From malnutrition to refeeding during anorexia nervosa

Anorexia nervosa is one of the most common forms of malnutrition observed in Western society in individuals without physical diseases, with an average risk of mortality of 20% in a younger population aged between 15 and 25 years. It is characterised by an initial dramatic decrease in food intake that leads to profound depletion in muscle and fat mass. During the course of the disease, the resting energy expenditure decreases proportionally to the loss of lean body mass with a decrease in thyroid hormone secretion. The metabolic adaptation during anorexia nervosa is similar to that observed during starvation with a relative sparing of protein stores. After an initial weight loss, the total energy expenditure is similar to that in normal individuals, with a decrease in resting energy expenditure and an increased energy-related physical activity. At the end stage of wasting, however, physical activity dramatically decreases as well as energy intake. This metabolic adaptation of semi-starvation is impaired during refeeding with an increase in the thermic effect of food and a high risk of refeeding syndrome with severe hypophosphatemia.     

Energy metabolism in fasting and subsequent refeeding

A metabolism trial with six adult sows was conducted to study the effect of fasting and realimentation on heat production, energy retention, and utilization of energy. Complete balance measurements by indirect calorimetry (CN-method, RQ-method) were carried out from the 8th to the 10th day of fasting, and thereafter from the 1st to the 7th day and from the 33rd to the 36th day of the realimentation phase. Previous to fasting and during the time of refeeding the energy supply was adapted to maintenance requirement. Heat production rose by 20% after refeeding the animals. This heat increment corresponded to 2.2 MJ/kg feed dry matter, or 12% of the energy intake, respectively. The stimulation of heat production induced by refeeding occurred spontaneously within one day. After the first day of refeeding a plateau was reached, which in the course of the steady energy supply was still present even after the 5th week of realimentation. Residual effects of fasting in the mode of a compensatory heat production were not observed. Therefore, a constant utilization of efficiency of metabolizable energy for maintenance was estimated at 82%. The change of body energy during the entire experimental period resulted in a loss of 198 MJ corresponding to about 5% of the body weight.     

Total body potassium,intracellular potassium and body composition in patients with anorexia nervosa during refeeding

The total body potassium content and the potassium concentration in serum and erythrocytes was measured in 16 patient with anorexia nervosa (8 “vomiters” and 8 “restricters”). The data were compared with results obtained for 11 normal controls, whose body weight was 99.6% ± 4.99% of ideal body weight (IBW). Patients were studied before treatment (IBW 72.8 ± 6.3%) and after an average weight gain of 19%. Serum potassium was not significantly different between groups, but potassium concentration was significantly reduced (p < 0.01) in both groups at the time of the first study. Total body potassium—as measured by the potassium-40 method—was significantly lower in both “vomiters” and “restricters” than in controls and was normalized during weight gain. Cell body mass and fat mass were calculated from the potassium-40 measurement. Both body compartments were significantly increased during weight gain; cell mass was normalized, but fat mass remained significantly below normal values.     

An autoradiographic study of new fat cell formation in adipose tissue in adult mice during malnutrition and refeeding

The renewal of adipose cells in adult mice has been autoradiographically studied. The number of adipose cells was diminished by eighty percent during malnutrition and the same number of adipose cells proliferated during the refeeding stage. The results of our study showed that adipose tissue, which had previously been believed to be stable in cell number, has the capacity for cell proliferation according to changes in nutritional status.     

Metabolic responses to prolonged fasting and subsequent refeeding in the pig

Metabolic responses associated with prolonged fasting and subsequent refeeding of pigs were investigated. Fasting for 14 or 28 days produced significant increases in serum levels of alanine, aspartic and glutamic acid in the three branched-chain amino acids. Glycine, serine and lysine levels were elevated after 28 days of fasting while the levels of histidine, methionine, threonine and phenylalanine were reduced. Fasting markedly stimulated hepatic and renal gluconeogenesis and the activity of the urea cycle enzymes. Fatty acid synthesis and glucose oxidation were virtually abolished in hepatic and adipose tissue in pigs subjected to a 14- or 28-day fast. After the first day of refeeding, the levels of amino acids returned to the control values. The activity of the hepatic urea cycle enzymes, fructose-1,6-diphosphatase and phosphoenolpyruvate carboxykinase remained elevated after the first day of refeeding but returned to the control levels thereafter. The activity of hepatic glucose-6-phosphate dehydrogenase, malic dehydrogenase and acetyl CoA carboxylase were slightly enhanced in pigs refed for 4 and 8 days. The activity of these enzymes in adipose tissue was enhanced 8 days after refeeding. Hepatic synthesis of fatty acids from glucose was slightly stimulated in refed pigs on days 4 and 8 but returned to control values on day 16. Refeeding did not enhance glucose incorporation into fatty acids in adipose tissue above the values observed in fed controls.     

Neocortex development during severe malnutrition in the rat.

Histological methods (Golgi-Cox and Nissl) were used to study the maturation of the large pyramidal cells of layer V of the occipital cortex in malnourished rats (according to the method of Araya et al.). The main alterations were observed in pyramidal cells of cortical alyer V; These showed a decrease of the number and span of dendritic basilar processes. An increase in cell density was also observed in this layer. We assume that malnutrition during this period of development provokes a derangement which disturbs the process of neuron differentiation, with effects that probably are permanent.     

Effects of early undernutrition and subsequent refeeding on alkaline ribonuclease activity of rat cerebrum and liver.

The effect of undernutrition and subsequent rehabilitation on free and total alkaline ribonuclease activity (RNase) of cerebrum and liver was studied in 14- and 21-day-old rats. Free RNase activity was higher in both organs at 14 and 21 days of age. However, at day 21 the difference was statistically significant only in liver. Total RNase activity was not changed by undernutrition in cerebrum and was reduced in liver. Nutritional rehabilitation returned both free and total RNase activities to control levels in liver but had no apparent effect on cerebrum. The elevation of free RNase seems to be secondary to a reduced concentration of inhibitor protein and not to de novo synthesis of RNase.     

Acute starvation and subsequent refeeding affect lymphocyte subsets and proliferation in cats

Although the early identification of patients with suboptimal nutritional status can allow the implementation of nutritional intervention to enhance the ability of the body to fight infection and disease, currently no definitive test of nutritional status exists. Therefore, this study was conducted to identify possible functional indicators of acute nutritional deprivation. The effects of total nutritional deprivation and subsequent refeeding on lymphocyte functions and subpopulations were examined in 23 healthy cats. Peripheral blood samples were analyzed at various times during food deprivation and refeeding periods. During the food deprivation period, decreases were observed in leukocyte number (P: < 0.05), lymphocyte number (P: < 0.05), percentage of CD4(+) cells [before stimulation with concanavalin-A (Con-A); P: < 0.05] and the CD4/CD8 ratio (before stimulation with Con-A; P: < 0.01) compared with d 0. Increases were observed in the percentage of CD8(+) cells [before (P: < 0.05) and after (P: < 0.01) stimulation with Con-A] and in intracellular calcium (P: < 0.01) during acute starvation. During the refeeding period, increases were observed in the percentage of CD4(+) cells (before and after stimulation with Con-A; P: < 0.01), the percentage of CD8(+) cells (before stimulation with Con-A; P: < 0.05) and lymphocyte number (P: < 0.05) compared with d 7. Lymphocyte proliferative capacity tended to decrease (P: = 0.07) during starvation and increased (P: < 0.01) during the refeeding period. These findings suggest that a 7-d starvation period had immunosuppressive effects on cats and that these effects were not completely normalized during 7 d of refeeding. CD4(+)/CD8(+) subset alterations and CD4/CD8 ratio in conjunction with lymphocyte proliferation may be useful as indices of nutritional status.     

Hepatic steatosis and serum very low density lipoproteins during two types of protein malnutrition followed by balanced refeeding

The relation of serum very low density lipoproteins (VLDL) to hepatic steatosis was studied during protein malnutrition followed by refeeding of a balanced diet in growing rats. A control group was fed a balanced diet containing 15% casein for 42 days. Two depleted groups were fed low protein diets containing 2% casein (group C) or 5% gluten (group GI) (protein malnutrition phase) for 28 days and then were fed the balanced diet for 14 days (refeeding phase). The concentrations of phospholipids and proteins in both liver and serum VLDL were decreased during protein malnutrition, whereas triacylglycerols, unesterified cholesterol, and cholesteryl esters were higher in the liver and lower in the serum VLDL in the C and GI groups compared with the control group. There was a significant inverse relation between serum VLDL apolipoproteins and liver triacylglycerols on the one hand and between serum VLDL triacylglycerols and liver triacylglycerols on the other hand, in both depleted groups, although this relation was less important in the GI group. The major fatty acid levels of liver triacylglycerols were negatively correlated with those of serum VLDL during protein malnutrition. Our results show that in spite of a similar fatty acid intake, protein malnutrition involved an important decrease in essential fatty acids in VLDL triacylglycerols and phospholipids. Moreover, triacylglycerol accumulation was accompanied by increases in unesterfied cholesterol and cholesteryl esters in the liver of rats fed low protein diets, especially with 5% gluten. Hence, the hepatic steatosis was not entirely attributable to impaired transport of triacylglycerols by VLDL.     

Messenger RNA levels of plasma proteins in rat liver during protein depletion and refeeding

The levels of mRNA for albumin, transferrin, transthyretin, the beta-chain of fibrinogen and apolipoprotein E in livers from rats during protein depletion and refeeding were measured by hybridization to specific cDNA probes. A period of protein depletion of 3 d resulted in a 30-40% decrease in mRNA levels for all five proteins. These levels were further decreased by only 15-20% after additional protein depletion for 6 d. There was no noticeable change in mRNA levels within 4 h of refeeding by gavage with a casein hydrolysate suspension supplemented with L-tryptophan and L-arginine. Upon refeeding a 30% protein diet, mRNA levels returned to normal after 3 d. The work presented here suggests that changes observed in the protein synthetic rate following protein depletion and repletion are due to changes in mRNA levels altered as a consequence of the availability of dietary protein.     

Age-related changes in ribosomal profiles and in vitro protein synthesis in skeletal muscle during fasting and subsequent refeeding of rats

Age-dependent changes in ribosomal profiles and in in vitro protein synthesis in skeletal muscle (gastrocnemius muscle) were studied in rats subjected to fasting and subsequent refeeding. Male rats of 4, 7, and 21 weeks of age were used. Incorporation of 14C-leucine into protein in vitro using skeletal muscle ribosomes from fed rats decreased with the age of the animals. Sucrose density gradient analyses of ribosomal profiles revealed that the changes in protein synthesis were accompanied by progressive declines in the concentrations of polyribosomes and total RNA in skeletal muscle. After fasting for 1 or 2 days, protein synthesis in muscle of young rats dropped markedly and this change could be attributed to the fall in the concentrations of polyribosomes. Also, the concentration and total RNA in the muscles of the young rats decreased. During refeeding of rats after fasting for 2 days, the incorporation of 14C-amino acids into protein recovered more efficiently using ribosomes of skeletal muscle of young animals compared with using those of older animals. This rapid increase in the protein synthesizing activity of skeletal muscle may be related to the efficient recovery of the ribosomes toward heavier aggregates. The results indicate that young animals adapt more efficiently to fasting and refeeding than do older animals.     

Ribonucleic acid metabolism in rat liver during long-term adaptation to malnutrition

Ornithine decarboxylase (ODC) and nucleolar DNA-dependent RNA polymerase (RNA polymerase I) activities increased in the liver of young adult male rats fed a 6% casein diet (malnourished) for 1 week when compared with rats fed a 25% casein diet (control). ODC activity increased progressively and reached a peak after 3 weeks of malnutrition and then decreased to control values by 5 weeks. RNA polymerase I reached peak activity 1 week after malnutrition was imposed, decreasing thereafter to control values by 3 weeks. At 4 and 5 weeks, RNA polymerase I activity in malnourished animals was lower than control. Nucleoplasmic DNA-dependent RNA polymerase activity remained unchanged in the first 2 weeks of malnutrition and decreased thereafter to values significantly lower than control. The data confirm our previous observations of cyclical changes during prolonged malnutrition and suggests a process of "biochemical adaptation" to malnutrition in which the organism enhances essential metabolic processes to maintain cellular homeostasis to the detriment of less essential functions like systemic growth.     

Refractory hypoglycemia and subsequent cardiogenic shock in starvation and refeeding: Report of three cases

ObjectiveAlthough starvation is associated with high in-hospital mortality, its related cardiac complications are not sufficiently understood. The aim of this study was to determine the clinical course and pathogenesis of cardiac complications in malnourished patients.MethodsWe reviewed three cases of hypoglycemia and hypotriglyceridemia with cardiac complications in starvation.ResultsThis report concerns three patients, respectively suffering from anorexia nervosa, esophageal carcinoma, and Parkinson's disease. Their ages ranged from 18 to 70 y, body mass index was 11.5 ± 1.5 kg/m² (mean ± SD), and the main symptom was coma. The average blood glucose level was 15.7 ± 7.8 mg/dL without any history of insulin use or diabetes mellitus. In all cases, hypoglycemia was refractory and repetitive so that continuous glucose administration was required to maintain euglycemia. Serum triglyceride and non-esterified fatty acid levels were also very low (7 ± 4 mg/dL and 10 ± 9.1 μEq/L, respectively). Levels of serum potassium, phosphate, and magnesium were almost normal at admission. The main cardiac complications included Takotsubo cardiomyopathy and cardiac arrest. All patients survived as a result of intensive treatment.ConclusionsRepetitive severe hypoglycemia without known background causes should be viewed as an important sign. Once this occurs, the administration of a much higher caloric input than usual accompanied by intensive monitoring will be required to maintain appropriate glucose levels. The early identification of such patients seems to be essential to reduce the high risk for cardiac complications during starvation and refeeding.     

Effect of malnutrition and short-term refeeding on peripheral blood mononuclear cell mitochondrial complex I activity in humans

BACKGROUND: Previous investigations in rats have shown that the first enzyme of the mitochondrial electron transport chain (complex I) is altered in peripheral blood mononuclear cells (PBMCs) and muscle by dietary manipulations. OBJECTIVE: We hypothesized that similar changes would occur in human PBMCs as a result of dietary malnutrition and short-term refeeding irrespective of the presence or absence of active inflammatory bowel disease (IBD). DESIGN: Fourteen malnourished patients with active IBD, 13 malnourished patients without IBD, and 42 healthy subjects were investigated. Complex I activity, body mass index, body composition, energy and protein intakes, and resting energy expenditure were measured. Five patients without IBD and 6 patients with IBD were investigated after 7 d of refeeding. RESULTS: In patients without IBD, weight loss was mainly due to a loss of fat mass. In contrast, weight loss in IBD patients was due to a loss of both fat-free mass and fat mass. Complex I activity was reduced to the same degree in both groups of patients and was significantly lower than that observed in healthy subjects. In both groups of patients, complex I activity correlated significantly with body weight, body mass index, percentage weight loss, and fat mass. Complex I activity increased significantly after 1 wk of refeeding in both groups of patients before observed changes of measured nutritional assessment indexes. CONCLUSION: Our study showed that mitochondrial complex I activity measured in PBMCs seems to be a specific marker of dietary malnutrition and responds rapidly to refeeding.