Non-alcoholic fatty liver disease among adult survivors of severe acute malnutrition

OBJECTIVE: To investigate whether malnutrition survivors had more liver fat than controls and whether marasmus survivors (Ms) had more liver fat than kwashiorkor survivors (Ks). SUBJECTS AND METHODS: We traced 726 of 1336 adults admitted to hospital as infants with a diagnosis of severe acute malnutrition. We used birthweight (BW) from hospital records and measured anthropometry, body composition (DEXA) and liver fat using single, crosssectional computed tomography (CT) scanning at T12/L1 vertebrae. Data were analysed using multivariate line arregression. RESULTS: We studied 45 Ms, 43 Ks and 84 age-, gender and body mass index (BMI)-matched controls (age 29.0 ±8.4 years, BMI 23.5 ± 5.0 kg/m2). Using LS ratio, malnutrition survivors had less liver fat than controls (1.3± 0.2 vs 1.2 ± 0.9, p = 0.03). Marasmus survivors had lower BW than Ks (-0.51 kg; p = 0.02), were younger (p =0.02), had smaller waists (p = 0.03), were thinner (p =0.01) and had less body fat (p = 0.05) compared to Ks.Marasmus survivors had more liver fat than Ks after adjusting for age, gender and BW (â = -2.62, SE = 1.23; p= 0.03). Lower BW infants had less liver fat after adjusting for diagnosis (â = -1.51, SE = 0.76; p = 0.04). CONCLUSION: Fatty liver occurs at lower BMI in Ms compared with Ks; this difference is likely due to both prenatal and postnatal factors acting independently. While further studies are needed to understand the mechanisms involved, our data suggest the need to monitor infants exposed to severe acute malnutrition beyond the acute episode.

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)

Relationship between hepatic glutathione and fatty liver in weanling rats on a low protein diet

Weanling rats were fed on one of four diets: laboratory chow, PLC; 23 percent casein protein, CC; 8 percent casein protein, LP; 8 percent casein protein with supplemental cysteine to the level found in CC diet, LPC. Liver and blood glutathione (GSH), total liver fat and hepatic triglyceride were measured at 6, 12 and 20 days. On the PLC diet the increase in body weight, liver weight and liver GSH were significantly greater than on the CC diet (p<0.01). After 20 days on the LP diet rats showed a significant increase in liver triglyceride and total fat. The addition of cysteine to the low protein diet was associated with a significant increase in body weight and liver GSH and prevented liver triglyceride and total fat from increasing. GSH levels in extrahepatic tissues were not affected to the same extent as in the liver. There was a significant negative linear correlation between hepatic GSH and both liver triglyceride and liver total fat. A low dietary cysteine can cause fatty infiltration of the liver and this may be mediated through a fall in liver GSH (AU)

Severe undernutrition in Jamaica - kwashiorkor and marasmus: the disease of the weanling

The syndromes of severe undernutrition, marasmus and kwashiorkor, have causes related to the interplay of social and medical considerations in the society. Kwashiorkor supervenes when the individual is exposed to a level of stress that exceeds the body's ability to cope. One final common pathway, through which a variety of environmental factors exert an effect, may be associated with oxidant damage to cells. In kwashiorkor there is a severe decrease in the level of both oxidised and reduced glutathione in the red cell. This could be caused by a decreased production, increased consumption or a combination of the two. This is discussed with specific reference to the metabolism of glycine and the possible causal relationship to the pathophysiology of the disease process.(AU)

Relationship between hepatic glutathione and fatty infiltration of the liver

One of the most serious complications of severe protein-energy malnutrition (PEM) is hepatic failure, which is usually associated with fatty infiltration of the liver. The precise biochemical cause of fatty liver is unknown. This study was designed to investigate the relationship between hepatic glutathione (GSH) and fat accumulation in the liver. Also, the experiment was designed in such a way as to determine the effects of different sources of dietary protein. Twenty-one days old weanling rats were fed for 20 days on diets containing adequate protein (Purina Laboratory Chow) (PLC) and Casein (CC - 23 percent protein), low protein (LP - 7 percent Casein), low protein supplemented with cysteine (LPC) to the level in the CC diet and, choline deficient diet (CD). The animals were weighed on the days of weaning and sacrifice. On the day of sacrifice, the blood, liver and kidney were rapidly removed, liver and kidney blotted on filter paper, weighed and GSH and fat measured using standard procedures. Animals on the CD diet lost weight and had twice the hepatic GSH levels compared to rats on the LP diet. However, they did not develop fatty livers as expected due to the deterioration of the diet in storage. Rats on the PLC diet had significantly gretaer body weight gains (p<0.01), higher liver GSH and cysteine values and lower liver triglyceride (TG) values than rats on the CC diet. Thus, the CC diet was used as the reference diet since the test diets were casein-based formulae. Rats on the LP diet showed reduced body weight gain and fat-free dry liver weight (FFDLW) values compared to the control. Liver glutathione (GSH) and cysteine concentrations were also reduced but there was no significant change in kidney and blood GSH concentrations. Liver fat and triglyceride (TG) values were significantly increased compared to the control (p<0.01). The addition of cysteine to the LP diet, dramatically increased liver GSH, FFDLW and body weight values and prevented liver fat and TG levels from increasing. It is concluded that the hepatic GSH and fat levels in weanling rats depend not only on the cysteine content of the diet but, also on the quality and composition of protein in the diet. Also, that cysteine directly or by maintaining liver GSH levels, prevented the increase of liver fat found in weanling rats on the LP diet (AU)

The relationship between glutathione and fatty infiltration of the liver in weanling rats - abstract

One of the most serious complications of severe malnutrition is hepatic failure, which is usually associated with fatty infiltration. The cause of fatty liver is unknown. We have speculated that a low hepatic glutathione (GSH) content may predispose to its development. Weanling rats have been fed low-protein diets, with and without supplemental cysteine, and the effect on gepatic GSH and fat measured. Three casein-based diets were fed for 20 days. The control diet contained 23 percent protein (C), the low-protein diet 6 percent (LP), and the supplemented diet was similar to the low protein diet with cysteine added to the level in the control diet (LPC). On the day of sacrifice, the liver was rapidly removed, weighed and GSH and fat measured using standard methods. By day 20, the rats on the LP diet had a significantly reduced body weight. GSH was significantly reduced, and fat significantly increased. These differences were almost completely reversed by adding cysteine to the diet. There was an inverse linear relationship between liver triglyceride and GSH (r=-o.76). A limited dietary availability of cysteine promotes a low hepatic GSH and fat accumulation. As GSH may be seen as an intracellular store for cysteine, it is not possible to imute a direct causal relationship between GSH level and fat accumulation. The results could be explained on the basis of cysteine being limiting for the synthesis of the apoprotein required for the formation of hepatic export lipoproteins. Alternatively, a low GSH may be directly responsible for hepatic fat accumulation as this tripeptide plays a central role in cellular detoxification, oxidation/reduction reactions and amino-acid transport. As we have shown that children with oedematous malnutrition have a reduced blood GSH, the findings of this study may be of relevance in clinical practice (AU)

Hepatic function in rats with dietary-induced fatty liver, as measured by the uptake of indocyanine green

The hepatic uptake of indocyanine green (ICG) has been measured in rats receiving a 50 g protein/kg diet for 6, 12 or 20 d or a choline-deficient diet for 2 or 6 d. There was no effect on ICG uptake on the choline-deficient diet, although all the rats developed an intense fatty infiltration of the liver by 6 d. THe rats on the 50 g protein/kg diet showed impaired uptake of ICG at 6, 12 and 20 d, which appeared to be related to the extent of fatty infiltration. It is concluded that ICG uptake is predominantly a function of the periportal zone of the liver lobule, and therefore likely to be sensitive to insults that exert their predominant effect in this zone. (AU)

Hepatic function in rats with dietary-induced fatty liver, as measured by the uptake of indocyanine green

The hepatic uptake of indocyanine green (ICG) has been measured in rats receiving a 50 g protein/kg diet for 6, 12 or 20 d or a choline-deficient diet for 2 or 6 d. There was no effect on ICG uptake on the choline-deficient diet, although all the rats developed an intense fatty infiltration of the liver by 6 d. The rats on the 50 g protein/kg diet showed impaired uptake of ICG at 6, 12 and 20 d, which appeared to be related to the extent of fatty infiltration. It is concluded that ICG uptake is predominantly a function of the periportal zone of the liver lobule, and therefore likely to be sensitive to insults that exert their predominant effect in this zone. (AU)

The effects of a protein-deficient and a choline-deficient diet on the liver function of adult rats, as measured by the rate of uptake of indocyanine green

It is shown that in children suffering from protein calorie malnutrition the mortality associated with fatty liver and liver failure is high. This study was designed to measure functional liver capacity using kinetics analysis of ICG uptake by the liver in animal models of malnutrition and fatty liver disease. Two models were used. Rats were kept either on a 5 percent low protein diet for 6, 12 and 20 days, or on a choline deficient diet for 2 and 6 days. Fatty liver developed in both groups of animals although the changes on the choline deficient diet were more marked than on the protein deficient diet. The choline deficient animals developed a more intense fatty liver at an earlier stage. On the low protein diet the accumulation of fat was inversely correlated to the change in the rate of hepatic uptake of ICG. This relationship could not be demonstrated in the choline deficient group; however, these animals did show a negative correlation between the rate of ICG uptake and FFDLW. It is suggested that the rate of ICG uptake may reflect the rate of liver is discussed in this light (Summary)

Amount and rate of disappearance of liver fat in malnourished infants in Jamaica

The fat content of the liver has been measured in 163 biopsy specimens taken from 95 malnourished children in Jamaica within a few days of admission to hospital and at various stages of recovery. The fat content was also measured in 38 samples from children who died. Severe degrees of fatty infiltration, up to 50 percent of the wet weight, were found. Fatty liver of this degree of severity may be a cause of death. The increase in fat was accompanied by an increase in water content. Repeat biopsies were done within 6 weeks of admission in 26 children. The average rate of clearance of fat expressed as a fraction of the amount present at any time was 5.5 percent per day. An attempt was made by more frequent biopsies to determine whether the rate of decrease was influenced by the protein content of the diet, but the results were inconclusive.(AU)

Serum and liver triglycerides in malnourished Jamaican children with fatty liver

Measurements were made of triglyceride concentrations in the liver, serum, and serum lipoproteins in malnourished Jamaican children with fatty liver. The fasting serum triglyceride concentrations of the patients, before treatment, were highly variable, ranging from 55.6 to 353 mg/100ml. The patterns of change for serum triglyceride concentration during treatment were also variable. Patients were grouped according to whether the concentrations of serum triglycerides after recovery were higher than, lower than, or unchanged from, the concentrations before treatment. The three groupings then exhibited concentrations before treatment that fell in discrete ranges, being respectively low, high, or normal. There was no clinical difference among the three groups of patients. There was also no difference in the serum lipoprotein pattern nor in the composition of the serum very low density lipoprotein. The latter did not change during treatment. In most patients the fasting serum triglyceride concentrations before treatment appeared to be correlated with age. The difference between these findings and those reported from other countries are discussed. (AU)

Fat metabolism in protein malnutrition

The aim of this work was to make an assessment of the role of impaired lipoprotein secretion from the liver in the pathogenesis of the fatty liver caused by protein malnutrition in infants. The only evidence for this role prior to the study was that serum lipid levels were lower than normal in patients with fatty liver. The proposed method for measuring the incorporation of amino acids into the lipoproteins of children with fatty liver was used first with the rat as a model. It was found, in the development of such a model, that there are great variations in the level of liver fat induced by protein depletion in the rat. The variations depend on the age and nutritional state of the animal at the time of introducing the low-protein diet, and depend on the calorie intake while thay are on the diet. It was found that there were always measurable increases in the liver fat content when 70-gram rats were fed a 6 percent casein diet for 7 to 10 days. The use of this model with either single-injection or constant-infusion techniques showed that the incorporation of labelled amino acids into the serum lipoproteins was reduced. The greatest reduction was in the VLDL fraction of the low-density lipoproteins. There was no evidence for any significant contribution to the fatty liver from increased lipogenesis at the time when the defect in lipoprotein synthesis was apparent. The incorporation of methionine-S35 into the low-density lipoproteins of malnourished children was measured; although the changes were not consistent throughout the group studied, there was some evidence that the incorporation of the amino acid into lipoproteins was less when the children were malnourished than when they had recovered. Some modification in the design of future experiments of this type are discussed. Routine measurements of serum triglycerides in the patients during treatment showed that there are some differences between the pattern seen here and that reported elsewhere. The patients had very low triglyceride levels after recovery. These low levels were found to be due to the high fat content of the diet which the patients received during treatment. The changes in serum triglycerides induced by changing the fat content of the diet were found to be more rapid and to be relatively greater than any changes previously reported for adults. No explanation for this is given at present. The unusual patterns for serum triglycerides found during treatment of the malnourished patients with a low-fat diet appeared at first to be inconsistent with reduced synthesis of lipoprotein being associated with the fatty liver; other changes in fat metabolism concurrent with such a defect, however, could account for the unusual patterns.(AU)

Observations on the origin of liver fat in infantile malnutrition

Liver samples were obtained by biopsy from malnourished children in Jamaica, and also from a group of children who had recovered from malnutrition. The activity of glucose-6-phosphatase was significantly reduced in the liver of the malnourished children. The ability of liver homogenates to synthesize fat from acetate was less in the malnourished children than in the recovered group, but the difference was not significant. In the malnourished children, the fasting levels of nonesterified fatty acids (NEFA) and glycerol in the plasma were increased. The origin of the excess liver fat in kwashiorkor is discussed, and it is concluded that it is derived directly from dietary carbohydrate (Summary)

A biochemical lesion in fatty liver

Enzymes leak from damaged liver tissue into the blood. An attempt has been made to measure this leakage in needle biopsy pieces of liver. However the results of such procedures are very difficult to interpret because of the absence of 'normal' values and because the biopsy needle probably inflicts differing amounts of trauma each time it is used (AU)