Peroxisomes and the hepatic pathology of childhood malnutrition

Liver specimens obtained immediately after death from eight severly malnourished children were examined by electron microscopy, and compared with seven liver biopsy specimens from children who recovered from malnutrition. The liver cells from the fatal cases showed mitochondrial swelling, with coarse densities in the matrix, cholestasis, depletion of the endoplasmic reticulum and Golgi apparatus, diminished glycogen stores, prominent lipid deposits and focal cytoplasmic degradation. The nucleoli were enlarged. There was marked reducation in peroxisomes. In contrast, the biopsies from recovering children showed good cellular organisation, and a normal frequency of peroxisomes. Multiple factors, including sepsis, may lead to depletion of peroxisomes. Loss of peroximes may interrupt beta-oxidation of long-chain fatty acids and accentuate the accumulation of lipid. Moreover, a reduction in the concentration of catalase may remove one avenue for the detoxification of free radicals. As the concentration of other anti-oxidants, notably glutathione, is also reduced, free radical damage may occur, leading to lipid peroxidation of membranes, mitochondrial damage, pump failure and influx of water and electrolyted into the cell (AU)

Peroxisomes and the hepatic pathology of childhood malnutrition

Liver specimens obtained immediately after death from eight severly malnourished children were examined by electron microscopy, and compared with seven liver biopsy specimens from children who recovered from malnutrition. The liver cells from the fatal cases showed mitochondrial swelling, with coarse densities in the matrix, cholestasis, depletion of the endoplasmic reticulum and Golgi apparatus, diminished glycogen stores, prominent lipid deposits and focal cytoplasmic degradation. The nucleoli were enlarged. There was marked reducation in peroxisomes. In contrast, the biopsies from recovering children showed good cellular organisation, and a normal frequency of peroxisomes. Multiple factors, including sepsis, may lead to depletion of peroxisomes. Loss of peroximes may interrupt beta-oxidation of long-chain fatty acids and accentuate the accumulation of lipid. Moreover, a reduction in the concentration of catalase may remove one avenue for the detoxification of free radicals. As the concentration of other anti-oxidants, notably glutathione, is also reduced, free radical damage may occur, leading to lipid peroxidation of membranes, mitochondrial damage, pump failure and influx of water and electrolyted into the cell.

Is there an acute-phase response in steady-state sickle cell disease?

Metabolic and serum changes during steady-state homozygous sicle cell (SS) disease are consistent with an acute-phase response and raise the possibility that inflammation occurs in SS disease even during the steady state. To test this hypothesis, we measured concentrations of acute phase reactants in patients with SS disease, in patients with sickle cell haemoglobin C (SC) disease, and in normal (AA) control subjects. The concentrations of C-reactive protein and serum amyloid A were increased above 10 mg/L and 5mg/L, respectively (our definition of an acute-phase response) in 18 percent (26/143) of subjects with SS disease even when they were symptom free, in 17 percent (6/35) of subjects with SC disease, and in 1 percent (1/80) of AA controls (p<0.001). We suggest that subclinical vaso-occlusion may generate a covert inflammatory response and that the cytokine mediators of this response may contribute to the metabolic abnormalities and growth failure in sickle cell disease.(AU)

Acute-phase protein response is impaired in severely malnourished children

The reponse of plasma levels of C-reactive protein and serum amyloid A were assessed in two groups of malnourished children. Sixty-six severely malnourished children were studied at admission. Fifty of these had clinical and/or laboratory evidence of infection. C-reactive protein was not elevated in 23 (46 percent) and serum amyloid A was not raised in 29 (58 percent) of these 50 children. Surviving children(n=62) received two doses of diphtheria-pertussis-tetanus vaccine, to which the C-reactive protein and serum amyloid A responses were measured. The first was given early in recovery, the second after nutritional rehabilitation. Ten mildly malnourished children acted as controls, receiving a single dose of diphtheria-pertussis-tetanus vaccine. The responses of both C-reactive protein and serum amyloid A to diphtheria-pertussis-tetanus vaccine were significantly less in early recovery than after nutritional recovery. The response of the midly malnourished group was no different from that of the severely malnourished group in early recovery, but was less than their response on discharge. The acute-phase protein response of malnourished children is impaired. This may have prognostic implications as the reponse plays a central role in promoting healing. (Summary)

Ultrasonographic assessment of the extent of hepatic steatosis in severe malnutrition

Ultrasonographic, blinded assessment was made of the extent of hepatic steatosis in 55 children with severe malnutrition: undernutrion (n=6), marasmus (n=18), marasmic-kwashiorkor (n=17), and kwashiorkor (n=14). The children were examined on admission, in early recovery (considered as baseline), and again discharge. Eleven healthy control children and eight of the previously malnourished children were studied as comparison groups. Both oedematous and non-oedematous malnourished children had significantly more steatosis than the comparison groups at each time. Children with oedematous malnutrition had significantly greater steatosis than non-oedematous children at admission, Half of the non-oedematous malnourished children had appreciable hepatic steatosis at both admission and at baseline. Hepatic fat was only slowly mobilised. The rate constant was 1.4 ñ 0.3 percent/day. One quarter of the children did not change steatosis grades during the period they were in hospital. There was no overall correlation between the extent of steatosis and liver size. Hepatic steatosis in childhood malnutrition is not confined to oedematous children: it is frequently present in marasmic and under-nourished children. Its extent is not necessarily related to the degree of hepatomegaly and accumulated lipid is only slowly mobilised (AU)

Peroxisomes and the fatty liver of malnutrition: an hypothesis 1-3

Peroxisomes play a role in hepatic á-oxidation of fat, a process that results in the production of hydrogen per-oxide. The fatty infiltration of the liver that occurs in severely malnourished children remains unexplained. We observed an almost total absence of peroxisomes in the hepatocytes of these children. We suggest that lack of available peroxisomes could contribute to the development of fatty liver.(AU)

New perspectives on the fatty liver of kwashiorkor - abstract

Samples of liver were examined from eight patients who died from protein-calorie malnutrition, and compared with biopsies taken at various stages of recovery from seven other patients. All specimens were taken from patients admitted to the Tropical Metabolism Research Unit, at Mona. Liver samples for electron microscopy were obtained within one hour of death, fixed in 2.5 per cent glutaraldehyde, passed through 1 per cent osmium tetroxide, dehydrated through graded ethanols, and embedded in Maraglas. Sections for electron microscopy were stained with lead citrate. The cells from recovering patients showed normal organization, apart from some increase in residual bodies, and prominent intramitochondrial swelling, and influx of calcium into the matrix. There were also canalicular and intracytoplasmic cholestasis, abundant lipid droplets, loss of glycogen reserves, scanty endoplasmic reticulum and Golgi membranes, focal cytoplasmic degradation, and depletion of peroxisomes. The depletion of peroxisomes may be an important factor in the accumulation of lipids, as they normally carry out beta-oxidation on long-chain fatty acids. They also contribute to cellular defences against free radicals. The disorganisation of cellular organelles is consistent with free radical damage and terminal anoxia (AU)

Vitamin E status in oedematous and non-oedematous malnourished children - abstract

The antioxidant function of vitamin E is essential for maintaining the integrity of cell membranes. During the early phase of recovery from severe malnutrition, we measured the plasma levels of Vitamin E in 58 children on admission (A), and after metabolic recovery (B). A total of 19 marasmic children, and 34 with oedematous malnutrition (19 with marasmic-kwashiorkor and 15 with kwashiorkor) were studied. A further group of 5 oedematous children who were clinically assessed as extremely sick received daily vitamin E supplements. The children were all fed on the same dietary regimen. The results indicated that although vitamin E intake was greater in the non-oedematous (marasmic) children, the rate of change of concentration in the plasma did not differ between the two groups. This could possibly be attributed to a difference in the absorption or utilization of the vitamin between the groups. In the group receiving supplements, there was a significant increase in plasma vitamin E concentration between A and B. However, the rate of increase and the concentration at B did not differ from that in the two groups of unsupplemented children. We conclude that in malnourished children: (1) plasma viatmin E levels are low on admission, (2) values normalize by time B, and (3) supplementation with alpha-tocopherol in oil did not affect the rate of increase in plasma vitamin E. The supplement did not seem to be bioavailable (AU)

The acute phase response in severely malnourished children - abstract

The acute phase response is a non-specific reaction to tissue injury, in which the liver plays a central role. We examined the acute phase response in 52 severely malnourished children by measuring the serum levels of C-Reactive Protein (CRP) and Serum Amyloid A (SAA), using an ELISA technique. Blood was taken both at admission and following a controlled stress, namely, Triple (DPT) Vaccine. Four children died. The surviving children received DPT either at admission (n=16) or early in recovery (time B) (n=32). All the children received a second vaccination with DPT once they had regained > 90 percent weight-for-height (discharge) (n=48). Both acute phase proteins responded in tandem. The admission values were elevated in only 44 percent of the children for CRP and 20 percent for SAA, despite clinical evidence of infection. The magnitude of the response of both acute phase proteins to DPT given at admission or at time B was significantly less than at discharge (p < 0.05). Even at discharge, approximately 20 percent of the children did not have the expected response. Children with oedematous malnutrition were less likely to respond than non-oedematous children. We suggest that, firstly, severly malnourished children are unable to mount an effective acute phase response, which may have functional implications. Secondly, that the inability to synthesize acute phase proteins represents one manifestation of the hepatic dysfunction that occurs in severe malnutrition (AU)

The effect of DPT inoculation on the hormonal control of glucose homeostasis in children recovered from malnutrition

The effect of a controlled stress (DPT inoculation) on the hormonal control of glucose homeostasis was investigated in children nutritionally rehabilitated from severe malnutrition. The age range of the 15 children studied was 6-26 months. Plasma insulin (INS), growth hormone (GH) and interleukin-1 (IL-1) were measured by radioimmunoassay; plasma glucose (GLU) by a glucoseoxidase method; and red cell insulin binding ( percentSB) was determined, using A-14 monoiodinated insulin. Measurements were made on two occasions: (T-O) at 10 a.m.,12 hr before DPT inoculation, and (T-36) 36 hr. after inoculation. On both occasions, 4 hr post-prandial blood samples were used, and the mean body temperature(T) on the day of the test was determined. Red cell insulin binding ( percentSB) was significantly higher at T-36 than at T-O (16.8 ñ 1.7 vs 12.1 ñ 1.2 (14), p=0.005). (Results were expressed as mean ñ SEM, numbers of paired observations in parentheses). The higher percentSB after DPT was accompanied by an increase in the number of receptor sites (S) (29.05 ñ 6.5 vs 15.6 ñ 2.5 (14),p=0.025). However, insulin receptor affinity (K x 10(9)M(-1)) was decreased 0.7 ñ 0.1 vs 1.5 ñ 0.3(14), p=0.008). There were no significant differences in the plasma levels of insulin, glucose and interleukin-1, but plasma growth hormone (æU/ml) was increased after DPT, (18.0 ñ 3.0 vs 11.5 ñ 1.2 (13), p=0.04). Body temperature (§C) was also significantly increased after DPT,(99.9 ñ 0.4 vs 98.3 ñ 0.2(14), p=0.006). The change in plasma glucose from T-O to T-36 tended to be associated with both a change in plasma insulin (p=0.06) and plasma growth hormone (p=0.07). Increased insulin binding, as one index of increased insulin sensitivity during fever, can contribute to a reduction in blood glucose. However, the elevation in plasma growth hormone cold buffer the hypoglycaemic effect of insulin, and help to maintain glucose homeostasis (AU)

The effect of the level of dietary protein, carbohydrate and fat on urea kinetics in young children during rapid catch-up weight gain

The kinetics of urea metabolism were measured in children recovering from severe malnutrition. For a period of up to 10 d they receive one of four diets which provided 711 kj (170 kcal)/kg per d. Two groups received a diet with a high protein:energy (P:E) ratio of 10.6 percent (HP), enriched with either fat (HP/F) or maize starch and sucrose HP/C). Two groups received a diet with a low P:E ratio of 8.8 percent (LP), enriched with either fat (LP/F) or maize starch and sucrose (LP/C). The rate of weight gain on the HP diets was significsntly greater than on the LP diets. There was no difference in urea production between any of the four diets: HP/F 1.23 (se 0.12), HP/C 1.37 (se 0.14), LP/F 1.64 (se 0.22) LP/C 1.15 (se 0.15) mmol nitrogen/kg per h. On the HP diets urea excretion was 0.77 (se0.07) mmol N/kg per h, 61 percent of production. There was significantly less urea excreted in the urine on diet LP/C than on LP/F (0.36 (se0.05) and 0.64 (se 0.04)mmol N/kg per h respectively). A significantly greater percentage of the urea production was hydrolysed on the LP diets (61 percent) compared with the HP diets (39 percent), with the consequence that 50 percent of urea-N produced was available for synthetic activity on the LP diets compared with 30 percent on the HP diets. The increase in the urea hydrolysed on the LP diets was equivalent in magnitude to the decreased intake of N, so that overall intake plus hydrolysis did not differ between the LP and HP diets. Crude N balance was similiar on diets HP/F, HP/C and LP/C, but was significantly reduced on diet LP/F. These results show that there is an accommodation in urea kinetics during rapid catch-up weight gain, which becomes evident when the P:E ratio of 8.8 percent, protein is limiting for catch-up growth. When the intake has a P:E ratio of 8.8 percent the pattern of urea kinetics can be modified by the relative proportion of fat and carbohydrate in the diet. The measurement of urea kinetics provides a useful approach to the definition of the adequacy of the protein in the diet. (AU)

The relationship between red cell glutathione and hepatic steatosis in malnourished Jamaican children - abstract

Low levels of red cell glutathione (a scavenger of free radicals) have been previously shown to correlate well with the presence of oedema in malnourished children. We addressed the possibility that they may also correlate with the extent of hepatic steatosis. Thirty-three children were studied on three occasions - on admission, in early weight gain and at discharge. Ultrasonography was used to assess hepatic fat. The oedematous children had significantly more hepatic fat on admission than the non-oedmatous (p<0.01), but no child had a normal ultrasound. We found a significant inverse relationship (r = -0.53, p<0.001) between hepatic fat and the level of red cell glutathione that disappeared over time. We conclude that, firstly, hepatic steatosis occurs commmonly in even non-oedematous malnourished children. Secondly, this is associated with low levels of glutathione which may have aetiological implications (AU)

Febrile response in malnutrition

The febrile response to a standard dose of triple (DPT) vaccine was assessed in sixteen malnourished children before and after recovery. Increase in temperature was significantly lower in the malnourished children (p<0.005) (AU)