Severe Fatty Liver Disease Research Articles

Nonalcoholic Fatty Liver Disease in North Indian Children and Association With Metabolic Syndrome: Are Normal-Weight Children Spared?

Nonalcoholic fatty liver disease (NAFLD) has recently emerged as the leading cause of chronic liver disease in children, but the epidemiology in Indian childen is not well documented. This study aimed to document the prevalence of NAFLD and its association with metabolic syndrome in north Indian urban school children. Between November 2011 and December 2012, 5,643 north Indian urban school children aged 5–10 years were screened. NAFLD was diagnosed via the presence of fatty liver on ultrasound and absence of viral and metabolic causes. Among study subjects, 8.8% were overweight and 61.5% were normal-weight; notably, 20% were hypertensive. Of the 961 subjects who underwent ultrasound examination, 215 (22.4%) had fatty liver (158/836 [18.9%] of normal-weight subjects vs 57/125 [45.6%] of overweight subjects). Presence of fatty liver disease and severity increased with body mass index (BMI) and age. Among 135 children with NAFLD underwent biochemical evaluation, 21.5% had elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and enzyme derangement was higher in males (24.7% vs 16.7% in females), overweight subjects (27% vs 19.4% in normal-weight) and those with moderate-degree fatty liver (28% vs 20% in those with mild cases). Low high-density lipoprotein cholesterol (HDL), hypertriglyceridemia and hyperglycemia were present in 37.8%, 16.3% and 12% of NAFLD cases, respectively. Eleven (8.1%) children had metabolic syndrome (MS) as per criteria of Ferreira et al, with hypertriglyceridemia, obesity and low HDL being the commonest abnormalities. Higher BMI (odds ratio [OR], 63), severe fatty liver disease (OR, 1.7) and female sex (OR, 1.9) had a strong association with MS. The proportion of subjects with MS changed with use of different cutoffs: 15.5% as per waist circumference (WC) cutoff by McCarthy et al, 5.2% as per the International Obesity Task Force BMI cutoff and 10.3% as per blood pressure cutoff by Manu Raj et al. The prevalence of NAFLD among north Indian children was higher compared to their Asian counterparts. A significant proportion of normal-weight children also have NAFLD. Lack of appropriate cutoffs for MS for Indian children and non-uniformity in criteria for MS makes comparisons between regions challenging.

Higher Fetuin-A Level Is Associated with Coexistence of Elevated Alanine Aminotransferase and the Metabolic Syndrome in the General Population

Higher fetuin-A levels have been linked to fatty liver disease (FLD), the most common cause of elevated alanine aminotransferase (ALT) levels, but associations between ALT and fetuin-A level have been inconsistent. The presence of the metabolic syndrome in individuals with elevated ALT levels has been shown to characterize more severe FLD. Thus, aim of the study was to investigate the association between fetuin-A level and the coexistence of elevated ALT levels and metabolic syndrome (ALT-MetS). A population-based cross-sectional study including 728 individuals (age 50-77 years) was conducted. We used multivariable logistic regression analysis to assess the association between serum fetuin-A level and the dichotomous outcome ALT-MetS, defined as coexistence of elevated ALT level (>75th percentile) and metabolic syndrome (any three of the components: abdominal obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, abnormal glucose metabolism). Individuals with a high fetuin-A level had an odds ratio (OR) for ALT-MetS of 2.22 [95% confidence interval (CI) 1.36-3.63; Ptrend=<0.001] comparing extreme tertiles. After excluding individuals with cancer, stroke, or myocardial infarction, individuals with high fetuin-A levels had an OR for ALT-MetS of 2.48 (95% CI 1.38-4.47) comparing extreme tertiles, and we observed statistical interaction between fetuin-A level and age (P=0.048). Fetuin-A level was associated with ALT-MetS in young individuals, defined as <64 years of age (OR 3.30, 95% CI 1.45-7.55; Ptrend=0.004), and not statistically significant in older individuals (OR 1.79, 95% CI 0.74-4.31; Ptrend=0.197). Fetuin-A level was positively associated with ALT-MetS, particularly in younger individuals. Prospective studies in larger populations are warranted.

Metabolic inflammation: role of cytokines in the crosstalk between adipose tissue and liver

The innate immune system and its major mediators, i.e., cytokines, are increasingly recognized as being of crucial importance in metabolic inflammation as observed in morbid obesity and type 2 diabetes (T2D). Morbid obesity is commonly associated with adipose tissue inflammation. Adipose tissue inflammation is characterized by an increased expression of various pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 and -6, and by a rather heterogenous cellular infiltrate including monocytes/macrophages, neutrophils, B lymphocytes, T lymphocytes, and others. It has been demonstrated that in patients with severe obesity and fatty liver disease, expression of these pro-inflammatory cytokines in adipose tissue is 100-1000 times higher compared with that in the liver. Therefore, the adipose tissue can be considered in the state of severe obesity as the "cytokine factory" of the body. Rapid weight loss almost entirely eliminates pro-inflammatory cytokines in the adipose tissue, and therefore provides a very potent anti-inflammatory strategy. In conclusion, there is increasing evidence that peripheral tissues such as the adipose tissue may affect disease processes in target organs such as the liver, pancreas, heart, or blood vessels, and may therefore significantly contribute to chronic inflammation as observed in obesity and T2D.

HEMOCHROMATOSIS AND FATTY LIVER DISEASE: BUILDING EVIDENCE FOR INSULIN RESISTANCE IN BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS)

Hemochromatosis in bottlenose dolphins (Tursiops truncatus) is associated with high postprandial plasma insulin levels, suggestive of insulin resistance. In humans, insulin resistance is associated with liver pathologies, including excessive iron deposition and nonalcoholic fatty liver disease. Dolphin liver tissues, in addition to excessive iron storage, were evaluated for other pathologies supportive of underlying insulin resistance. Archived liver tissues collected postmortem during 1985-2010 from 18 dolphins (median age 27.9 yr, range 0.7-51.4) that were part of the Navy Marine Mammal Program's managed collection were assessed for the presence and severity of hemosiderin deposition, fatty liver disease, and hepatitis. Demographics, clinical pathology values, and percentage weight loss were compared among dolphins with and without these changes. Twelve (66.7%) dolphins had mild to moderate hemosiderin deposition, 7 (38.9%) had mild to severe fatty liver disease, and 11 (61.1%) had mild to moderate hepatitis. Of the 12 dolphins with hemosiderosis, deposition occurred in the Kupffer cells among 11 (91.7%). Dolphins with fatty liver disease were more likely to have higher postprandial serum hyperglycemia (>140 mg/dl), leukocytosis (>11,000 cells/microl), and hyperglobulinemia (>3.5 g/dl). Unlike in many nonhuman terrestrial animals, fatty liver disease was not associated with rapid weight loss or hypoglycemia. Interestingly, there were no significant associations among dolphins with hemosiderosis, fatty liver disease, and hepatitis. This study supports that both hemochromatosis and fatty liver disease were present in the dolphin study population, and histopathology and clinical pathology among these animals suggest a nonhereditary, metabolic etiology. Bottlenose dolphin, fatty liver disease, hemochromatosis, hemosiderosis, hepatic lipidosis, hepatitis, Tursiops truncatus.

The blood concentration and organ distribution of haloperidol at therapeutic and toxic doses in severe fatty liver disease

The aim of this study was to investigate the difference between the pharmacokinetics of haloperidol in normal rats and in rats with fatty liver disease. A therapeutic dosage (0.1 mg/kg) and a toxic dose (15 mg/kg) of haloperidol were administrated to normal 9-week-old male rats or those with severe fatty liver disease, and the blood concentration of haloperidol was determined 15 min, 1, 2, and 3 h following haloperidol administration. The concentration of haloperidol in the organs was determined 1, 2, and 3 h after the haloperidol administration. Additionally, the volume of the portal vein blood flow was measured 3 h after haloperidol administration. When given at the therapeutic dosage, the concentrations of haloperidol in both the blood and organs of the rats with fatty liver disease were significantly higher than those in the normal rats. However, when given at the toxic level, the blood and organ haloperidol concentrations 1 h after administration tended to be lower in the rats with fatty liver disease than those in the normal rats; these lower haloperidol levels returned to be the levels in the normal rats 3 h after the administration of haloperidol. The volume of the portal vein blood flow significantly increased following the toxic haloperidol dose as compared with the volume pre-administration and following the therapeutic haloperidol dose in the normal rats. However, the volume did not change after the toxic or the therapeutic dose of haloperidol compared with pre-administration in rats with severe fatty liver disease, although it was significantly higher than in the normal rats. The pathway for haloperidol metabolism might have been saturated before the administration of haloperidol in rats with fatty liver disease; thus, it is possible that the blood concentration of haloperidol tends to be much higher in individuals with severe fatty liver disease than in those with normal livers in an inverse proportion to the dosage of haloperidol.

Serum sex hormone-binding globulin levels are independently associated with nonalcoholic fatty liver disease in people with type 2 diabetes

Aim To clarify the association between serum sex hormone-binding globulin (SHBG) levels and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes. Methods Two hundred seventy nine patients with type 2 diabetes were consecutively enrolled and metabolic parameters were checked. High-grade NAFLD was defined as moderate or severe fatty liver disease, measured using liver ultrasound. SHBG, testosterone, and estradiol levels were measured. Results SHBG levels were lower in patients with high-grade NAFLD than in those with normal ultrasound and decreased significantly based on the severity of fatty liver disease. SHBG levels were negatively correlated with hypertension, body mass index (BMI), waist circumference, high-grade NAFLD, triglycerides, alanine aminotransferase (ALT), γ-glutamyltransferase (γGT), homeostasis model assessment-estimated insulin resistance (HOMA-IR), and C-reactive protein (CRP) and were positively correlated with testosterone and estradiol levels. The odds ratios (ORs) predicting the presence of high-grade NAFLD in men and women decreased significantly with increasing SHBG tertile. The ORs remained significant even after further adjusting for BMI, waist circumference, hypertension, triglycerides, γGT, ALT, CRP, HOMA-IR, testosterone, estradiol, and anti-diabetic medications. Conclusions Serum SHBG levels were independently associated with the high-grade NAFLD in patients with type 2 diabetes.

Stress Signaling in the Methionine-Choline–Deficient Model of Murine Fatty Liver Disease

Stress signaling, both within and outside the endoplasmic reticulum, has been linked to metabolic dysregulation and hepatic steatosis. Methionine-choline-deficient (MCD) diets cause severe fatty liver disease and have the potential to cause many types of cellular stress. The purpose of this study was to characterize hepatic stress in MCD-fed mice and explore the relationship between MCD-mediated stress and liver injury. Stress signaling was examined in mice fed MCD formulas for 4-21 days. Signaling also was evaluated in mice fed MCD formulas supplemented with clofibrate, which inhibits hepatic triglyceride accumulation. The role of the pro-apoptotic stress protein C/EBP homologous protein (CHOP) in MCD-mediated liver injury was assessed by comparing the responses of wild-type and CHOP-deficient mice to an MCD diet. MCD feeding caused steatohepatitis coincident with the activation of cJun N-terminal kinase and caspase-12. In contrast, MCD feeding did not activate inositol-requiring protein-1 and actually suppressed the expression of X-box protein-1s. MCD feeding caused weak stimulation of double-stranded RNA-activated protein kinase-like endoplasmic reticulum-resident kinase, but robust activation of general control nonderepressible-2, followed by the phosphorylation of eukaryotic initiating factor-2α and induction of CHOP. Clofibrate eliminated MCD-mediated hepatic steatosis but did not inhibit diet-induced stress. CHOP deficiency did not alleviate, and in fact worsened, MCD-mediated liver disease. MCD feeding causes an integrated stress response in the liver rather than a classic unfolded protein response. This stress response does not by itself lead to liver injury. CHOP, despite its identity as a mediator of stress-related cell death, does not play a central role in the pathogenesis of MCD-mediated liver disease.

Functional analysis of two novel splice site mutations of APOB gene in familial hypobetalipoproteinemia

Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by reduced plasma levels of low density lipoprotein cholesterol (LDL-C) and its protein constituent apolipoprotein B (apoB), which may be due to mutations in APOB gene, mostly located in the coding region of this gene. We report two novel APOB gene mutations involving the acceptor splice site of intron 11 (c.1471-1G>A) and of intron 23 (c.3697-1G>C), respectively, which were identified in two patients with heterozygous FHBL associated with severe fatty liver disease. The effects of these mutations on APOB pre-mRNA splicing were assessed in COS-1 cells expressing the mutant APOB minigenes. The c.1471-1G>A APOB minigene generated two abnormal mRNAs. In one mRNA the entire intron 11 was retained; in the other mRNA exon 11 joined to exon 12, in which the first nucleotide was deleted due to the activation of a novel acceptor splice site. The predicted products of these mRNAs are truncated proteins of 546 and 474 amino acids, designated apoB-12.03 and apoB-10.45, respectively. The c.3697-1G>C APOB minigene generated a single abnormal mRNA in which exon 23 joined to exon 25, with the complete skipping of exon 24. This abnormal mRNA is predicted to encode a truncated protein of 1220 amino acids, designated apoB-26.89. These splice site mutations cause the formation of short truncated apoBs, which are not secreted into the plasma as lipoprotein constituents. This secretion defect is the major cause of severe fatty liver observed in carriers of these mutations.

Steatohepatitis und Leberzirrhose: Erstmanifestation 23 Jahre nach ejunoilealem Bypass

Intestinal shunting procedures followed by gastrointestinal bypass surgery have been used as therapeutic modalities in the treatment of morbid obesity since the mid 1950s. Enthusiasm reached its peak in the early 1960s with the introduction of the jejunoileal bypass, however began to wane as various complications were identified in the remote postoperative period and later. Finally, the jejunoileal bypass was abandoned in the 1980s. Apart from renal disorders, it frequently resulted in abnormal liver function and liver failure which are attributed to fatty infiltration. We report a 56-year-old woman, who underwent jejunoileal bypass surgery 23 years ago. She was admitted to our ICU because of hepatic encephalopathy IV, caused by upper gastrointestinal bleeding. Beside hepatic encephalopathy there were signs of severe liver failure (INR 2.8, cholesterol 32 mg/dl, ICG PDR 5%). Liver biopsy showed fatty infiltration and cirrhosis. Excluding other causes of liver disease, severe fatty liver disease following jejunoileal bypass surgery was diagnosed. The very late onset of severe liver disease emphasizes the importance of lifelong follow-up of these patients.

Analysis of neuroendocrine tumour metastases in the liver using contrast enhanced ultrasonography

Background. Imaging of liver tumours might be improved by contrast-enhanced ultrasonography, which allows much better demonstration of the microvascular system. The aim of this study was to assess the sonographic morphology and vascularity of neuroendocrine liver metastases. Methods. Forty-eight patients with histologically proven neuroendocrine tumours (NET) and suspected liver metastases – as well as 50 consecutive patients with liver metastases of other origins – were included in a prospective study to evaluate tumour characteristics using B-mode, colour Doppler (CDI) and contrast-enhanced ultrasound (CEUS). Results. In 4/48 patients with NET, liver biopsy revealed hemangiomas. The typical B-mode appearance was that of both echo-rich and echo-poor combined, also inhomogeneous depending on the size, and often centrally cystic. With CDI, neuroendocrine metastases appeared hypervascular (66%) or isovascular (34%). Metastases of another origin were hypovascular in 82%. With CEUS, neuroendocrine metastases showed increased arterial enhancement in 38 patients and hypoechoic appearance in the portalvenous phase in 39 patients. In liver metastases of another origin, the sensitivity for malignancy due to a hypoechoic appearance during the portalvenous phase was 100%. In liver metastases of NET origin the sensitivity for malignancy was 39/48 (82%). Conclusions. Neuroendocrine tumour metastases might show characteristics which are similar to hemangiomas. In patients with liver cirrhosis and severe fatty liver disease the identification of NET with CEUS as a malignant lesion is more difficult. The sensitivity of CEUS in identifying malignancy based on the lack of portalvenous enhancement is higher for metastases of other origin.

The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase

Endogenously formed reactive oxygen species continuously damage cellular constituents including DNA. These challenges, coupled with exogenous exposure to agents that generate reactive oxygen species, are both associated with normal aging processes and linked to cardiovascular disease, cancer, cataract formation, and fatty liver disease. Although not all of these diseases have been definitively shown to originate from mutations in nuclear DNA or mitochondrial DNA, repair of oxidized, saturated, and ring-fragmented bases via the base excision repair pathway is known to be critical for maintaining genomic stability. One enzyme that initiates base excision repair of ring-fragmented purines and some saturated pyrimidines is NEIL1, a mammalian homolog to Escherichia coli endonuclease VIII. To investigate the organismal consequences of a deficiency in NEIL1, a knockout mouse model was created. In the absence of exogenous oxidative stress, neil1 knockout (neil1-/-) and heterozygotic (neil1+/-) mice develop severe obesity, dyslipidemia, and fatty liver disease and also have a tendency to develop hyperinsulinemia. In humans, this combination of clinical manifestations, including hypertension, is known as the metabolic syndrome and is estimated to affect >40 million people in the United States. Additionally, mitochondrial DNA from neil1-/- mice show increased levels of steady-state DNA damage and deletions relative to wild-type controls. These data suggest an important role for NEIL1 in the prevention of the diseases associated with the metabolic syndrome.

Fatty Liver Disease in Morbid Obesity

About 90 per cent of morbidly obese patients show histological abnormalities of the liver. One third of patients have fatty change involving more than 50 per cent of hepatocytes. Fatty liver disease can be divided into four histological groups: Fatty liver, fatty hepatitis, fatty liver with portal fibrosis, and cirrhosis. Most patients show only fatty change. Alcohol, drugs, diabetes, poor nutrition, and weight-reducing surgery contribute to progressive liver damage, but morbid obesity alone may lead to severe disease showing all the features of alcoholic hepatitis and may end in cirrhosis and liver failure. The accumulation of fat alone is unlikely to be the stimulus to inflammation and fibrosis. Only one fifth of patients have complaints that arise from the liver. The development of severe fatty liver disease may also be asymptomatic and rarely shows the florid picture associated with alcoholic hepatitis. There is poor correlation of liver function test results with morphology in obesity. ALT levels exceeding twice the normal limit have some predictive value for histological grades of severity, but they are present in few patients. Pericentral and pericellular fibrosis in prebypass liver biopsies may be an important prognostic lesion for the development of fatty hepatitis and cirrhosis. In contrast with the frequent progression to massive fatty change, inflammation and fibrosis after bypass surgery, weight loss by low-calorie dieting, or starvation is accompanied by improvement in fatty change and return of liver function tests to normal.