Metabolic Syndrome in Childhood from Impaired Carbohydrate Metabolism to Nonalcoholic Fatty Liver Disease

Compelling evidence supports the concept that nonalcoholic fatty liver disease (NAFLD) represents the hepatic component of metabolic syndrome (MetS). Intrahepatic fat seems to predict more strongly than does visceral adiposity an individual's cardiovascular risk and the likelihood that metabolic abnormalities are present in youth.

Key teaching points:

? Overweight and obese youth should be screened for fatty liver disease once after puberty by liver function tests and ultrasonography.

? Screening for fatty liver should be accurately performed in young patients with features of metabolic syndrome.

? Obese patients with fatty liver are at increased risk for altered glucose metabolism, thus they should undergo an oral glucose tolerance test.

? A nutritional and behavioral intervention aimed at achieving a permanent change of the lifestyle in patients and their parents is recommended.

     

Analysis of TPI gene promoter variation in three sub‐Saharan Africa population samples

Population samples from Angola, Mozambique, and S. Tomé e Príncipe were screened for the TPI gene promoter variants ‐5A→G, ‐8G→A and ‐24T→G. Three haplotypes were identified in the three populations: the haplotype ‐5A‐8G‐24T (average frequency 65.3%) and two less common haplotypes ‐5G‐8G‐24T (average frequency 24.7%) and ‐5G‐8A‐24T (average frequency 10.0%). A population sample from Central Portugal showed the haplotype ‐5A‐8G‐24T in 139 chromosomes and one subject heterozygous for haplotype ‐5G‐8A‐24G. The exact test of sample differentiation among three groups of malaria‐infected individuals classified according to the severity of the disease showed no significant differences. We confirmed TPI gene diversity in sub‐Saharan Africa, but we could not detect any association between TPI promoter variation and a malarial protective effect. Larger scale epidemiological studies are thus required to clarify this putative mechanism of natural host defense against this worldwide public health problem. Am. J. Hum. Biol., 2009. © 2008 Wiley‐Liss, Inc.     

The Decrease of Serum Levels of Human Neutrophil Alpha-Defensins Parallels with the Surgery-Induced Amelioration of NASH in Obesity

Background  

Innate immune system participates actively into inflammatory processes, with immune cells and liver secreting a number of immune peptides. Among them, both soluble CD14 receptor (sCD14) and human neutrophil alpha-defensins (HNDs) may represent serum markers of necro-inflammation in obese patients with non-alcoholic fatty liver disease.     

Mechanisms of hyperinsulinaemia in Child's disease grade B liver cirrhosis investigated in free living conditions

AIMS: Human liver cirrhosis is commonly associated with increased fasting and glucose induced insulin concentrations. However, whether the hyperinsulinaemia is a consequence of increased pancreatic insulin secretion, decreased hepatic insulin removal, or impaired feedback regulation of insulin secretion is still doubtful. To investigate these issues, insulin secretion-during 24 hours of standardised living conditions-insulin sensitivity, and hepatic insulin extraction were assessed in cirrhotic patients compared with matched healthy subjects. PATIENTS: Nine Child's disease grade B cirrhotic patients and seven healthy volunteers, participated in the study. The subjects were studied on two separate days, one for the assessment of insulin secretion during a standardised 24 hour life period (calorimetric chamber), and one for the determination of insulin sensitivity. METHODS: Insulin secretion rates were reconstructed from plasma C peptide concentrations by deconvolution, and indices of beta cell function were derived using a mathematical model describing the functional dependence of insulin secretion on plasma glucose concentrations. Insulin sensitivity was determined using the euglycaemic hyperinsulinaemic clamp technique. RESULTS: Cirrhotic patients showed a marked hypersecretory response, both in absolute terms (mean (SEM) 295 (53) versus 138 (11) nmol/m(2), p<0.02), and in relation to glucose (175 (26) versus 57 (5) pmol/min/m(2), p<0.02). In particular, the beta cell dose-response function was shifted upward compared with controls. The sensitivity of insulin secretion to the rate of glucose change was also increased. Insulin sensitivity, markedly reduced in cirrhosis (157 (10) versus 296 (30) ml/min/m(2), p<0.002), was strongly inversely correlated (r=0.89, p<0.002) in these patients with insulin secretion at 5 mM glucose. Insulin clearance and hepatic insulin extraction were not reduced. A frank hypermetabolism with increased lipid oxidation was found in this series. CONCLUSIONS: This study suggests that hyperinsulinaemia, at least in Child's disease grade B cirrhotic patients, is the consequence of increased beta cell sensitivity to glucose, while hepatic insulin extraction does not seem to play a significant part.     

Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment

In many organs, including the intestine and skin, cancers originate from cells of the stem or progenitor compartment. Despite its nomenclature, the cellular origin of hepatocellular carcinoma (HCC) remains elusive. In contrast to most organs, the liver lacks a defined stem cell population for organ maintenance. Previous studies suggest that both hepatocytes and facultative progenitor cells within the biliary compartment are capable of generating HCC. As HCCs with a progenitor signature carry a worse prognosis, understanding the origin of HCC is of clinical relevance. Here, we used complementary fate-tracing approaches to label the progenitor/biliary compartment and hepatocytes in murine hepatocarcinogenesis. In genotoxic and genetic models, HCCs arose exclusively from hepatocytes but never from the progenitor/biliary compartment. Cytokeratin 19–, A6- and α-fetoprotein–positive cells within tumors were hepatocyte derived. In summary, hepatocytes represent the cell of origin for HCC in mice, and a progenitor signature does not reflect progenitor origin, but dedifferentiation of hepatocyte-derived tumor cells.     

Albuminuria and insulin resistance in children with biopsy proven non-alcoholic fatty liver disease

Insulin resistance may favor increased urinary albumin excretion (UAE), leading progressively to chronic kidney disease (CKD). A recent study on non-alcoholic fatty liver disease (NAFLD), a condition of insulin resistance, associated this disease with the incidence of CKD in patients with type 2 diabetes. The aim of our study was to determine whether there is an association between insulin resistance and kidney function, based on estimates of UAE and creatinine clearance in children with biopsy-proven NAFLD. Kidney function was assessed in 80 patients with NAFLD and 59 individuals of normal weight matched for age and sex. Insulin resistance was measured by means of the homeostatic model assessment-insulin resistance (HOMA-IR) and limited to NAFLD patients by using the whole-body insulin sensitivity index. The HOMA-IR was found to differ significantly between the two groups (2.69 ± 1.7 vs. 1.05 ± 0.45; p = 0.002), while UAE (9.02 ± 5.8 vs. 8.0 ± 4.3 mg/24 h; p = 0.9) and creatinine clearance (78 ± 24 vs. 80 ± 29 mg/min; p = 0.8) did not. We found a significant but weak inverse correlation between insulin sensitivity and creatinine clearance in NAFLD patients (r _s = –0.25;p = 0.02). No difference was observed in kidney function between NAFLD children presenting with or without metabolic syndrome, low or normal HDL-cholesterol, and different degrees of histological liver damage (grade of steatosis ≥2, necro-inflammation, and fibrosis). Patients with hypertension had increased levels of UAE (p = 0.04). A longer exposure to insulin resistance may be required to cause the increase in urinary albumin excretion and to enable the detection of the effect of the accelerated atherogenic process most likely occurring in children with fatty liver disease. Longitudinal studies are needed to rule out any causative relationship between insulin resistance and urinary albumin excretion.