Article

Histopathology of pediatric nonalcoholic fatty liver disease

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Abstract

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common in children and adolescents. However, standard histological criteria for pediatric NAFLD and NASH are undeveloped. We reviewed consecutive patients ages 2 to 18 years with biopsy-proven NAFLD diagnosed between 1997 and 2003. Biopsies were evaluated by two pathologists for individual features of steatohepatitis. Agglomerative hierarchical cluster analysis demonstrated two different forms of steatohepatitis. Type 1 was characterized by steatosis, ballooning degeneration, and perisinusoidal fibrosis; type 2 was characterized by steatosis, portal inflammation, and portal fibrosis. The study included 100 children with NAFLD. Simple steatosis was present in 16% of subjects, and advanced fibrosis was present in 8%. Type 1 NASH was present in 17% of subjects, and type 2 NASH was present in 51%. Boys were significantly (P < .01) more likely to have type 2 NASH and less likely to have type 1 NASH than girls. The NASH type differed significantly (P < .001) by race and ethnicity. Type 1 NASH was more common in white children, whereas type 2 NASH was more common in children of Asian, Native American, and Hispanic ethnicity. In cases of advanced fibrosis, the pattern was generally that of type 2 NASH. In conclusion, type 1 and type 2 NASH are distinct subtypes of pediatric NAFLD, and type 2 is the most common pattern in children. NASH subtypes should be considered when interpreting liver biopsies and planning studies of the pathophysiology, genetics, natural history, or response to treatment in pediatric NAFLD.

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... According to Brunt's pathological classification, necrosis and inflammation grades are extremely low, and the fibrosis stage is very high in many children. Schwimmer et al. [26] previously reviewed patients aged 2-18 years with NAFLD, and classified them into two different groups of steatohepatitis by agglomerative hierarchical cluster analysis. Type one was characterized by steatosis, ballooning degeneration, and perisinusoidal fibrosis; type two was characterized by steatosis, portal inflammation, and portal fibrosis. ...
... In cases of advanced fibrosis, the pattern was generally that of type two NASH. The authors concluded that type one and type two NASH are distinct subtypes of pediatric NAFLD, with type two being the most common presentation in children [26]. ...
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Purpose: Hepcidin levels have previously been reported to be correlated with liver damage. However, the association between hepcidin levels and liver fibrosis in children with fatty liver disease remains unclear. This study therefore aimed to investigate the pathophysiology of fibrosis in children with fatty liver disease and its association with hepcidin levels. Methods: This retrospective case series included 12 boys aged 6-17 years who were diagnosed with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) at the Tokyo Medical University Hospital. Sixteen liver biopsy samples from 12 subjects were analyzed. Serum hepcidin levels were assayed using enzyme-linked immunosorbent assay. Immunostaining for hepcidin was performed, and the samples were stratified by staining intensity. Results: Serum hepcidin levels were higher in pediatric NAFLD/NASH patients than in controls. Conversely, a significant inverse correlation was observed between hepcidin immunostaining and Brunt grade scores and between hepcidin scores and gamma-glutamyltranspeptidase, hyaluronic acid, and leukocyte levels. We observed inverse correlations with a high correlation coefficient of >0.4 between hepcidin immunostaining and aspartate aminotransferase, alanine aminotransferase, total bile acid, and platelet count. Conclusion: There was a significant inverse correlation between hepcidin immunoreactivity and fibrosis in pediatric NAFLD patients; however, serum hepcidin levels were significantly higher, suggesting that these patients experienced a reduction in the hepcidin-producing ability of the liver in response to iron levels, leading to subsequent fibrosis. Therefore, hepcidin levels can be used as markers to identify the progression of fibrosis in patients with NAFLD.
... NAFLD prevalence positively correlates with aging [34,41,42]; however, pediatric NAFLD seems a distinct entity with a more severe phenotype [41]. Indeed, NASH-related cirrhosis has been reported already in children of eight years old [42]. ...
... NAFLD prevalence positively correlates with aging [34,41,42]; however, pediatric NAFLD seems a distinct entity with a more severe phenotype [41]. Indeed, NASH-related cirrhosis has been reported already in children of eight years old [42]. ...
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Although most same-stage non-alcoholic fatty liver disease (NAFLD) patients exhibit similar histologic sequelae, the underlying mechanisms appear to be highly heterogeneous. Therefore, it was recently proposed to redefine NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) in which other known causes of liver disease such as alcohol consumption or viral hepatitis do not need to be excluded. Revised nomenclature envisions speeding up and facilitating anti-MAFLD drug development by means of patient stratification whereby each subgroup would benefit from distinct pharmacological interventions. As human-based in vitro research fulfils an irrefutable step in drug development, action should be taken as well in this stadium of the translational path. Indeed, most established in vitro NAFLD models rely on short-term exposure to fatty acids and use lipid accumulation as a phenotypic benchmark. This general approach to a seemingly ambiguous disease such as NAFLD therefore no longer seems applicable. Human-based in vitro models that accurately reflect distinct disease subgroups of MAFLD should thus be adopted in early preclinical disease modeling and drug testing. In this review article, we outline considerations for setting up translational in vitro experiments in the MAFLD era and allude to potential strategies to implement MAFLD heterogeneity into an in vitro setting so as to better align early drug development with future clinical trial designs.
... Peroxisome proliferator-activated receptors isoforms, particularly PPAR-γ are well expressed in reproductive tissues, including testicular cells such as Leydig cells, Sertoli cells and germ cells, where lipid metabolism, specifically β-oxidation of fatty acids are important for testicular functions and in addition plays essential role in spermatogenesis [29,30]. Earlier studies have associated defects in PPAR-γ with metabolic-related syndrome [31,32]. However, PPAR-γ agonist, pioglitazone has been shown to improve testicular function and semen quality in diabetic rabbits [33]. ...
... Therefore, the present results that showed a decrease in testicular Nrf2 with corresponding increase in oxidative stress and pro-inflammatory mediators as well as subsequent testicular dysfunction suggests at least in part the critical role of Nrf2 in testicular redox imbalance associated with obese animals. In addition, PPAR-γ level has been earlier shown to be suppressed in metabolic-related syndrome, contributing to lipid/glucose dysmetabolism [31,32]. The animals fed with HFD demonstrated a decrease in circulating and testicular PPAR-γ, which contributed to impaired spermatogenesis as earlier documented by Gumieniczek et al. in diabetic rabbits [33], indicating the impact of defective PPAR-γ in the progression of testicular dysfunction in obese animals. ...
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PurposeSeveral studies have established impaired testicular function in obese male population, including the young males with childhood obesity, contributing to increased male infertility, which is a universal trend in the last few decades. Short chain fatty acids (SCFAs) have been recently demonstrated to inhibit progression to metabolic comorbidities. The present study therefore hypothesized that SCFAs, acetate attenuates testicular dysfunction in high fat diet (HFD)-induced obese rat model, possibly by modulating Nrf2/PPAR-γ.Methods Adult male Wistar rats weighing 160–190 g were randomly allotted into three groups (n = 6/group): The groups received vehicle (distilled water), 40% HFD and sodium acetate (200 mg/kg) plus 40% HFD respectively. The administration lasted for 12 weeks.ResultsHFD caused obesity, which is characterized with increased body weight and visceral adiposity and insulin resistance/hyperinsulinemia. In addition, it increased testicular lipid deposition, malondialdehyde, pro-inflammatory mediators, lactate/pyruvate ratio, γ-Glutamyl transferase, and circulating leptin as well as decreased testicular glutathione, nitric oxide, Nrf2, PPAR-γ and circulating follicle stimulating hormone and testosterone without a significant change in testicular lactate dehydrogenase, blood glucose and luteinizing hormone when compared to the control group. Nevertheless, administration of acetate reversed the HFD-induced alterations.Conclusion The present results demonstrates that HFD causes obesity-driven testicular dysfunction, associated with testicular lipid deposition, oxidative stress, and inflammation. The study in addition suggests the restoration of testicular function in obese animals by acetate, an effect that is accompanied by elevated Nrf2/PPAR-γ.
... Understanding the natural history, pathophysiology and phenotypes of childhood and adolescent NAFLD has advanced in the past two decades, including through articulation of clinically relevant subtypes of paediatric NASH [47][48][49] . NAFLD in children with T2DM has a unique pathological phenotype, which seems to be more aggressive than the adult form 50 . ...
... NAFLD in children with T2DM has a unique pathological phenotype, which seems to be more aggressive than the adult form 50 . Further research is still needed to elucidate the pathophysiology, genetics, natural history and responses to treatment in paediatric NAFLD 47 and therefore inform prevention and management approaches. ...
Article
Full-text available
Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease that affects approximately one-quarter of the global adult population, causing a substantial burden of ill health with wide-ranging social and economic implications. It is a multisystem disease and is considered the hepatic component of metabolic syndrome. Unlike other highly prevalent conditions, NAFLD has received little attention from the global public health community. Health system and public health responses to NAFLD have been weak and fragmented, and, despite its pervasiveness, NAFLD is largely unknown outside hepatology and gastroenterology. There is only a nascent global public health movement addressing NAFLD, and the disease is absent from nearly all national and international strategies and policies for non-communicable diseases, including obesity. In this global Delphi study, a multidisciplinary group of experts developed consensus statements and recommendations, which a larger group of collaborators reviewed over three rounds until consensus was achieved. The resulting consensus statements and recommendations address a broad range of topics — from epidemiology, awareness, care and treatment to public health policies and leadership — that have general relevance for policy-makers, health-care practitioners, civil society groups, research institutions and affected populations. These recommendations should provide a strong foundation for a comprehensive public health response to NAFLD.
... Understanding the natural history, pathophysiology and phenotypes of childhood and adolescent NAFLD has advanced in the past two decades, including through articulation of clinically relevant subtypes of paediatric NASH [47][48][49] . NAFLD in children with T2DM has a unique pathological phenotype, which seems to be more aggressive than the adult form 50 . ...
... NAFLD in children with T2DM has a unique pathological phenotype, which seems to be more aggressive than the adult form 50 . Further research is still needed to elucidate the pathophysiology, genetics, natural history and responses to treatment in paediatric NAFLD 47 and therefore inform prevention and management approaches. ...
Article
Full-text available
... As previously noted, NAFLD is seen as a pattern that ranges from steatosis to NASH, showing various degrees of fibrosis to cirrhosis. Fibrosis was present in 70% of autopsy studies for children/adolescents with NAFLD, with advanced stages of fibrosis being present in 15-30% [50][51][52]. ...
... Type 2 is associated with younger age, male gender, a more severe degree of fibrosis and a higher prevalence in youth with Hispanic or Asian descent. While Type 2 pattern is more frequently diagnosed in children, most children show a combination of Type 1 and 2 NASH [50][51][52]. ...
Article
Background: Nonalcoholic fatty liver disease (NAFLD) is the leading hepatic disease in children, ranging from steatosis to steatohepatitis and fibrosis. Age, sex, hormonal levels, pubertal stages, genetic risk- and epigenetic factors are among the many influencing factors. Appearing predominantly in children with obesity, but not exclusively, it is the liver's manifestation of the metabolic syndrome but can also exist as an isolated entity. Summary: Pediatric NAFLD differs from the adult phenotype. This narrative review on NAFLD in children with obesity provides an overview of the current knowledge on risk factors, screening, and diagnostic methods, as well state-of-the-art treatment. The recent discussion on the proposition of a new nomenclature - Metabolic [Dysfunction-] Associated Liver Disease - is featured, and current gaps of knowledge are discussed. Key Messages: Currently, there is no international consensus on screening and monitoring of pediatric NAFLD. With lifestyle interventions being the cornerstone of treatment, no registered pharmacological treatment for pediatric NAFLD is available. Development and validation of additional noninvasive biomarkers, scores and imaging tools suitable to subcategorize, screen and monitor pediatric patients are necessary. With a variety of upcoming and promising agents, clear recommendations for pediatric nonalcoholic steatohepatitis trials are urgently needed.
... The gender differences might be explained by the liver-protective role of estrogens in females, but also by the well-documented negative role of androgens in aggravating MAFLD [63,64]. Nevertheless, variation in MAFLD rates were noticed in children of different races, revealing that being of Hispanic race is a risk factor, while being of a black race seems to have a protective effect [13,62,65,66]. In addition, children that originate from families with obesity, MAFLD, insulin resistance, and type 2 diabetes mellitus should be screened for MAFLD [67]. ...
... Several key features were defined as diagnostic and staging characteristics for MAFLD in adults, like steatosis, hepatocyte ballooning, inflammation and fibrosis. Nevertheless, these features often differ in children [65,98], having been proved that most of these patients are found with overlapping features of NASH type 1 and 2 [99,100]. Studies that aimed to find an explanation for these differences found that genetic background, along with the activation of the Hedgehog signaling pathway, might be incriminated in triggering these variations between children of different ethnicities, as well as between the two types of NASH [45,101]. ...
Article
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Non-alcoholic fatty liver disease has become the most common chronic liver disease in children due to the alarmingly increasing incidence of pediatric obesity. It is well-documented that MAFLD prevalence is directly related to an incremental increase in BMI. The multiple hits theory was designed for providing insights regarding the pathogenesis of steatohepatitis and fibrosis in MAFLD. Recent evidence suggested that the microbiome is a crucial contributor in the pathogenesis of MAFLD. Aside from obesity, the most common risk factors for pediatric MAFLD include male gender, low-birth weight, family history of obesity, MAFLD, insulin resistance, type 2 diabetes mellitus, obstructive sleep apnea, and polycystic ovarium syndrome. Usually, pediatric patients with MAFLD have nonspecific symptoms consisting of fatigue, malaise, or diffuse abdominal pain. A wide spectrum of biomarkers was proposed for the diagnosis of MAFLD and NASH, as well as for quantifying the degree of fibrosis, but liver biopsy remains the key diagnostic and staging tool. Nevertheless, elastography-based methods present promising results in this age group as potential non-invasive replacers for liver biopsy. Despite the lack of current guidelines regarding MAFLD treatment in children, lifestyle intervention was proven to be crucial in the management of these patients.
... In the NASH Clinical Research Network multicenter, cross-sectional study of children with NAFLD, children with high birth weight had significantly greater odds of severe steatosis and NASH even after controlling for childhood BMI, while those with low birth weight were more likely to have advanced fibrosis, suggesting that early exposures play an important role in the disease (11). Additionally, pediatric patients with NAFLD are more likely to have inflammation and fibrosis in the portal regions of the liver, rather than the typical pericentral distribution observed in adults (12,13). This is clinically significant because periportal inflammation is associated with greater severity of liver disease (14). ...
... Clinically, children with zone 1 (periportal) distribution of fibrosis have an important subphenotype of pediatric NAFLD; they are characterized by increased periportal-based (vs. pericentral) inflammation relative to similarly affected adults (12,45). SHG imaging is a highly sensitive technique that detects fibrillar collagens quantitatively, compared with more standard histological techniques, and has been efficacious in detecting subtle changes in periportal collagen deposition in pediatric NAFLD (24,25,46). ...
Article
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Maternal obesity affects nearly one-third of pregnancies and is a major risk factor for nonalcoholic fatty liver disease (NAFLD) in adolescent offspring, yet the mechanisms behind NAFLD remain poorly understood. Here, we demonstrate that nonhuman primate fetuses exposed to maternal Western-style diet (WSD) displayed increased fibrillar collagen deposition in the liver periportal region, with increased ACTA2 and TIMP1 staining, indicating localized hepatic stellate cell (HSC) and myofibroblast activation. This collagen deposition pattern persisted in 1-year-old offspring, despite weaning to a control diet (CD). Maternal WSD exposure increased the frequency of DCs and reduced memory CD4+ T cells in fetal liver without affecting systemic or hepatic inflammatory cytokines. Switching obese dams from WSD to CD before conception or supplementation of the WSD with resveratrol decreased fetal hepatic collagen deposition and reduced markers of portal triad fibrosis, oxidative stress, and fetal hypoxemia. These results demonstrate that HSCs and myofibroblasts are sensitive to maternal WSD-associated oxidative stress in the fetal liver, which is accompanied by increased periportal collagen deposition, indicative of early fibrogenesis beginning in utero. Alleviating maternal WSD-driven oxidative stress in the fetal liver holds promise for halting steatosis and fibrosis and preventing developmental programming of NAFLD.
... Understanding the natural history, pathophysiology and phenotypes of childhood and adolescent NAFLD has advanced in the past two decades, including through articulation of clinically relevant subtypes of paediatric NASH [47][48][49] . NAFLD in children with T2DM has a unique pathological phenotype, which seems to be more aggressive than the adult form 50 . ...
... NAFLD in children with T2DM has a unique pathological phenotype, which seems to be more aggressive than the adult form 50 . Further research is still needed to elucidate the pathophysiology, genetics, natural history and responses to treatment in paediatric NAFLD 47 and therefore inform prevention and management approaches. ...
Article
Full-text available
Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease that affects approximately one-quarter of the global adult population, causing a substantial burden of ill health with wide-ranging social and economic implications. It is a multisystem disease and is considered the hepatic component of metabolic syndrome. Unlike other highly prevalent conditions, NAFLD has received little attention from the global public health community. Health system and public health responses to NAFLD have been weak and fragmented, and, despite its pervasiveness, NAFLD is largely unknown outside hepatology and gastroenterology. There is only a nascent global public health movement addressing NAFLD, and the disease is absent from nearly all national and international strategies and policies for non-communicable diseases, including obesity. In this global Delphi study, a multidisciplinary group of experts developed consensus statements and recommendations, which a larger group of collaborators reviewed over three rounds until consensus was achieved. The resulting consensus statements and recommendations address a broad range of topics — from epidemiology, awareness, care and treatment to public health policies and leadership — that have general relevance for policy-makers, health-care practitioners, civil society groups, research institutions and affected populations. These recommendations should provide a strong foundation for a comprehensive public health response to NAFLD.
... These studies have found that neonatal NAFLD progressed more rapidly compared to adult NAFLD (99). Furthermore, paediatric NAFLD can be categorised into 2 phenotypes; adult-type (type 1 non-alcoholic steatohepatitis (NASH)) and paediatric-type (type 2 NASH) depending on histology (99,100). Portal inflammation is mainly seen in children with NAFLD compared to lobular inflammation seen in adults (100). ...
... Furthermore, paediatric NAFLD can be categorised into 2 phenotypes; adult-type (type 1 non-alcoholic steatohepatitis (NASH)) and paediatric-type (type 2 NASH) depending on histology (99,100). Portal inflammation is mainly seen in children with NAFLD compared to lobular inflammation seen in adults (100). Adults have pericellular fibrosis whereas paediatric NAFLD show portal-periportal fibrosis (100). ...
Article
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B lymphocytes are multitasking cells that direct the immune response by producing pro- or anti-inflammatory cytokines, by presenting processed antigen for T cell activation and co-stimulation, and by turning into antibody-secreting cells. These functions are important to control infection in the liver but can also exacerbate tissue damage and fibrosis as part of persistent inflammation that can lead to end stage disease requiring a transplant. In transplantation, immunosuppression increases the incidence of lymphoma and often this is of B cell origin. In this review we bring together information on liver B cell biology from different liver diseases, including alcohol-related and metabolic fatty liver disease, autoimmune hepatitis, primary biliary and primary sclerosing cholangitis, viral hepatitis and, in infants, biliary atresia. We also discuss the impact of B cell depletion therapy in the liver setting. Taken together, our analysis shows that B cells are important in the pathogenesis of liver diseases and that further research is necessary to fully characterise the human liver B cell compartment.
... NAFLD represents a spectrum of liver disorders ranging from simple steatosis to inflammatory nonalcoholic steatohepatitis (NASH) with or without fibrosis [3]. The pathogenesis of pediatric NAFLD is multifactorial and may be distinct from the adult form of the disease due to its rapid onset and histopathological changes within the liver [4][5][6]. Pediatric NAFLD can initiate prior to obesity [6,7] and leads to hepatic as well as systemic insulin resistance [5]. ...
... The pathogenesis of pediatric NAFLD is multifactorial and may be distinct from the adult form of the disease due to its rapid onset and histopathological changes within the liver [4][5][6]. Pediatric NAFLD can initiate prior to obesity [6,7] and leads to hepatic as well as systemic insulin resistance [5]. ...
Article
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Maternal obesity and consumption of a high-fat diet significantly elevate risk for pediatric nonalcoholic fatty liver disease (NAFLD), affecting 10% of children in the US. Almost half of these children are diagnosed with nonalcoholic steatohepatitis (NASH), a leading etiology for liver transplant. Animal models show that signs of liver injury and perturbed lipid metabolism associated with NAFLD begin in utero; however, safe dietary therapeutics to blunt developmental programming of NAFLD are unavailable. Using a mouse model of maternal Western-style diet (WD), we previously showed that pyrroloquinoline quinone (PQQ), a potent dietary antioxidant, protected offspring of WD-fed dams from development of NAFLD and NASH. Here, we used untargeted mass spectrometry-based lipidomics to delineate lipotoxic effects of WD on offspring liver and identify lipid targets of PQQ. PQQ exposure during pregnancy altered hepatic lipid profiles of WD-exposed offspring, upregulating peroxisome proliferator-activated receptor (PPAR) α signaling and mitochondrial fatty acid oxidation to markedly attenuate triglyceride accumulation beginning in utero. Surprisingly, the abundance of very long-chain ceramides, important in promoting gut barrier and hepatic function, was significantly elevated in PQQ-treated offspring. PQQ exposure reduced the hepatic phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio in WD-fed offspring and improved glucose tolerance. Notably, levels of protective n − 3 polyunsaturated fatty acids (PUFAs) were elevated in offspring exposed to PQQ, beginning in utero, and the increase in n − 3 PUFAs persisted into adulthood. Our findings suggest that PQQ supplementation during gestation and lactation augments pathways involved in the biosynthesis of long-chain fatty acids and plays a unique role in modifying specific bioactive lipid species critical for protection against NAFLD risk in later life.
... Analyzing data from a different pediatric cohort, our group previously showed that increased WHR is related to increased VAT and fasting insulin levels in children with obesity and increased hepatic liver fat content (28). This is in keeping with a plethora of studies reporting that WHR and VAT can be identified as indirect parameters of insulin resistance (29,30). In our study, univariate analysis not only indicated a significant relationship of fasting insulin, VAT, MRI liver fat content with glucagon in our cohort of children and adolescents with overweight and obesity, but also with the liver enzyme alanine transaminase (ALT). ...
... In our study, univariate analysis not only indicated a significant relationship of fasting insulin, VAT, MRI liver fat content with glucagon in our cohort of children and adolescents with overweight and obesity, but also with the liver enzyme alanine transaminase (ALT). Alanine transaminase levels are accepted as surrogates of NAFLD in clinical practice (30,31), although liver enzymes are known to be limited in sensitivity and specificity in the diagnosis of pediatric NAFLD (31,32). It is worth mentioning in this context, that children with overweight/ obesity and elevated ALT values had a more than 2-fold increased risk for future dysglycemia independent of age, sex and BMI-SDS in a survival analysis of up to 11 years of follow-up of 510 children with overweight and obesity from the Leipzig Childhood Cohort. ...
Article
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Objective Over the years, non-alcoholic fatty liver (NAFLD) disease has progressed to become the most frequent chronic liver disease in children and adolescents. The full pathology is not yet known, but disease progression leads to cirrhosis and hepatocellular carcinoma. Risk factors included hypercaloric diet, obesity, insulin resistance and genetics. Hyperglucagonemia appears to be a pathophysiological consequence of hepatic steatosis, thus, the hypothesis of the study is that hepatic fat accumulation leads to increased insulin resistance and impaired glucagon metabolism leading to hyperglucagonemia in pediatric NAFLD.Methods132 children and adolescents between 10 and 18 years, with varying degrees of obesity, were included in the study. Using Magnetic Resonance Imaging (MRI) average liver fat was determined, and patients were stratified as NAFLD (>5% liver fat content) and non-NAFLD (<5%). All patients underwent a standardized oral glucose tolerance test (OGTT). Additionally, anthropometric parameters (height, weight, BMI, waist circumference, hip circumference) such as lab data including lipid profile (triglycerides, HDL, LDL), liver function parameters (ALT, AST), uric acid, glucose metabolism (fasting insulin and glucagon, HbA1c, glucose 120 min) and indices evaluating insulin resistance (HIRI, SPISE, HOMA-IR, WBISI) were measured.ResultsChildren and adolescents with NAFLD had significantly higher fasting glucagon values compared to the non-NAFLD cohort (p=0.0079). In the NAFLD cohort univariate analysis of fasting glucagon was associated with BMI-SDS (p<0.01), visceral adipose tissue volume (VAT) (p<0.001), average liver fat content (p<0.001), fasting insulin concentration (p<0.001), triglycerides (p<0.001) and HDL (p=0.034). This correlation equally applied to all insulin indices HOMA-IR, WBISI, HIRI (all p<0.001) and SPISE (p<0.002). Multivariate analysis (R² adjusted 0.509) for the same subgroup identified HIRI (p=0.003) and VAT volume (p=0.017) as the best predictors for hyperglucagonemia. Average liver fat content is predictive in pediatric overweight and obesity but not NAFLD.Conclusions Children and adolescents with NAFLD have significantly higher fasting plasma glucagon values, which were best predicted by hepatic insulin resistance and visceral adipose tissue, but not average liver fat content.
... 6 The major risk factors for NAFLD are metabolic factors such as obesity, dyslipidemia, hypertension and diabetes Mellitus. (7)(8)(9)(10)(11) Further, the socio-demographic risk factors such as old age, ethnicity, and being male, a higher level of education, higher income level, low physical activity were also recognized as risk factors for NAFLD. (4,5,8,10) One study indicated that the hematocrit level is signi cantly associated with brosis in NAFLD in patients in Europe. ...
... (7)(8)(9)(10)(11) Further, the socio-demographic risk factors such as old age, ethnicity, and being male, a higher level of education, higher income level, low physical activity were also recognized as risk factors for NAFLD. (4,5,8,10) One study indicated that the hematocrit level is signi cantly associated with brosis in NAFLD in patients in Europe. 12 There is also a hypothesis that states high level of haemoglobin is a factor associated with NAFLD. ...
... The prevalence among adults is 1.4%-8% (69,70), whereas in an international series of 781 pediatric patients, the prevalence of AIH in children with PSC was 33% (71). Uncertainty in rates of progression to liver disease with clinically meaningful outcomes is currently a major barrier to drug development (72,73). ...
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Autoimmune liver disease (AILD) spans a spectrum of chronic disorders affecting the liver parenchyma and biliary system. Three main categories of AILD are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). This review condenses the presentation and discussions of the single topic conference (STC) in AILD that was held in Ottawa, Ontario, in November 2019. We cover generalities regarding disease presentation and clinical diagnosis; mechanistic themes; treatment paradigms; clinical trials, including approaches and challenges to new therapies; and looking beyond traditional disease boundaries. Although these diseases are considered autoimmune, the etiology and role of environmental triggers are poorly understood. AILDs are progressive and chronic conditions that affect survival and quality of life. Advances have been made in PBC treatment because second-line treatments are now available (obeticholic acid, bezafibrate); however, a significant proportion still present suboptimal response. AIH treatment has remained unchanged for several decades, and data suggest that fewer than 50% of patients achieve a complete response and as many as 80% develop treatment-related side effects. B-cell depletion therapy to treat AIH is in an early stage of development and has shown promising results. An effective treatment for PSC is urgently needed. Liver transplant remains the best option for patients who develop decompensated cirrhosis or hepatocellular carcinoma within specific criteria, but recurrent AILD might occur. Continued efforts are warranted to develop networks for AILD aimed at assessing geo-epidemiological, clinical, and biochemical differences to capture the new treatment era in Canada.
... To induce MAFLD (as evidenced by hepatic steatosis, T2DM and obesity and therefore fitting the criteria described above), young male mice were given a diet rich in saturated fatty acids and allowed access to drinking water ad libitum containing a blend of high sucrose and fructose (HFHS). The sex and age of mice and addition of simple carbohydrates were selected based on the evidence that the rates of childhood obesity and pediatric MAFLD are increased, and singularly reported in young male boys where the consumption of soft drinks is increased [41][42][43][44][45][46] the Care and Use of Laboratory Animals. Four-week-old male C57BL/6 mice were purchased from Charles River (Wilmington, MA, USA). ...
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Purpose: Metabolic dysfunction-associated fatty liver disease (MAFLD) is fueled by escalations in both sedentary behavior and caloric intake and is noted in obese type 2 diabetic (T2DM) patients. This study aimed to examine the effects of exercise and the phytoestrogen genistein in mice fed a high fat (60% fat) high sugar (55% fructose with 45% sucrose), HFHS diet. Methods: Male C57BL/6J mice were assigned to five groups: HFHS, HFHS with genistein (600 mg/kg diet, HFHS+Gen), HFHS with moderate exercise (HFHS+Ex), and HFHS with combined genistein and moderate exercise (HFHS-Gen+Ex). Control lean mice were fed standard chow and water. Exercise consisted of 30-minute sessions of treadmill running five days/week for the 12-week study duration. Body weight was assessed weekly. Liver, kidney, fecal pellets and serum were extracted at the end of the study and maintained at -80°C. Results: After 12 weeks of treatment, mice in the HFHS group had the highest hepatic lipid content. Plasma levels of glucose, insulin, leptin, cholesterol, amylin, and total fat content were significantly elevated in HFHS mice compared to control mice. HFHS feeding increased protein expression of carnitine palmitoyltransferase 1b (CPT-1b isoform) in gastrocnemius, CPT1a, glucose transporter protein 2 (GLUT2), glucocorticoid receptor (GR), and fructose 1,6-bisphosphate 1 (FBP1) expression in liver. Exercise alone had minor effects on these metabolic abnormalities. Genistein alone resulted in improvements in body weight, fat content, amylin, insulin sensitivity, and liver histopathology, GR, FBP1, and acetyl-CoA carboxylase 1 (ACC1). Combination treatment resulted in additional metabolic improvements, including reductions in hepatic lipid content and lipid area, alanine transferase activity, CPT1b, and CPT1a. Conclusion: Our results indicate that a HFHS diet is obesogenic, inducing metabolic perturbations consistent with T2DM and MAFLD. Genistein alone and genistein combined with moderate intensity exercise were effective in reducing MAFLD and the aberrations induced by chronic HFHS feeding.
... Insulin resistance increases the rate of adipose tissue lipolysis and the flow of free fatty acids to the liver cell. Hyperglycemia also causes lipid−related changes in the liver cells by increasing lipogenesis while blocking fatty acid oxidation (FAO) and lipid transport in the liver (Kleiner et al., 2005;Schwimmer et al., 2005). ...
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Background: Vitamin D was reported to be associated with non−alcoholic fatty liver disease (NAFLD). This systematic review and meta−analysis aimed to investigate the effects of the vitamin D supplementation on anthropometric and biochemical indices in patient with NAFLD. Methods: PubMed, Web of science, Scopus, and Embase databases were explored to identify all randomized controlled trial (RCT) investigating the effects of vitamin D supplementation on anthropometric and biochemical indices in patients with NAFLD. A random−effects model was used to pool weighted mean difference (WMD) and corresponding 95% confidence intervals (CIs). The statistical heterogeneity among the studies was assessed using I2 statistic (high ≥ 50%, low < 50%) and Cochran’s Q−test. Results: Sixteen RCTs were included in this meta−analysis. The results identified that high−density lipoprotein−cholesterol (HDL−C) level significantly increased following vitamin D supplementation ( P = 0.008). Vitamin D reduced body weight ( P = 0.007), body mass index ( P = 0.002), waist circumstance (WC) ( P = 0.02), serum alanine transaminase (ALT) ( P = 0.01), fasting blood sugar (FBS) ( P = 0.01), homeostatic model assessment for insulin resistance (HOMA−IR) ( P = 0.004), and calcium ( P = 0.01). No significant changes were found on body fat, triglyceride (TG), total cholesterol, low−density lipoprotein−cholesterol (LDL−C), aspartate transaminase, alkaline phosphatase, gamma−glutamyl transferase, and adiponectin following vitamin D supplementation. Conclusion: Vitamin D had significant effects on anthropometric and biochemical indices including HDL−C, body weight, BMI, WC, serum ALT, serum FBS, HOMA−IR, and calcium. Vitamin D supplementation can be considered as an effective strategy in management of patients with NAFLD. Systematic Review Registration : [website], identifier [registration number]
... Initially, it was intended as the non-invasive score for chronic liver disease severity stratification in HCV/HIV coinfected patients. [121] Concerning its simplicity; it can be used even on GP level. [92,95] Additionally, Fib-4 was shown as a very reliable score for NASH detection (AUROC 0.86-0.90). ...
Article
Abstract Non-alcoholic fatty liver disease (NAFLD) is among the most frequently encountered chronic liver diseases in everyday clinical practice. It is considered the hepatic manifestation of metabolic syndrome. Today, liver biopsy is still the gold standard for NAFLD confirmation and assessing NAFLD’s possible progression to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Because of the high prevalence of NAFLD and potential associated risks of invasive diagnostic procedures, it is of great interest to recruit the patients for liver biopsy. However, as the presence of liver fibrosis determines the further clinical course, liver biopsy is expectedly reserved for those with increased fibrosis risk. The quality of liver biopsy recruitment and patient monitoring could be significantly improved by using non-invasive tools to assess liver fibrosis presence and interactive collaboration between general practitioners, gastroenterologists, and endocrinologists. As a result, the quality of liver biopsy recruitment and patients monitoring could be significantly improved. Here, we proposed clinical practice guidelines that could be implemented for everyday clinical practice in NAFLD patients. Keywords: Diagnostics of NAFLD, Fatty liver index, Fibrosis score-4, Management of NAFLD, Non-alcoholic fatty liver disease
... US children and adolescents first diagnosed with NAFLD frequently display features of NASH and advanced fibrosis has been present in in 10-25% of these cases [30]. Children with NAFLD display a different histological pattern of the liver compared with adults, with evidence for a more aggressive disease phenotype [31][32][33]. Abdominal visceral obesity in particular correlates with histological damage and hepatic fibrosis in children [34]. ...
Article
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Paediatric non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in childhood. Obesity is the main risk factor. Nutrition and lifestyle are the key elements in preventing and treating NAFLD in the absence of approved drug therapy. Whilst recommendations and studies on macronutrients (carbohydrates, fat and protein) in adult NAFLD exist, the discussion of this topic in paediatric NAFLD remains contradictory. The purpose of this review is to provide state-of-the-art knowledge on the role of macronutrients in paediatric NAFLD regarding quality and quantity. PubMed was searched and original studies and review articles were included in this review. Fructose, sucrose, saturated fatty acids, trans-fatty acids and ω-6-fatty-acids are strongly associated with paediatric NAFLD. High consumption of fibre, diets with a low glycaemic index, mono-unsaturated-fatty-acids and ω-3-fatty-acids reduce the risk of childhood-onset NAFLD. Data regarding the role of dietary protein in NAFLD are contradictory. No single diet is superior in treating paediatric NAFLD, although the composition of macronutrients in the Mediterranean Diet appears beneficial. Moreover, the optimal proportions of total macronutrients in the diet of paediatric NAFLD patients are unknown. Maintaining a eucaloric diet and avoiding saturated fatty acids, simple sugars (mainly fructose) and a high-caloric Western Diet are supported by literature.
... However, even in adults, liver biopsies are invasive, inconvenient, and often related to severe morbidity and mortality. Moreover, pediatric patients with NAFLD often have a liver histology that differs from that in adults (11). To overcome these challenges, several non-invasive methods have been used to predict the presence and risk stratification of liver fibrosis in patients with NAFLD. ...
Article
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Background and Purpose The prevalence of non-alcoholic fatty liver disease (NAFLD) in children has been increasing associated with insulin resistance. However, there is a scarcity of related studies in children with NAFLD with type 2 diabetes mellitus (T2DM) compared to adults. We conducted this study to investigate the association between non-invasive diagnostic methods of liver fibrosis and T2DM in pediatric patients with NAFLD. Methods We enrolled a total of 152 patients aged <18 years with NAFLD, and compared their data according to the presence of T2DM. We evaluated fibrosis by transient elastography (TE, FibroScan®), and calculated the following fibrosis scores for each patient: NAFLD fibrosis score (NFS), AST: platelet ratio index (APRI), Fibrosis-4 (FIB-4) index, and pediatric NAFLD fibrosis index (PNFI). Results In the NAFLD–T2DM group, the NFS and mean controlled attenuation parameter in FibroScan were significantly higher than those in the nondiabetic group. The receiver operating characteristic (ROC) curve values for predicting the presence of T2DM were 0.78 for NFS, 0.64 for FIB-4, 0.62 for PNFI, and 0.61 for APRI. The cutoff HbA1c levels for predicting fibrosis progression in APRI, NFS, and PNFI were 5.7% [area under the curve (AUC) 0.74], 6.4% (AUC 0.71), and 6.4% (AUC 0.55), respectively. In the multivariate analysis, hepatosteatosis on abdomen sonography, NFS, FibroScan F, and APRI were independently associated with T2DM risk. Conclusions We significantly characterized non-invasive fibrosis markers and elastography in pediatric NAFLD with T2DM compared with the nondiabetic group. We suggest evaluating the progression of fibrosis in the prediabetic stage in children using a combination of these non-invasive methods.
... A rising trend is found in Europe, the United States, the Middle East and Asia [64][65][66][67][68][69][70]. An NAFLD prevalence of 9.6% was revealed after children were autopsied and, among obese children, 38% were diagnosed with NAFLD [71,72]. NAFLD is a term that includes non-alcoholic steatohepatitis (NASH) with inflammation, hepatocellular injury, fibrosis, cirrhosis derived from fibrosis [60] and non-alcoholic fatty liver (NAFL) [61]. ...
Article
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Viral infections or persistent alcohol or drug abuse, together with intrinsic factors, lead to hepatitis, which often ends in the development of liver cirrhosis or hepatocellular carcinoma (HCC). With this review, we describe inflammatory liver diseases, such as acute liver failure, virus-induced hepatitis, alcoholic- and non-alcoholic steatohepatitis, and autoimmune hepatitis, and highlight their driving mechanisms. These include external factors such as alcohol misuse, viral infection and supernutrition, as well as intrinsic parameters such as genetic disposition and failure, in immune tolerance. Additionally, we describe what is known about the translational machinery within all these diseases. Distinct eukaryotic translation initiation factors (eIFs) with specific functional roles and aberrant expression in HCC are reported. Many alterations to the translational machinery are already triggered in the precancerous lesions described in this review, highlighting mTOR pathway proteins and eIFs to emphasize their putative clinical relevance. Here, we identified a lack of knowledge regarding the roles of single eIF proteins. A closer investigation will help to understand and treat HCC as well as the antecedent diseases.
... In particular, studies have shed light on the potential for more rapid progression of liver damage in children with NAFLD (3,4,37) and have described an alternate histological pattern of NASH (type 2 or pediatric-type NASH), which is common in younger children and characterized by moderate-high steatosis with portal inflammation and fibrosis, but little or no ballooning. (38,39) The exact mechanism to explain these differences in children versus adults remain unclear, but it may not be a coincidence that participants with advanced fibrosis in our pediatric NAFLD cohort tended to be younger than those with none/ mild fibrosis, and may therefore reflect a unique population of children who develop progressive NAFLD at a young age, which will require different biomarkers than adults due to the simultaneous onset of the pubertal growth spurt. As a proof-of-concept study, there are some limitations that should be noted. ...
Article
Full-text available
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease in children and may lead to cirrhosis requiring liver transplant. Thus, prompt diagnosis of advanced fibrosis is essential. Our objectives were to examine PRO‐C3 (a neo‐epitope pro‐peptide of type III collagen formation) levels across childhood/adolescence and associations with advanced fibrosis in pediatric NAFLD. This cross‐sectional study included 88 children and adolescents with biopsy‐proven NAFLD (mean age: 13.9 ± 2.9 years, 71% male) and 65 healthy participants (11.8 ± 4.5 years, 38% male). PRO‐C3, and the bone remodeling biomarkers C‐terminal telopeptide of type I collagen (CTX‐I; bone resorption) and osteocalcin (N‐MID; bone formation), were measured in serum by enzyme‐linked immunosorbent assay. Fibrosis was assessed by liver biopsy in participants with NAFLD, who were categorized as having advanced (Ishak score ≥ 3) or none/mild fibrosis (Ishak score ≤ 2). Overall, PRO‐C3 was similar in participants with NAFLD (median [interquartile range]: 20.6 [15.8, 25.9] ng/mL) versus healthy participants (19.0 [13.8, 26.0] ng/mL), but was significantly lower in older adolescents ≥ 15 years old (16.4 [13.0, 21.2] ng/mL) compared with children ≤ 10 years old (22.9 [18.1, 28.4] ng/mL; P
... Moreover, because this diet does not restrict either fat or protein, it may also be more behaviorally sustainable and can therefore result in better adherence over time [27]. Lastly, it could be that the rapid and significant reversal in liver histology, compared to the adult population, stems from the differences in histologic distribution among the 2 populations in terms of inflammation and hepatocellular damage [16,20,28]. ...
Article
Full-text available
Background Non-alcoholic fatty liver disease (NAFLD) can range from simple steatosis to steatohepatitis with or without fibrosis. The predictors for liver fibrosis and the effect of nutritional intervention on hepatic fibrosis in pediatric population are not well established. We aimed to investigate the predictors for liver fibrosis and the effects of short-term nutritional intervention on steatosis and fibrosis among obese adolescents with NAFLD. Methods Cross-sectional study among obese adolescents. Sociodemographic and clinical data were collected. Liver fibrosis was estimated by Shearwave elastography. All participants were recommended to consume a low carbohydrate diet and were followed biweekly. Blood tests and elastography were performed upon admission and repeated after 3 months. Results Fifty-seven pediatric patients were recruited (35 males, mean age 13.5±2.9 years, mean body mass index [BMI] 38.8±9.7). Liver fibrosis was diagnosed in 34 (60%) subjects, which was moderate/severe (F≥2) in 24 (70%). A higher BMI Z score and moderate/severe steatosis correlated with moderate/severe fibrosis (P < 0.05). Seventeen patients completed 3 months of follow-up and displayed a decrease in BMI Z score (from BMI Z score 2.6±0.5 before intervention to 2.4±0.5 after intervention), with a significant decrease in liver fibrosis (P = 0.001). Conclusion Pediatric patients with high BMIs and severe liver steatosis are at risk for severe liver fibrosis. Nutritional intervention with minimal weight loss may improves hepatic fibrosis among the pediatric population. Trial registration TRN NCT04561804 (9/17/2020)
... In the study done by Schwimmer et al. in biopsy-proven 100 NAFLD children and adolescents in the United States, obesity was found in 92% of cases. [22] We found vitamin D deficiency in 46.7% (n = 28) and insufficiency in 38.3% (n = 23) of obese cases. This is similar to the Indian study by Reddy et al., which was done in 16 obese and 14 overweight adolescents, in which 62.5% of obese and 71.4% of overweight adolescents had vitamin D deficiency, 6.25% of obese and 21.4% of overweight adolescents had vitamin D insufficiency. ...
Article
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Context: Childhood obesity is a global health problem. A percentage of 2.3 of Indian boys and 2.5 of Indian girls are obese. Childhood obesity is associated with many morbidities like diabetes mellitus, coronary artery disease, musculoskeletal problems, and increased mortality. Aims: The aim of this study is to estimate burden of metabolic complications of obesity in child and parents of obese children and compare it with normal-weight children. Settings and Design: The study was done at a tertiary health center in northern India. It was a cross-sectional study. Methods and Material: We enrolled 60 obese children and age- and sex-matched 26 controls, based on Indian Academy of Pediatrics (IAP) 2015 body mass index (BMI) charts. Anthropometric parameters and metabolic complications in family were compared between cases and controls. Clinical markers of metabolic derangements and laboratory metabolic profile were assessed for obese children. Statistical Analysis Used: Descriptive statistics was used to describe frequencies. Chi-square test and Mann–Whitney test and Spearman correlation were used for comparison. Results: The prevalence of obesity and obesity-related complications was high in families of obese children. Ten percent of obese children had impaired fasting glucose and 30% had Haemoglobin A1c (HbA1c) in prediabetes category. Forty percent of obese children had dyslipidemia, 45% had transaminitis, and 46.7 were vitamin D deficient. A percentage of 41.7 of obese children had fatty liver on ultrasound. Conclusions: The family health and child weight are linked through home environment and genetics. The metabolic complications of obesity prediabetes, dyslipidemia, fatty liver, and lower vitamin D level are common in childhood obesity. Regular screening and interventions of metabolic complications are essential for saving child's future health.
... Non-alcoholic fatty liver disease (NAFLD) is presently considered a manifestation of MS [13,14]. There is increasing evidence that obesity, hyperglycemia and insulin resistance are risk factors for NAFLD in children [15][16][17]. Pooling data from studies performed mainly in tertiary care centers, the mean prevalence of NAFLD in children from general population studies was between 7.6% and 34.2% in studies based on child obesity clinics [18]. ...
Article
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As in adults, obesity also plays a central role in the development of metabolic syndrome (MS) in children. Non-alcoholic fatty liver disease (NAFLD) is considered a manifestation of MS. Not only MS but also NAFLD seem to be inversely associated with serum bilirubin concentrations, an important endogenous tissue protector when only mild elevated. The aim of the study was to evaluate the association between serum bilirubin levels and the prevalence of MS and NAFLD in Italian obese children and adolescents. A retrospective cross-sectional study was performed in 1672 patients aged from 5 to 18 years. Clinical and laboratory parameters were assessed. NAFLD was measured by liver ultrasonography. The study was approved by the Ethical Committee of the Istituto Auxologico Italiano (research project code 1C021_2020, acronym BILOB). MS was present in 24% and fatty liver (FL) in 38% of this population. Bilirubin was not associated with FL and MS as a whole, but it was inversely associated only with selected components of MS, i.e., large WC, high blood pressure and high triglycerides. Our data suggest that bilirubin is not protective against MS and NAFLD in the presence of severe obesity.
... The prevalence of childhood obesity is increasing, whereas the incidence of hepatic steatosis is estimated to be almost 10% in the pediatric population and may be as high as 38% in obese children [2]. Children with NAFLD are at higher risk of progressive liver disease and cirrhosis, with a consequent need for liver transplantation [3][4][5][6]. Environmental risk factors are widely known to influence the development and progression of NAFLD [7]. Genetic variability plays a critical role in NAFLD predisposition and is characterized by gene polymorphisms. ...
Article
Background: Several studies have detected a strong association linking rs738409 and rs2896019 polymorphisms in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene with hepatic steatosis and steatohepatitis. In the present study we aimed to determine the association of those PNPLA3 variants with nonalcoholic fatty liver disease (NAFLD) susceptibility in obese and nonobese Greek children and adolescents. Methods: The study recruited 91 children and adolescents of Greek descent with NAFLD or biopsy-proven nonalcoholic steatohepatitis, and 91 healthy subjects of normal weight (control group) with sex distribution similar to the patient group. DNA samples were amplified using polymerase chain reaction with specifically designed primers. Data were analyzed using the statistical software SPSS version 24.0. Results: A significant correlation was shown between the rs738409 polymorphism (CG and GG genotypes) and the rs2896019 polymorphism (TG genotype) with the development of hepatic steatosis (P<0.001). The incidences of rs738409 GG, rs738409 CG and rs2896019 TG genotypes were found to be increased in patients with hepatic steatosis (obese and nonobese), but not in obese patients without liver disease. The combined expression of the 2 polymorphisms was associated with a lower age of diagnosis of hepatic steatosis in nonobese patients. Conclusions: We confirmed a strong association between the 2 polymorphisms and hepatic steatosis. The association of the rs2896019 single-nucleotide polymorphism with hepatic steatosis in obese and nonobese pediatric patients, and the combined study of both polymorphisms in a pediatric population of Greek origin are described for the first time.
... In older children, autoimmune hepatitis, viruses, nonalcoholic fatty liver disease (NAFLD), cystic fibrosis and primary sclerosing cholangitis are common causes [3]. Chronic liver disease can lead to fibrosis and cirrhosis, which can cause portal hypertension, variceal bleeding, hepatocellular carcinoma, liver failure and even death [4,5]. ...
Article
Full-text available
Background Magnetic resonance (MR) elastography of the liver measures hepatic stiffness, which correlates with the histopathological staging of liver fibrosis. Conventional Cartesian gradient-echo (GRE) MR elastography requires breath-holding, which is challenging for children. Non-Cartesian radial free-breathing MR elastography is a potential solution to this problem. Objective To investigate radial free-breathing MR elastography for measuring hepatic stiffness in children. Materials and methods In this prospective pilot study, 14 healthy children and 9 children with liver disease were scanned at 3 T using 2-D Cartesian GRE breath-hold MR elastography (22 s/slice) and 2-D radial GRE free-breathing MR elastography (163 s/slice). Each sequence was acquired twice. Agreement in the stiffness measurements was evaluated using Lin’s concordance correlation coefficient (CCC) and within-subject mean difference. The repeatability was assessed using the within-subject coefficient of variation and intraclass correlation coefficient (ICC). Results Fourteen healthy children and seven children with liver disease completed the study. Median (±interquartile range) normalized measurable liver areas were 62.6% (±26.4%) and 44.1% (±39.6%) for scan 1, and 60.3% (±21.8%) and 43.9% (±44.2%) for scan 2, for Cartesian and radial techniques, respectively. Hepatic stiffness from the Cartesian and radial techniques had close agreement with CCC of 0.89 and 0.94, and mean difference of 0.03 kPa and −0.01 kPa, for scans 1 and 2. Cartesian and radial techniques achieved similar repeatability with within-subject coefficient of variation=1.9% and 3.4%, and ICC=0.93 and 0.92, respectively. Conclusion In this pilot study, radial free-breathing MR elastography was repeatable and in agreement with Cartesian breath-hold MR elastography in children.
Article
The new compound sodium 4,4′-(propanediamido)dibenzoate (malaben) exhibits pronounced activity in the treatment of non-alcoholic fatty liver disease, which could potentially allow it to be used as a drug. To study the content of related impurities in the malaben sample, conditions for electrophoretic separation were developed. The determination of impurities was carried out in a fused-silica capillary (length 60/50 cm × 50 μm i.d.) using a 50 mM borate buffer, at +20 kV voltage and a temperature of 25 °C, the hydrodynamic injection time was 7 s at a pressure of 30 mbar, with detection at 270 nm. Under these conditions, 4 related impurities were found, 2 of which were identified based on the synthesis scheme while the other 2 required structural elucidation. According to the obtained data on their electrophoretic behavior, the structures were approximately described. To identify the contaminants, HPLC-ESI/MS analysis conditions were developed. Separation was carried out on a Kromasil Zorbax 100–3.5 C18 column (150 × 2.1 mm), using an eluent of methanol and 0.05% formic acid solution with a flow of 0.2 ml min⁻¹ at a column temperature of 40 °C and an injection volume of 20 μL. The structures of the 2 investigated impurities have been proven.
Article
Nonalcoholic fatty liver disease (NAFLD) is the most common form of pediatric liver disease in the United States, and often associated with obesity and metabolic syndrome. NAFLD comprises a broad spectrum of liver diseases, from hepatic steatosis to steatohepatitis, fibrosis and cirrhosis. Disease progression is considered a multi-modal process of liver injury. The intestinal microbiome has been implicated in several aspects of NAFLD pathophysiology. Pediatric studies associating the intestinal microbiome with NAFLD have been limited in number and complicated by inconsistencies in study design and approach. Nevertheless, they provide support for involvement of the intestinal microbiome in NAFLD development and progression and point to common mechanisms shared by microbiome-associated inflammatory diseases with potential to inform future therapeutic intervention.
Article
Context: Childhood obesity is a global health problem. A percentage of 2.3 of Indian boys and 2.5 of Indian girls are obese. Childhood obesity is associated with many morbidities like diabetes mellitus, coronary artery disease, musculoskeletal problems, and increased mortality. Aims: The aim of this study is to estimate burden of metabolic complications of obesity in child and parents of obese children and compare it with normal-weight children. Settings and design: The study was done at a tertiary health center in northern India. It was a cross-sectional study. Methods and material: We enrolled 60 obese children and age- and sex-matched 26 controls, based on Indian Academy of Pediatrics (IAP)2015 body mass index (BMI) charts. Anthropometric parameters and metabolic complications in family were compared between cases and controls. Clinical markers of metabolic derangements and laboratory metabolic profile were assessed for obese children. Statistical analysis used: Descriptive statistics was used to describe frequencies. Chi-square test and Mann-Whitney test and Spearman correlation were used for comparison. Results: The prevalence of obesity and obesity-related complications was high in families of obese children. Ten percent of obese children had impaired fasting glucose and 30% had Haemoglobin A1c (HbA1c) in prediabetes category. Forty percent of obese children had dyslipidemia, 45% had transaminitis, and 46.7 were vitamin D deficient. A percentage of 41.7 of obese children had fatty liver on ultrasound. Conclusions: The family health and child weight are linked through home environment and genetics. The metabolic complications of obesity prediabetes, dyslipidemia, fatty liver, and lower vitamin D level are common in childhood obesity. Regular screening and interventions of metabolic complications are essential for saving child's future health.
Article
Non‐alcoholic fatty liver disease (NAFLD) exists as a spectrum ranging from simple steatosis to histologically defined hepatocyte injury and inflammatory changes that define steatohepatitis (NASH), and increase risk for fibrosis. Although zonal differences in NASH have not been systematically studied, periportal involvement has been associated with worse metabolic outcomes and more hepatic fibrosis as compared to pericentral disease. These data suggest that hepatic zonation of disease may influence the diversity of clinical presentations. Similarly, several randomized clinical trials suggest a differential response based on zonation of disease, with preferential effects on periportal (cysteamine) or pericentral disease (obeticholic acid, pioglitazone). Intriguingly, morphogenic pathways known to affect zonal development and maintenance – WNT/β‐Catenin, Hedgehog, HIPPO/Yap/TAZ, and Notch – have been implicated in NASH pathogenesis, and nuclear hormone receptors downstream of potential NASH therapeutics show zonal preferences. In this review, we summarize these data and propose that patient‐specific activation of these pathways may explain the variability in clinical presentation, and the zone‐specific response observed in clinical trials.
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The incidental finding of a fatty liver on an abdominal ultrasound scan performed for an unrelated reason in an overweight child is an increasingly common phenomenon in paediatric practice. This article will explain the steps to be taken when receiving such an ultrasound report.
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Background & aims: Longitudinal data are scarce regarding the natural history and long-term risk of mortality, in children and young adults with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD). Methods: This nationwide, matched cohort study included all Swedish children and young adults (≤25 years) with biopsy-confirmed NAFLD (1966-2017; n=718). NAFLD was confirmed histologically from all liver biopsies submitted to Sweden's 28 pathology departments, and further categorized as simple steatosis or steatohepatitis (NASH). NAFLD patients were matched to ≤5 general population controls by age, sex, calendar year and county (n=3,457). To account for shared genetic and early-life factors, we also matched NAFLD patients to full-sibling comparators. Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs) and 95%CIs. Results: Over a median of 15.8 years, 59 NAFLD patients died (5.5/1000 person-years [PY]), compared to 36 population controls (0.7/1000PY; difference=4.8/1000PY; multivariable aHR=5.88 [95%CI=3.77-9.17]), corresponding to 1 additional death per each 15 patients with NAFLD, followed for 20 years. The 20-year absolute risk of overall mortality was 7.7% among NAFLD patients, and 1.1% among controls (difference=6.6%, 95%CI=4.0-9.2). Findings persisted after excluding subjects who died within the first 6 months (aHR=4.65, 95%CI=2.92-7.42), and after using full-sibling comparators (aHR=11.72, 95%CI=3.18-43.23). Simple steatosis was associated with a 5.26-fold higher adjusted rate of mortality, compared to controls (95%CI=3.05-9.07), and this was amplified with NASH (aHR=11.51, 95%CI=4.77-27.79). Most of the excess mortality was from cancer (1.67 vs. 0.07/1000PY; aHR=15.60, 95%CI=4.97-48.93), liver disease (0.93 vs. 0.04/1000PY; aHR=16.46, 95%CI=2.75-98.43) and cardiometabolic disease (1.12 vs. 0.14/1000PY; aHR=4.32, 95%CI=1.73-10.79). Conclusions: Swedish children and young adults with biopsy-confirmed NAFLD have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality, compared to matched general population controls. Lay summary: Currently, the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) is unknown. This nationwide cohort study evaluated the risk of all-cause and cause-specific mortality in pediatric and young adult patients in Sweden with biopsy-confirmed NAFLD, compared to matched general population controls. We found that compared to controls, children and young adults with biopsy-confirmed NAFLD and NASH have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality.
Article
Background Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. Primary-care physicians (PCPs) play a key role in identifying patients requiring specialist referral. In this study, we aim to determine PCPs’ practice patterns for paediatric NAFLD, as knowledge gaps have been reported for adult NAFLD. Methods A survey was sent to 60 PCPs in the Eastern Ontario Network from July 2019 to January 2020. Results Thirty-seven (62%) PCPs responded to the survey. Twenty-one incorrectly considered the prevalence of paediatric NAFLD to be ≤10%. The majority (35/36) cared for less than five paediatric NAFLD patients. Thirty-four (92%) were only ‘slightly familiar’ or ‘not familiar at all’ with paediatric NAFLD. Only one PCP routinely screens for NAFLD. Only one PCP was aware of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) clinical guidelines for paediatric NAFLD. Twenty-five (68%) correctly selected lifestyle modifications as a treatment option. Lack of confidence in the knowledge of NAFLD was the most common barrier for managing paediatric cases. Conclusion The majority of PCPs are not screening for paediatric NAFLD and are not familiar with its clinical spectrum, citing a lack of knowledge regarding NAFLD as the greatest barrier. This may cause delays in diagnosis and a presentation with advanced fibrosis at the time of specialist referral. Dissemination and implementation of clinical guidelines have the potential to improve knowledge and screening rates for NAFLD in children at the primary-care level.
Article
Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in children, paralleling the increasing prevalence of obesity worldwide. The pathogenesis of paediatric NAFLD is not fully understood, but it is known that obesity, nutrition, lifestyle variables, genetic and epigenetic factors may be causally involved in the development of this common metabolic liver disease. In particular, obesity and nutrition are among the strongest risk factors for paediatric NAFLD, which may exert their adverse hepatic effects already before birth. Excess energy intake induces hypertrophy and hyperplasia of adipose tissue with subsequent development of systemic insulin resistance, which is another important risk factor for NAFLD. Diet composition and in particular simple carbohydrate intake (especially high fructose intake) may promote the development of NAFLD, whereas non-digestible carbohydrates (dietary fiber), by affecting gut microbiota, may favour the integrity of gut wall and reduce inflammation, opposing this process. Saturated fat intake may also promote NAFLD development, whereas unsaturated fat intake has some beneficial effects. Protein intake does not seem to affect the development of NAFLD, but further investigation is needed. In conclusion, lifestyle modifications to induce weight loss, through diet and physical activity, remain the mainstay of treatment for paediatric NAFLD. The use of dietary supplements, such as omega-3 fatty acids and probiotics, needs further study before recommendation.
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Children with obesity are at risk for numerous health problems, including nonalcoholic fatty liver disease (NAFLD). This review focuses on progress made in the epidemiology of NAFLD in children for the years 2015–2020. The estimated prevalence of NAFLD in children with obesity is 26%. The incidence of NAFLD in children has risen rapidly over the past decade. An understanding of the reasons for this rise is incomplete, but over the past 5 years, many studies have provided additional insight into the complexity of risk factors, diagnostic approaches, and associated comorbidities. Risk factors for NAFLD are wide-ranging, including perinatal factors involving both the mother and newborn, as well as environmental toxin exposure. Progress made in the noninvasive assessment will be critical to improving issues related to variability in approach to screening and diagnosis of NAFLD in children. The list of serious comorbidities observed in children with NAFLD continues to grow. Notably, for many of these conditions, such as diabetes and depression, the rates observed have exceeded the rates reported in children with obesity without NAFLD. Recent advancements reviewed show an increased awareness of this problem, while also calling attention to the need for additional research to guide successful efforts at prevention and treatment.
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Introduction The pediatric obesity epidemic is associated with early development of hepatic macrosteatosis, a hallmark of non-alcoholic fatty LI disease, which is thought to be more rapidly progressive in children than adults. Macrosteatosis in adult allografts is associated with allograft loss, but this has not been examined in pediatric donors. Methods We studied all pediatric potential whole LI donors (2005–2018) who had a LI biopsy in the SRTR (n = 862) and whose LI was transplanted (n = 862). Macrosteatosis was abstracted from biopsy reports and compared to values in the SRTR standard analytic file. Recipients of macrosteatotic pediatric allografts were matched 1:1 to recipients of non-macrosteatotic pediatric allografts by propensity score matching on donor/recipient variables. All-cause allograft loss was estimated via Kaplan–Meier analysis and Cox proportional hazards model. Results From 2005 to 2018, the proportion of pediatric donors (age ≥2 years) with obesity increased (14.8% to 21.7%; p < .001), as did the proportion of pediatric deceased whole LI-only donor allografts with macrosteatosis (n = 10 648; 1.8% to 3.9%; p < .001). The median degree of macrosteatosis among macrosteatotic donors was 10% (IQR 5–30). There were no significant differences in all-cause allograft loss between recipients of pediatric LI allografts with and without macrosteatosis at 90 days (p = .11) or 1 year (p = .14) post-transplant in Kaplan–Meier analysis or a Cox proportional hazards model (p > .05). Conclusion Obese pediatric LI donors have increased over time and were more likely to have hepatic macrosteatosis; however, pediatric macrosteatosis did not appear to adversely affect recipient outcomes.
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American Indians and Alaska Natives (AI/AN) are underserved populations who suffer from several health disparities, 1 of which is cancer. Malignancies, especially cancers of the breast, liver, and lung, are common causes of death in this population. Health care disparities in this population include more limited access to diagnostic radiology because of geographic and/or health system limitations. Early detection of these cancers may be enabled by improving patient and physician access to medical imaging. Awareness by the radiology community of the cancer disparities among this population is needed to support research targeted to this specific ethnic group and to support outreach efforts to provide more imaging opportunities. Providing greater access to imaging facilities will also improve patient compliance with screening recommendations, ultimately improving mortality in these populations.
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Non-alcoholic fatty liver disease (NAFLD) is a heterogeneous condition with a wide spectrum of clinical presentations and natural history and disease severity. There is also substantial inter-individual variation and variable response to a different therapy. This heterogeneity of NAFLD is in turn influenced by various factors primarily demographic/dietary factors, metabolic status, gut microbiome, genetic predisposition together with epigenetic factors. The differential impact of these factors over a variable period of time influences the clinical phenotype and natural history. Failure to address heterogeneity partly explains the sub-optimal response to current and emerging therapies for fatty liver disease. Consequently, leading experts across the globe have recently suggested a change in nomen- clature of NAFLD to metabolic-associated fatty liver disease (MAFLD) which can better reflect current knowledge of heterogeneity and does not exclude conco- mitant factors for fatty liver disease (e.g. alcohol, viral hepatitis, etc.). Precise identification of disease phenotypes is likely to facilitate clinical trial recruitment and expedite translational research for the development of novel and effective therapies for NAFLD/MAFLD.
Article
Background & aims: To date, no pharmacotherapy exists for pediatric nonalcoholic fatty liver disease (NAFLD). Losartan, an angiotensin II receptor blocker, has been proposed as a treatment due to its anti-fibrotic effects. Approach & results: The Nonalcoholic Steatohepatitis Clinical Research Network conducted a multicenter, double-masked, placebo-controlled, randomized clinical trial in children with histologically-confirmed NAFLD at 10 sites (September 2018- April 2020). Inclusion criteria were age 8-17 years, histologic NAFLD activity score ≥3, and serum alanine aminotransferase (ALT) ≥50 U/L. Children received 100 mg of losartan or placebo orally once daily for 24 weeks. The primary outcome was change in ALT levels from baseline to 24 weeks and the pre-set sample size was n=110. Treatment effects were assessed using linear regression of change in treatment group adjusted for baseline value. 83 participants (81% male, 80% Hispanic) were randomized to losartan (n=43) or placebo (n=40). During an enrollment pause, necessitated by the COVID-19 pandemic, an unplanned interim analysis showed low probability (7%) of significant group difference. The Data and Safety Monitoring Board recommended early study termination. Baseline characteristics were similar between groups. The 24-week change in ALT did not differ significantly between losartan vs. placebo groups (adjusted mean difference: 1.1 U/L; 95% CI=-30.6, 32.7; p=0.95), although alkaline phosphatase decreased significantly in the losartan group (adjusted mean difference: -23.4 U/L; 95% CI=-41.5, -5.3; p=0.01). Systolic blood pressure decreased in the losartan group but increased in placebo (adjusted mean difference: -7.5 mmHg; 95% CI=-12.2, -2.8; p=0.002). Compliance by pill counts and numbers and types of adverse events did not differ by group. Conclusion: Losartan did not significantly reduce ALT in children with NAFLD when compared to placebo.
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Nonalcoholic steatohepatitis (NASH) is part of a spectrum of conditions collectively referred to as nonalcoholic fatty liver disease (NAFLD). NASH/NAFLD is the most common chronic liver disease. NASH is defined as ≥5% hepatic steatosis along with hepatocellular injury. Histopathological features that indicate hepatocellular injury in NASH include ballooning degeneration, lobular inflammation, and apoptotic bodies. Scoring schemes, such as the NASH Clinical Research Network (CRN), use those histopathological features to grade the severity of the disease and determine a stage based on the amount of fibrosis. Among the NAFLD spectrum, NASH has the highest risk of developing fibrosis and progressing to liver cirrhosis. Therefore, accurate and timely diagnosis is crucial in order to initiate therapy and prevent disease complications as well as liver-related mortality. Although several imaging modalities and laboratory assays have been introduced to diagnose NASH, a liver biopsy remains the gold standard for diagnosing, grading, and staging the disease.
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Objectives: The significance of antinuclear antibody (ANA) positivity in pediatric Hispanic patients with nonalcoholic fatty liver disease (NAFLD) is unknown. Methods: ANA status was correlated with clinical, laboratory, and histologic parameters in Hispanic patients with a histologic diagnosis of NAFLD. Results: Thirty-eight Hispanic children (27 male and 11 female) underwent liver biopsy at a median age of 12.1 years. Twenty patients (53%) had positive ANAs. The ANA-positive patients had higher fasting insulin levels (median [interquartile range (IQR)], 32.4 [25.4] µU/mL) and higher insulin resistance (median [Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) IQR], 5.9 [3.1]) than the ANA-negative patients (fasting insulin: median [IQR], 17 [13.9] µU/mL and median [HOMA-IR IQR], 3.5 [2.6] µU/mL; P = .05 and .01, respectively). Serum high-density lipoprotein (HDL) cholesterol levels were higher in the ANA-negative patients (median [IQR], 47 [18] mg/dL) than the ANA-positive patients (38 [12] mg/dL) (P = .03). There were no statistical differences in a series of demographic, clinical, laboratory, and histologic parameters between the ANA-positive and the ANA-negative patients. At a median follow-up of 2.6 years, alanine aminotransferase was significantly lower than the baseline levels in both groups. In 1 patient undergoing ANA retesting, the titer had normalized from a baseline of 1:1,280 3.8 years earlier. Conclusions: In pediatric Hispanic patients with NAFLD, a positive ANA result is associated with insulin resistance and lower HDL cholesterol levels.
Article
Non-alcoholic fatty liver disease (NAFLD) is becoming an increasingly important healthcare issue along with the rising rates of obesity worldwide. It is the most common chronic liver disease in the paediatric population and the fastest growing indication for liver transplant in young adults. The pathogenesis is complex with contributions from multiple factors and genetic predisposition. While non-invasive laboratory tests and imaging modalities are being increasingly used, the liver biopsy continues to play a crucial role in the diagnosis and prognosis of NAFLD. Histologically, the assessment of paediatric fatty liver disease requires special considerations with respect to a periportal predominant pattern seen in prepubertal patients, as well as a different set of disease processes in the differential diagnosis. In this review, we provide a summary of current knowledge on the epidemiology, pathogenesis and clinical course of paediatric NAFLD as well as the clinical guidelines on diagnosis and management. We discuss the indications and limitations of liver biopsy, histological patterns seen in paediatric NAFLD, other entities to be considered in the differential diagnosis, and conclude with appropriate triaging of liver biopsies and essential elements of pathology reporting.
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Background and aims: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Large pediatric studies identifying single nucleotide polymorphisms (SNPs) associated with risk and histologic severity of NAFLD are limited. Study aims included investigating SNPs associated with risk for NAFLD using family trios and association of candidate alleles with histologic severity. Approach and results: Children with biopsy-confirmed NAFLD were enrolled from the NASH Clinical Research Network. The Expert Pathology Committee reviewed liver histology. Genotyping was conducted with allele specific primers for 60 candidate SNPs. Parents were enrolled for trio analysis. To assess risk for NAFLD, the transmission disequilibrium test was conducted in trios. Among cases, regression analysis assessed associations with histologic severity. 822 children with NAFLD had mean age 13.2 years (SD 2.7) and mean ALT 101 U/L (SD 90). PNPLA3 (rs738409) demonstrated the strongest risk (p = 2.24x10-14 ) for NAFLD. Among children with NAFLD, stratifying by PNPLA3 s738409 genotype, the variant genotype associated with steatosis (p=0.005), lobular (p=0.03) and portal inflammation (p=0.002). Steatosis grade associated with TM6SF2 (p=0.0009), GCKR (p=0.0032), PNPLA3 rs738409 (p=0.0053), and MTTP (p=0.0051). Fibrosis stage associated with PARVB rs6006473 (p=0.0001), NR1I2 (p=0.0021), ADIPOR2 (p=0.0038), and OXTR (p=0.0065). PNPLA3 rs738409 (p=0.0002) associated with borderline zone 1 NASH. Conclusions: This study demonstrated novel disease-associated SNPs in children with NAFLD. In particular, rs6006473 was highly associated with severity of fibrosis. These hypothesis-generating results support future mechanistic studies of development of adverse outcomes such as fibrosis and generation of therapeutic targets for NAFLD in children.
Article
The prevalence of nonalcoholic fatty liver disease (NAFLD) and the more severe and inflammatory type, nonalcoholic steatohepatitis (NASH), is increasing rapidly. Especially in high‐risk patients, that is those with obesity, metabolic syndrome, and type 2 diabetes mellitus, the prevalence of NAFLD can be as high as 80% while NASH may be present in 20% of these subjects. With the worldwide increase of obesity, it is most likely that these numbers will rise. Since advanced stages of NAFLD and NASH are strongly associated with morbidity and mortality—in particular, cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma—it is of great importance to identify subjects at risk. A great variety of noninvasive tests has been published to diagnose NAFLD and NASH, especially using blood‐ and imaging‐based tests. Liver biopsy remains the gold standard for NAFLD/NASH. This review aims to summarize the different mechanisms leading to NASH and liver fibrosis, the different noninvasive liver tests to diagnose and evaluate patients with severe obesity.
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The objective of this study was to investigate the effect of dietary fatty acid (FA) composition on bile acid (BA) metabolism in a pig model of NAFLD, by using a multiomics approach combined with histology and serum biochemistry. Thirty 20-d-old Iberian pigs pair-housed in pens were randomly assigned to receive 1 of 3 hypercaloric diets for 10 weeks: 1) lard-enriched (LAR; n=5 pens), 2) olive oil-enriched (OLI, n=5), and 3) coconut oil-enriched (COC; n=5). Animals were euthanized on week 10 after blood sampling, and liver, colon and distal ileum (DI) were collected for histology, metabolomics, and transcriptomics. Data were analyzed by multivariate and univariate statistics. Compared with OLI and LAR, COC increased primary and secondary BAs in liver, plasma and colon. In addition, both COC and OLI reduced circulating fibroblast growth factor 19, increased hepatic necrosis, composite lesion score, and liver enzymes in serum, and upregulated genes involved in hepatocyte proliferation and DNA repair. The severity of liver disease in COC and OLI pigs was associated with increased levels of phosphatidylcholines, medium-chain triacylglycerides, trimethylamine-N-oxide, and long-chain acylcarnitines in the liver, and the expression of pro-fibrotic markers in DI, but not with changes in the composition or size of BA pool. In conclusion, our results indicate a role of dietary FAs in the regulation of BA metabolism and progression of NAFLD. Interventions that aim to modify the composition of dietary FAs, rather than to regulate BA metabolism or signaling, may be more effective in the treatment of NAFLD.
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The prevalence of nonalcoholic fatty liver disease (NAFLD) continues to increase rapidly, and NAFLD has become the most common cause of chronic liver disease in children and young people. Closely associated with the rise in obesity, the precise aetiology and pathophysiology of NAFLD are not fully understood. Both genetic and environmental factors contribute to the development of the disease. The diagnosis of NAFLD is one of exclusion and made on histology however such as the potential prevalence of the disease that biopsy is not always practical – thus, there is a need to further develop noninvasive biomarkers to reliably identify and stage the disease. The histological pattern of the disease in children and young people frequently differs from that found in adults. Long-term outcome is not yet certain; however, significant nonalcoholic steatohepatitis may progress to end-stage liver disease and/or hepatocellular carcinoma. Management in children and young people is largely focused on lifestyle change; however, there are emerging pharmacological therapies under investigation.
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Whole body insulin resistance results largely from impaired insulin-stimulated glucose disposal into skeletal muscle. We carried out muscle gene expression profiling to identify differentially expressed genes associated with insulin resistance. Skeletal muscle total RNA samples from six pairs of non-diabetic insulin-resistant and insulin-sensitive Pima Indians matched for percent body fat were analyzed by DDPCR with 90 primer combinations. The mRNA expression concentrations of selected 13 known genes and four expressed sequences tags were measured by quantitative real-time RT-PCR in 50 non-diabetic Pima subjects. From over 6500 displayed DDPCR cDNA bands, 36 of the most differentially expressed cDNAs were identified, revealing 29 unique sequences: 16 known genes, 10 expressed sequences tags and three unknown transcripts. Multiple regression analyses indicated that whole body insulin-mediated glucose disposal rates of the subjects, independent of age, sex, and percent body fat, were negatively correlated with mRNA concentrations of an EST (DD23; r=-0.38, p=0.007), ATP1A2 (r=-0.27, p=0.05), MAP2K4 (r=-0.34, p=0.02), and PRPSAP1 (r=-0.37, p=0.008). Transcript concentrations of DD23 (r=0.27, p=0.05) and MTND4 (r=-0.29, p=0.05) were correlated with plasma insulin concentration, independent of age, sex, and percent body fat. Altered expression concentrations of these genes might be causes or consequences of insulin resistance, and these genes serve as candidate susceptibility genes for insulin resistance.
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We present the fourth case of an adult man (29 yr old) affected by aromatase deficiency resulting from a novel homozygous inactivating mutation of the CYP19 (P450arom) gene. At first observation, continuing linear growth, eunuchoid body proportions, diffuse bone pain, and bilateral cryptorchidism were observed. The patient presented also a complex dysmetabolic syndrome characterized by insulin resistance, diabetes mellitus type 2, acanthosis nigricans, liver steatohepatitis, and signs of precocious atherogenesis. The analysis of the effects induced by the successive treatment with high doses of testosterone, alendronate, and estradiol allows further insight into the roles of androgens and estrogens on several metabolic functions. High doses of testosterone treatment resulted in a severe imbalance in the estradiol to testosterone ratio together with the occurrence of insulin resistance and diabetes mellitus type 2. Estrogen treatment resulted in an improvement of acanthosis nigricans, insulin resistance, and liver steatohepatitis, coupled with a better glycemic control and the disappearance of two carotid plaques. Furthermore, the study confirms previous data concerning the key role of estrogens on male bone maturation, at least in part, and regulation of gonadotropin secretion. The biopsy of the testis showed a pattern of total germ cell depletion that might be due to the concomitant presence of bilateral cryptorchidism. Thus, a possible role of estrogen in male reproductive function is suggested but without revealing a direct cause-effect relationship. Data from this case provide new insights into the role of estrogens in glucose, lipid, and liver metabolism in men. This new case of aromatase deficiency confirms previous data on bone maturation and mineralization, and it reveals a high risk for the precocious development of cardiovascular disease in young aromatase-deficient men.
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Genetically obese fatty/fatty rats and obese/obese mice exhibit increased sensitivity to endotoxin hepatotoxicity, quickly developing steatohepatitis after exposure to low doses of lipopolysaccharide (LPS). Among obese animals, females are more sensitive to endotoxin liver injury than males. LPS induction of tumor necrosis factor alpha (TNF alpha), the proven affecter of endotoxin liver injury, is no greater in the livers, white adipose tissues, or sera of obese animals than in those of lean controls. Indeed, the lowest serum concentrations of TNF occur in female obese rodents, which exhibit the most endotoxin-induced liver injury. Several cytokines that modulate the biological activity of TNF are regulated abnormally in the livers of obese animals. After exposure to LPS, mRNA of interferon gamma, which sensitizes hepatocytes to TNF toxicity, is overexpressed, and mRNA levels of interleukin 10, a TNF inhibitor, are decreased. The phagocytic activity of liver macrophages and the hepatic expression of a gene encoding a macrophage-specific receptor are also decreased in obesity. This new animal model of obesity-associated liver disease demonstrates that hepatic macrophage dysfunction occurs in obesity and suggests that this might promote steatohepatitis by sensitizing hepatocytes to endotoxin.
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Nonalcoholic fatty liver disease is now recognized as the most common liver disease in the United States, with a prevalence of approximately 5% in the general population and up to 25% to 75% in patients with obesity and type II diabetes mellitus. Nonalcoholic fatty liver disease is a clinicopathologic syndrome with a wide spectrum of histologic abnormalities and clinical outcomes. Hepatic steatosis has a benign clinical course. In contrast, nonalcoholic steatohepatitis (NASH) may progress to cirrhosis and liver-related death in 25% and 10% of patients, respectively. Cases occur most commonly in obese, middle-aged women with diabetes. However, NASH may also occur in children and normal-weight men with normal glucose and lipid metabolism. The pathophysiology involves two steps. The first is insulin resistance, which causes steatosis. The second is oxidative stress, which produces lipid peroxidation and activates inflammatory cytokines resulting in NASH. Liver biopsy provides prognostic information and identifies NASH patients who may benefit from therapy. Treatment consists of managing the comorbidities: obesity, diabetes, and hyperlipidemia. Although antioxidant therapy with vitamin E is often used, ursodeoxycholic acid is the only drug that has shown benefit and is the most promising of the drugs currently being investigated. Future therapies will depend on a greater understanding of the pathophysiology and should focus on diminishing fibrosis.
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Fatty liver is a common cause of liver disease in children. However, the epidemiology of pediatric fatty liver is limited to single-center case series of nonalcoholic fatty liver disease (NAFLD). Obesity and insulin resistance are major established risk factors for NAFLD. The role of gender, race, and ethnicity on the prevalence of fatty liver in obese children is unknown. We recruited obese 12th-grade participants from the Child and Adolescent Trial for Cardiovascular Health in California, Louisiana, Minnesota, and Texas. Serum samples were collected at school when the participants were well. Alanine aminotransferase (ALT) was measured by kinetic enzymatic assay, and ALT >40 U/L was defined as abnormal. Causes of abnormal ALT other than NAFLD were excluded by serum testing. A total of 127 obese students (73 female, 54 male) had a mean BMI of 35.2 kg/m2. Unexplained ALT elevation was present in 23% of participants overall. The mean ALT for participants with normal values was 28 U/L and for participants with an abnormal ALT was 56 U/L. Abnormal ALT was significantly more prevalent in boys (44%) than in girls (7%). The prevalence of abnormal ALT differed significantly by race and ethnicity (Hispanic: 36%; white: 22%; black: 14%). Serum ALT value was significantly predicted by the combination of gender, race/ethnicity, and BMI. After controlling for gender and BMI, Hispanic ethnicity significantly predicted greater ALT than black race. In a national, school-based sample of obese adolescents, boys were 6 times more likely than girls to have an unexplained elevated ALT. Given that participants were well and causes of chronic liver disease were excluded, we speculate that obese adolescent boys have an increased prevalence of fatty liver compared with obese adolescent girls. This population-based study also supports the hypothesis that NAFLD is more common in Hispanic adolescents. These findings have implications for both disease screening and studies of fatty liver pathophysiology.
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Background/Aims: In the past, nonalcoholic steatohepatitis has been described mostly in obese women with diabetes. The aim of this study was to describe a series of patients with nonalcoholic steatohepatitis with a different clinical profile. Methods: The clinical, biochemical, and histological features of 33 patients with nonalcoholic steatohepatitis seen from July 1990 to June 1993 were analyzed. Results: The mean age was 47 years. All patients were antibody to hepatitis C virusnegative. Nineteen of 33 (58%) were men, 20 of 33 (61%) were nonobese, 26 of 33 (79%) had normal glucose levels, and 26 of 33 (79%) had normal lipid levels. Fourteen of 33 (42%) had normal glucose and lipid levels and were not obese. Thirteen of 33 (39%) had pathological increases in fibrosis, 5 of whom had micronodular cirrhosis. Of these 13 with severe, progressive disease, 8 (62%) were women, 8 (62%) were obese, 4 (31%) were diabetic or had an elevated glucose level, and 3 (23%) had hyperlipidemia. Although serum iron studies (transferrin saturation and ferritin) were abnormal in 18 of 31 (58%), no patient had hemochromatosis. Conclusions: Nonalcoholic Steatohepatitis can be a severe, progressive liver disease leading to the development of cirrhosis. It should no longer be considered a disease predominantly seen in obese women with diabetes.
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To describe the clinical characteristics of nonalcoholic fatty liver disease (NAFLD) in children, including insulin resistance, and to test for correlation with liver pathology. A retrospective review of children with biopsy-proven NAFLD at Children's Hospital San Diego from 1999 to 2002. Liver biopsy specimens were independently reviewed by two pathologists. Children with NAFLD (n=43) were mostly male (70%), Hispanic American (53%) and obese (88%). The criteria for insulin resistance were met by 95% of subjects. Steatosis was predicted by the combination of quantitative insulin sensitivity check index, age, and ethnicity (P<.0001). Portal inflammation was predicted by the combination of ALT and fasting insulin (P=.0009). Perisinusoidal fibrosis was predicted by the combination of AST, fasting insulin, and BMI Z score (P<.0001). Portal fibrosis was predicted by the combination of right upper quadrant pain and homeostasis model assessment of insulin resistance (P=.0028). We identified significant predictors of liver pathology in children with NAFLD. Children being evaluated for NAFLD should be screened for insulin resistance, which is nearly universal and correlates with liver histology.
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Alcohol-like liver injury (ALLI) in non-alcoholics has not been elucidated in Japan. The present study attempted to characterize the clinicopathologic features of ALLI in routine liver biopsies. ALLI was found in 1% of 561 biopsy cases obtained from 1988 to May, 1991 at Kanazawa University Hospital. Laboratory data characteristically showed only a mild to moderate degree of dysfunction, and none of the cases exhibited jaundice. Hepatic histology showed a mild to moderate degree of perivenular, pericellular and/or portal stellate fibrosis with a varying degree of fatty change and inflammatory cell infiltration. Portal stellate fibrosis with a varying degree of cell infiltration was more severe than the centrilobular or pericellular fibrosis in all cases. Intralobular inflammatory cell infiltration was associated with spotty or single hepatocyte necrosis, but extensive hepatocyte necrosis was not observed. Neutrophil infiltration was absent or minimal, and lymphocytes predominated in all cases. Mallory bodies were rare and were found in a few hepatocytes of only one of the 7 cases. The above histologic findings in ALLI were very similar to those seen in liver disease in Japanese alcoholics, and were somewhat different from ALLI reported in Western countries. In cases in which hepatic fibrosis, characterized by pericellular, perivenular or portal stellate fibrosis dominated without apparent hepatic necrosis and inflammation, the term “non-alcoholic steatofibrosis” is more suitable to depict its liver histology, being very similar to the alcoholic fibrosis frequently seen in Japanese alcoholics.
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OJECTIVE: Steatohepatitis is a morphological pattern of liver injury that may be seen in alcoholic or nonalcoholic liver disease. This pattern may occur with obesity, diabetes, the use of certain drugs, or the cause may be idiopathic. The well-recognized histopathological features of nonalcoholic steatohepatitis (NASH) include hepatocellular steatosis and ballooning, mixed acute and chronic lobular inflammation, and zone 3 perisinusoidal fibrosis. Currently, there are no systems for grading necroinflammatory activity or for staging fibrosis as exist for various other forms of chronic liver disease. The purpose of this study was to develop such a grading and staging system and was based on review of liver biopsies from 51 patients with nonalcoholic steatohepatitis from Saint Louis University Health Sciences Center.METHODS: For determination of grade, 10 histological variables of activity were initially analyzed; an overall impression of mild, moderate, and severe was made and the variables considered to be most significant were used to develop the necroinflammatory grade.RESULTS: The histological lesions considered to be significant were: steatosis, ballooning, and intra-acinar and portal inflammation. A staging score was developed to reflect both location and extent of fibrosis. The fibrosis score was derived from the extent of zone 3 perisinusoidal fibrosis with possible additional portal/periportal fibrosis and architectural remodeling. Fibrosis stages are as follows: Stage 1, zone 3 perisinusoidal fibrosis; Stage 2, as above with portal fibrosis; Stage 3, as above with bridging fibrosis; and Stage 4, cirrhosis.CONCLUSION: We propose a grading and staging system that reflects the unique histological features of nonalcoholic steatohepatitis.
Article
Alcohol-like liver injury (ALLI) in non-alcoholics has not been elucidated in Japan. The present study attempted to characterize the clinicopathologic features of ALLI in routine liver biopsies. ALLI was found in 1% of 561 biopsy cases obtained from 1988 to May, 1991 at Kanazawa University Hospital. Laboratory data characteristically showed only a mild to moderate degree of dysfunction, and none of the cases exhibited jaundice. Hepatic histology showed a mild to moderate degree of perivenular, pericellular and/or portal stellate fibrosis with a varying degree of fatty change and inflammatory cell infiltration. Portal stellate fibrosis with a varying degree of cell infiltration was more severe than the centrilobular or pericellular fibrosis in all cases. Intralobular inflammatory cell infiltration was associated with spotty or single hepatocyte necrosis, but extensive hepatocyte necrosis was not observed. Neutrophil infiltration was absent or minimal, and lymphocytes predominated in all cases. Mallory bodies were rare and were found in a few hepatocytes of only one of the 7 cases. The above histologic findings in ALLI were very similar to those seen in liver disease in Japanese alcoholics, and were somewhat different from ALLI reported in Western countries. In cases in which hepatic fibrosis, characterized by pericellular, perivenular or portal stellate fibrosis dominated without apparent hepatic necrosis and inflammation, the term "non-alcoholic steatofibrosis" is more suitable to depict its liver histology, being very similar to the alcoholic fibrosis frequently seen in Japanese alcoholics.
Article
Adult obese patients have been reported to present with hepatic abnormalities characterized by fatty hepatitis, fibrosis, and cirrhosis. These abnormalities however, have not been reported to occur in children. We report three obese children with steatohepatitis that presented with nonspecific abdominal pain and abnormal liver-function tests. Obese children should have a thorough investigation of their liver function even in the absence of symptoms or signs.
Article
To describe the clinical, laboratory, and histopathologic features of idiopathic steatohepatitis in children. Retrospective review of all liver biopsies performed at Boston Children's Hospital, Massachusetts General Hospital, and the University of Massachusetts Medical Center from 1991 to 1994. Chart review was performed when biopsies demonstrated steatosis. Eighty-two patients had biopsy-proven hepatic steatosis. Fourteen patients had fatty liver without evidence of inherited, infectious, autoimmune, endocrinologic, toxicologic, or iatrogenic causes. All 14 patients were obese, averaging 159% of ideal body weight (range, 121% to 222%). Nine patients initially had transient abdominal pain, two had hepatomegaly, and one was identified by incidental laboratory evaluation. These 12 patients had biopsies because of persistent elevations of aminotransferase levels. Two other patients without risk factors for steatosis were identified at staging laparotomy for Hodgkin lymphoma. The 10 boys and 4 girls had an average age of 13.5 years (range, 10 to 18 years). Aminotransferase elevations were modest, with aspartate aminotransferase and alanine aminotransferase values averaging 77 +/- 38 IU and 129 +/- 73 IU, respectively. All had imaging studies demonstrating diffuse fatty change. Histologic examination of biopsy specimens revealed varying degrees of steatosis with inflammation and fibrosis. Idiopathic steatohepatitis occurs predominantly or exclusively in obese peripubertal children. This entity represents a frequent reason for liver biopsy in this age group. The degree of steatosis, fibrosis, and inflammation does not correlate with symptoms or signs, and significant liver injury with bridging fibrosis may be present.
Article
In the past, nonalcoholic steatohepatitis has been described mostly in obese women with diabetes. The aim of this study was to describe a series of patients with nonalcoholic steatohepatitis with a different clinical profile. The clinical, biochemical, and histological features of 33 patients with nonalcoholic steatohepatitis seen from July 1990 to June 1993 were analyzed. The mean age was 47 years. All patients were antibody to hepatitis C virus-negative. Nineteen of 33 (58%) were men, 20 of 33 (61%) were nonobese, 26 of 33 (79%) had normal glucose levels, and 26 of 33 (79%) had normal lipid levels. Fourteen of 33 (42%) had normal glucose and lipid levels and were not obese. Thirteen of 33 (39%) had pathological increases in fibrosis, 5 of whom had micronodular cirrhosis. Of these 13 with severe, progressive disease, 8 (62%) were women, 8 (62%) were obese, 4 (31%) were diabetic or had an elevated glucose level, and 3 (23%) had hyperlipidemia. Although serum iron studies (transferrin saturation and ferritin) were abnormal in 18 of 31 (58%), no patient had hemochromatosis. Nonalcoholic steatohepatitis can be a severe, progressive liver disease leading to the development of cirrhosis. It should no longer be considered a disease predominantly seen in obese women with diabetes.
Article
A prospective study of 21 patients with the diagnosis of non-alcoholic steatohepatitis (NASH) was carried out. All patients had hepatomegaly and in 10 (48%) image studies were consistent with steatosis and/or fibrosis. Biochemically, there was increase of AST, ALT and cholesterol in 48%, of GGT in 52% and of alkaline phosphatase in 38%. 18 patients were obese, 2 of them diabetic, 2 others had a history of exposure to drugs (amiodarone and isopropilic alcohol) and the last one presented hypothyroidism. Liver biopsies were studied using a semiquantitative scale to evaluate the degree of steatosis, inflammation and fibrosis in a scale from 1 to 3. Results showed a medium score of 2.6 for steatosis, 1.5 for inflammation and 1.8 for fibrosis. Four patients had cirrhosis and Mallory bodies were found in 11 cases (52%). NASH is an oligosymptomatic disease that can be found in different clinical conditions, mainly obesity, and is more frequent in women. It is histologically indistinguishable from alcoholic steatohepatitis. It is frequently underdiagnosed clinically and must be taken into account as a possible cause of cryptogenetic cirrhosis.
Article
NASH is a form of chronic liver disease that is defined by biopsy findings and has the appearance of alcoholic hepatitis. Although this disease was once thought to be a problem of women, diabetics, and the obese, more recent studies have identified a significant proportion of patients who do not fit these risk factors. In a fraction of patients, the disease can progress to various stages of fibrosis leading ultimately to cirrhosis and death from end-stage liver disease. For this reason, recognition of NASH is important and provides a further impetus for performing a liver biopsy as part of the evaluation of unexplained liver biochemical abnormalities. The mainstay of treatment is weight reduction in the obese. For those individuals who are not obese, continued observation is the only available option at this point. With increasing knowledge about the pathophysiology of hepatic steatosis, perhaps more specific diagnostic tests for the cause of the disease in specific patients will be available and will guide appropriate therapy.
Article
The metabolic syndrome X, characterized by insulin resistance, dyslipidemia, hypertension, and a male, visceral distribution of adipose tissue, is associated with increased morbidity and mortality from several prevalent diseases, such as diabetes, cancers, myocardial infarction, and stroke. Because the liver has a central role in carbohydrate, lipid, and steroid metabolism, we investigated the relationships between liver pathology and the metabolic syndrome. Blood chemistry, anthropometry (waist/hip circumference ratio), and intraoperative routine knife biopsies of the liver were obtained in 551 (112 men) severely obese patients (body mass index, 47 +/- 9; mean +/- SD) undergoing antiobesity surgery. Steatosis was found in 86%, fibrosis in 74%, mild inflammation or steatohepatitis in 24%, and unexpected cirrhosis in 2% (n = 11) of the patients. The risk of steatosis was 2.6 times greater in men than in women (P < 0.0001). With each addition of 1 of the 4 components of the metabolic syndrome, elevated waist/hip ratio, impaired glucose tolerance, hypertension, and dyslipidemia, the risk of steatosis increased exponentially from 1- to 99-fold (P < 0.001). Fibrosis correlated with steatosis (r = 0.56; P < 0.0001), whereas patients with diabetes or impaired glucose tolerance had a 7-fold increased risk of fibrosis (P < 0.0001). Diabetes, steatosis, and age were all significant indicators of cirrhosis, whereas inflammation was only associated with age. We conclude that the metabolic syndrome via impaired glucose tolerance is strongly correlated with steatosis, fibrosis, and cirrhosis of the liver.
Article
Nonalcoholic steatohepatitis (NASH) may present with increased hepatic fibrosis progressing to end-stage liver disease. No factors that determine increasing fibrosis and histologically advanced disease have been recognized, thus, liver biopsy is recommended in all patients for diagnosis and prognosis. Our aim was to identify independent predictors of severe hepatic fibrosis in patients with NASH. One hundred and forty-four patients were studied. All patients underwent liver biopsy. Clinical and biochemical variables were examined with univariate and multivariate analysis. Thirty-seven (26%) patients had no abnormal fibrosis, 53 (37%) had mild fibrosis, 15 (10%) had moderate fibrosis, 14 (10%) had bridging fibrosis, and 25 (17%) had cirrhosis. In multivariate analysis, older age (P =. 001), obesity (P =.002), diabetes mellitus (P =.009), and aspartate transaminase/alanine transaminase (AST/ALT) ratio greater than 1 (P =.03) were significant predictors of severe liver fibrosis (bridging/cirrhosis). Body mass index (P =.003) was the only independent predictor of the degree of fat infiltration. Increased transferrin saturation correlated positively with the severity of fibrosis (P =.02) in univariate analysis, and there was a trend for more female patients among those with more advanced fibrosis (P =. 09). However, iron studies or gender were not significant when controlled for age, obesity, diabetes, and AST/ALT ratio. In conclusion, older age, obesity, and presence of diabetes mellitus help identify those NASH patients who might have severe liver fibrosis. This is the subgroup of patients with NASH who would be expected to derive the most benefit from having a liver biopsy and considering investigational therapies.
Article
Nonalcoholic steatohepatitis occurs commonly in adults with obesity or diabetes mellitus. There are only a few reports of this condition in children. Prospective consecutive clinical series. Between December 1985 and April 1995, 36 children (21 boys, 15 girls) were diagnosed with nonalcoholic steatohepatitis at the Hospital for Sick Children, Toronto. The median age at diagnosis was 12 years (range, 4-16 years). Most patients were referred because of elevated serum aminotransferases or abnormal hepatic sonogram. Thirty patients (83%) were obese. Two patients had diabetes mellitus at diagnosis, and it developed later in two. Fifteen patients had palpable hepatomegaly, and one of these had splenomegaly. None had physical signs of chronic liver disease. Thirteen of 36 patients had acanthosis nigricans. Serum aminotransferases were elevated in all but one patient. Tests for Wilson disease and chronic hepatitis B and C were negative. Serum lipid profiles were abnormal in 18 patients: 7 had hypercholesterolemia, and 11 had hypertriglyceridemia. Twenty-four of 31 examined had abnormal liver sonograms suggestive of fatty infiltration. Twenty-four patients underwent percutaneous liver biopsy: all showed large-droplet fat. Inflamm