been defined as such a subtype; although this disease is characterized by distinct clinical and pathologic features, its exact etiology is still controversial. On the basis of a review of the literature, supplemented by our own observations of 138 cases endemic to western Austria, we hypothesize that idiopathic copper toxicosis is caused by a synergy of an autosomal-recessive inherited defect in copper metabolism and excess dietary copper. Increased awareness of the disease should enable early diagnosis and lead to successful treatment, thereby improving the overall poor prognosis of affected patients.

Wilson disease and canine copper toxicosis.

Year 1998
Brewer GJ.
Department of Human Genetics, University of Michigan Medical School, Ann Arbor 48109-0618, USA. brewergj@umich.edu
In this article we review the current clinical and research status of Wilson disease and canine copper toxicosis. One of the main clinical challenges in Wilson disease is for clinicians to recognize the possibility of Wilson disease when young patients present with liver disease, psychiatric disease, or a movement-disorder type of neurologic disease. Once the possibility of the disease is recognized, many copper-related tests are available that are quite accurate in making the diagnosis or ruling it out. It is important to remember that this is an inherited disease and that family members at risk should be screened, particularly siblings. The cloning of the Wilson disease gene opened up the possibility that a direct DNA test could be developed, allowing convenient screening of certain patients and family members. However, the large number of mutations already found, with no small set of mutations dominating the picture, have thwarted this approach. Once the diagnosis has been made, a variety of treatments are available. For maintenance therapy, therapy of presymptomatic patients, and therapy of pregnant patients, we use zinc. For initial therapy of patients with liver disease, we use a combination of zinc and trientine. For initial therapy of patients with neurologic disease we use tetrathiomolybdate. Canine copper toxicosis in Bedlington terriers is due to a gene different from the gene for Wilson disease. However, the disease is treatable with the same array of anticopper therapies that work in humans. Recently, we established linkage of the copper toxicosis gene to a microsatellite marker, which has made available a linkage test to breeders of Bedlington terriers.