Non-alcoholic steatohepatitis in children

Obesity has emerged as a significant new health problem in the pediatric population. Non-alcoholic steatohepatitis (NASH) is an entity in the spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from fat in the liver -- simple steatosis, NASH/ steatohepatitis -- fat with inflammation and/or fibrosis to advanced fibrosis and cirrhosis when fat may no longer be present. NASH is associated with obesity, diabetes, insulin resistance (IR), and hypertriglyceridemia. While majority of individuals with risk factors like obesity and IR have steatosis only a minority develop steatohepatitis, possible mechanisms have been discussed. Clinical experience with pediatric NASH is limited. Children generally present in the prepubertal age group, have a male predominance with a higher incidence in children of Hispanic origin. Body mass index (BMI) of 25-29.9 is considered to be overweight and that > or =30 obese. Acanthosis nigricans as a marker of IR should be looked for. As NASH is a diagnosis of exclusion, other causes of chronic liver disease must be excluded. Increased echogenicity in the liver is noted on ultrasound. Liver biopsy is considered the gold standard in establishing the diagnosis. Histopathological lesions thought to be necessary for diagnosis of NASH include steatosis (macrovesicular > microvesicular), mixed mild lobular inflammation and hepatocyte ballooning. A system of grading depending on degree of steatosis and/or inflammation and staging depending on the extent of fibrosis has also been proposed. Although there is no consensus for the treatment for NASH, effort needs to be made to prevent development of fibrosis, which results in cirrhosis and portal hypertension. Slow, consistent weight loss has been shown to be effective in childhood NAFLD, based on improvement of serum aminotransferases or liver sonogram. A low glycemic index diet has been shown to be more effective than a low fat diet in lowering BMI. Family based behavioral intervention may also enhance success with diet. Several pharmacological agents have been used including ursodeoxycholic acid, vitamin E, betaine, n-acetyl cysteine, and insulin sensitizing agents like metformin, rosiglitazone, and pioglitazone. Transplantation for overt NASH is rare, accounting for < 1% of liver transplantations in the USA. The disease can recur after liver transplantation. A strong association exists between the presence of steatosis in a donor liver and poor graft function. As a result, cadaveric donor livers with macrovesicular steatosis >40% are not used routinely. Prognosis in NASH is dependent not only on severity and number of risk factors but also on the degree of histological damage. Clinical trials are needed to identify an effective treatment that halts the progression of NAFLD to NASH in both pretransplantation and post-transplantation patients.     

Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research

Although population prevalence is very difficult to establish, nonalcoholic fatty liver disease (NAFLD) is probably the most common cause of liver disease in the preadolescent and adolescent age groups. There seems to be an increase in the prevalence of NAFLD, likely related to the dramatic rise in the incidence of obesity during the past 3 decades. Despite an increase in public awareness, overweight/obesity and related conditions, such as NAFLD, remain underdiagnosed by health care providers. Accurate diagnosis and staging of nonalcoholic steatohepatitis (NASH) requires liver biopsy. The development of noninvasive surrogate markers and the advancements in imaging technology will aid in the screening of large populations at risk for NAFLD. Two distinct histological patterns of NASH have been identified in the pediatric population, and discrete clinical and demographic features are observed in children with these 2 patterns. The propensity for NASH to develop in obese, insulin-resistant pubertal boys of Hispanic ethnicity or a non-Hispanic white race may provide clues to the pathogenesis of NAFLD in children. The natural history of pediatric NASH has yet to be defined, but most biopsies in this age group demonstrate some degree of fibrosis. In addition, cirrhosis can be observed in children as young as 10 years. While the optimal treatment of pediatric NAFLD has yet to be determined, lifestyle modification through diet and exercise should be attempted in children diagnosed with NAFLD. A large, multicenter trial of vitamin E and metformin is underway as part of the NASH clinical research network.     

Pediatric non-alcoholic fatty liver disease: an increasing public health issue

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition that encompasses a wide spectrum of liver abnormalities ranging from simple liver steatosis to steatohepatitis (non-alcoholic steatohepatitis), which may be associated with fibrosis and progress to cirrhosis and end-stage liver disease. NAFLD has recently become the most common cause of chronic liver disease in children and adolescents. NAFLD prevalence, alongside obesity, continues to increase among pediatric patients. Obesity is believed to represent a major risk factor for NAFLD, which is considered to be the liver presentation of the metabolic syndrome. Although the pathogenesis of NAFLD is not fully understood, the notion that multiple factors affect disease development and progression is widely accepted. Both genetic background and environmental factors contribute to NAFLD development. A more complete understanding of the pathogenesis may aid in developing non-invasive diagnostic tools and identifying new therapeutic targets. Liver biopsy currently remains the gold standard for NAFLD diagnosis and staging. Although lifestyle and diet modifications are key in NAFLD treatment, the development of new pharmacological therapies is crucial for patients who are unresponsive to first-line therapy. Conclusion: Pediatric NAFLD is an increasing public health issue that remains underdiagnosed. A large-scale screening in the high-risk population, especially among the overweight pediatric patients, should be considered, including measurement of serum transaminases and liver ultrasound. It is crucial to treat this condition as soon as possible in order to avoid the progression to end-stage liver disease.     

Pediatric non-alcoholic fatty liver disease: recent advances and challenges

Non-alcoholic fatty liver disease (NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes. A more advanced form of NAFLD, non-alcoholic steatohepatitis (NASH), includes inflammation and liver cell injury, progressive to cryptogenic cirrhosis. Although prevalence in children is very difficult to establish, NAFLD is probably the most common cause of liver disease in preadolescent and adolescent groups. Over the last two decades the rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide. NAFLD is strongly associated with abdominal obesity, type 2 diabetes, and dyslipidemia, and most patients have evidence of insulin resistance. Thus, NAFLD shares many features of the metabolic syndrome, a highly atherogenic condition, and its presence could signify a substantial cardiovascular risk. Accurate diagnosis and staging of NAFLD requires liver biopsy. The development of non-invasive surrogate markers and the advancement in imaging technology will aid in the screening of large populations at risk for NAFLD. While the optimal treatment has yet to be determined, lifestyle modification through diet and exercise should be attempted in children diagnosed with NAFLD. This review outlines current understanding, recent advances and challenges on pediatric NAFLD for both clinicians and researchers. Key words: Fatty liver.     

Fatty Liver Disease in Children—What Should One Do?

The world’s population is increasingly overweight and obese. According to the World Health Organization (WHO) as of 2010, 43 million children under the age of five were overweight. Once considered to be limited to developed countries, overweight and obese children are now found in low- and middle-income countries, though most commonly in urban areas. Furthermore the WHO now cites the conditions of overweight and obesity as being associated with more deaths around the globe than those associated with being underweight. With this increased prevalence of overweight and obese children has come a host of other medical problems including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). This review will focus on NAFLD and NASH, their definitions, epidemiology, diagnosis and treatment. The authors will also discuss NAFLD in the Indian subcontinent, and the future of NAFLD and NASH.     

Recurrence of non-alcoholic steatohepatitis after liver transplantation in a 13-yr-old boy

Nonalcoholic steatohepatitis (NASH) is the most severe form of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to highlight NASH as a rare but possible problem in children. We present a case of 13-yr-boy with a well-established diagnosis of liver cirrhosis secondary to NASH, who underwent orthotopic liver transplantation (OLT) at the age of 13 years. Six months after transplantation recurrence of NASH in the graft was diagnosed. In the treatment metformin was used with good effect.     

Resolution of non‐alcoholic steatohepatitis after growth hormone replacement in a pediatric liver transplant patient with panhypopituitarism

NAFLD is a common condition linked to obesity, type 2 diabetes, and metabolic syndrome. Simple hepatic steatosis is a risk factor for inflammatory reactions in the liver (NASH), which may lead to cirrhosis. While the mechanism is unclear, NAFLD and NASH are associated with panhypopituitarism, which in the pediatric population often results from craniopharyngioma or pituitary adenoma and the sequelae of treatment, causing hypothyroidism, adrenal insufficiency, hypogonadotropic hypogonadism, and GH deficiency. Refractory NAFLD in panhypopituitarism may be amenable to GH replacement. Here, we report a pediatric case of NASH secondary to panhypopituitarism from craniopharyngioma, which recurred by 11 months after LDLT. Despite low‐dose GH replacement, the patient remained GH deficient. Pubertal dosed GH therapy led to rapid and complete resolution of hepatic steatosis, which we tracked using serial ¹H MRS. Pediatric patients with NASH cirrhosis secondary to panhypopituitarism can be good candidates for liver transplantation, but hormone deficiencies predispose to recurrence after transplant. High‐dose GH replacement should be considered in pediatric patients with GH deficiency and recurrent disease. A multidisciplinary team approach is essential for successful outcomes.     

非酒精性脂肪性肝病儿童血清TIMP-1和TIMP-2检测及临床意义

目的：了解非酒精性脂肪性肝病患儿基质金属蛋白酶组织抑制物（TIMP）-1和TIMP-2的水平及价值。方法根据诊断标准将105例肥胖儿童分为单纯性肥胖（n=44）、单纯性非酒精性脂肪肝（SNAFL,n=25）和非酒精性脂肪肝炎（NASH,n=36）3组,采用酶联免疫吸附方法(ELISA)测定血清TIMP-1、TIMP-2,全自动酶法测定丙氨酸氨基转移酶(ALT)和γ-谷氨酸转肽酶(γ-GT)。结果随着单纯性肥胖向SNAFL和NASH发展,TIMP-1和γ-GT水平逐步升高,差异有统计学意义(P0.05)。结论 血清TIMP-1和TIMP-2指标均可不同程度地反映肝脏的纤维化程度,其中以TIMP-1更为可靠、有效。［中国当代儿科杂志,2010,12（6）：455-458］     

Liver steatosis in Polish children assessed by medicolegal autopsies

Background

Cases of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasing in the pediatric population. Their growing prevalence coincides with the obesity epidemic. Assessment of the incidence requires liver biopsies on a representative population sample, which are hampered by the absence of indications for invasive examination on children without clinical symptoms. The aim of the current study was to assess the incidence of liver steatosis in the population of children up to 18 years old from Lower Silesia.

Methods

We retrospectively reviewed 342 medico-legal autopsy reports from 2000 to 2009. We separated a group of 256 children whose death was caused by trauma. Liver steatosis was diagnosed according to the results of histopathological examinations and typical macroscopic imaging.

Results

In the 265 children who died from trauma, liver steatosis was reported in 11 (4.2%) children (6 boys) aged between 6 months and 18 years old. Six of the 11 children (54.5%) were found to be overweight. In all 342 children, steatosis was found in 18 (5.3%) children (13 boys), while NASH was diagnosed in 1 (0.3%). Excess body weight was observed in 55.6% (10/18) of children with steatosis.

Conclusions

Liver steatosis can occur at any age, even in infancy. Being overweight is a very important risk factor. Gross examination of the liver is insufficient for the diagnosis of steatosis because of its lower sensitivity and specificity. Verification of liver steatosis requires reference histopathological examination.     

Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adolescents in the United States, and most probably also in the rest of the industrialized world.As the prevalence of NAFLD in childhood increases with the worldwide obesity epidemic, there is an urgent need for diagnostic standards that can be commonly used by pediatricians and hepatologists. To this end, we performed a PubMed search of the adult and pediatric literature on NAFLD diagnosis through May 2011 using Topics and/or relevant Authors as search words. According to the present literature, NAFLD is suspected based on the association of fatty liver combined with risk factors (mainly obesity), after the exclusion of other causes of liver disease. The reference but imperfect standard for confirming NAFLD is liver histology. The following surrogate markers are presently used to estimate degree of steatosis and liver fibrosis and risk of progression to end-stage liver disease: imaging by ultrasonography or magnetic resonance imaging, liver function tests, and serum markers of liver fibrosis.NAFLD should be suspected in all of the overweight or obese children and adolescents older than 3 years with increased waist circumference especially if there is a NAFLD history in relatives. The typical presentation, however, is in children ages 10 years and older. The first diagnostic step in these children should be abdominal ultrasound and liver function tests, followed by exclusion of other liver diseases. Overweight/obese children with normal ultrasonographic imaging and normal liver function tests should still be monitored due to the poor sensitivity of these tests at a single assessment.Indications for liver biopsy include the following: to rule out other treatable diseases, in cases of clinically suspected advanced liver disease, before pharmacological/surgical treatment, and as part of a structured intervention protocol or clinical research trial.     

Nicht alkoholische Fettleberkrankheit (NAFLK)

Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver damage: steatosis, steatohepatitis, and fibrosis and cirrhosis of the liver. The main risk factors are obesity, type-2 diabetes and hyperlipidaemia. NAFLD is found in 57–74% of obese adults and 22–53% of obese children. The pathogenesis is determined by the insulin resistance syndrome with lipolysis and hyperinsulinism, and oxidative stress resulting from free fatty acids via lipid peroxidation (two-hit hypothesis). Unspecific abdominal pain is reported; an enlarged liver is frequently detected on clinical examination. A third of the patients are found to have acanthosis nigricans. Transaminases are elevated (GOT<GPT), but there is no clear correlation with the liver histology. Computer sonography of the liver reveals an enhanced bright echo, while MRT allows quantification of the fatty degeneration. Differential diagnoses include hepatitis B/C, alpha-1 antitrypsin deficiency, CF, Wilson disease, autoimmune hepatitis, hypothyroidism, and coeliac disease. Weight loss (max. 500 g per week) and good metabolic control of diabetes are mandatory for the management of NAFLD. The long-term prognosis of NAFLD in children is unknown, but transaminases usually normalise after successful weight reduction. Fibrosis has an unfavourable prognosis.     

Non-alcoholic fatty liver disease: epidemiology,pathophysiology, diagnosis and treatment

Non-alcoholic fatty liver disease (NAFLD) in most of the world is the most common cause of liver disease in children and adolescents. The term NAFLD includes a spectrum of liver findings with macrovesicular steatosis, either in isolation, or with inflammation and evidence of cellular injury (non-alcoholic steatohepatitis), to cirrhosis. Particular factors responsible for progression of NAFLD from bland to more severe forms remain unknown. Multiple genetic and environmental risk factors are associated with increased risk for NAFLD including obesity, male gender, older age, Hispanic ethnicity or Asian race, and a positive family history. Non-invasive methods of investigation suggesting NAFLD include hepatic ultrasound and MRI, although definitive diagnosis is based on liver biopsy. The current standard of care for treatment of NAFLD is lifestyle modifications in the form of diet and exercise. Rigorous trials of additional treatment modalities such as antioxidants and insulin sensitizers are being explored.     

Fatty liver disease in children.

NAFLD/NASH is now recognised as an increasing clinical problem in children and adolescents. Risk factors include obesity, insulin resistance, and hypertriglyceridaemia. Drug hepatoxicity and genetic or metabolic diseases that can cause hepatic steatosis must be excluded. Affected children are usually asymptomatic although a few may complain of malaise, fatigue, or vague recurrent abdominal pain. Liver biopsy is the gold standard for diagnosis, and is important in determining disease severity and prognosis. The natural history of childhood NASH may be progressive liver disease for a significant minority. Long term follow up studies in this population are still lacking. The mainstay of treatment is weight reduction. The use of pharmacological therapy, though promising, ideally needs further evaluation in well designed randomised controlled studies in children.     

A cross-sectional study on the prevalence rate and influencing factors of nonalcoholic fatty liver disease in overweight/obese children北大核心CSCD

目的 调查医院就诊的超重/肥胖儿童非酒精性脂肪肝病(non-alcoholic fatty liver disease,NAFLD)的患病率,并探讨NAFLD发生的影响因素,为超重/肥胖儿童NAFLD的预防提供依据。方法 招募2019年6月-2021年9月在湖南省儿童医院就诊的超重/肥胖儿童作为研究对象,调查NAFLD患病率,并采用logistic回归分析探讨NAFLD,包括单纯性脂肪肝(non-alcoholic fatty liver,NAFL)和非酒精性脂肪肝炎(non-alcoholic steatohepatitis,NASH)发生的影响因素。采用受试者操作特征曲线分析评价影响因素对NAFL及NASH的预测价值。结果 共纳入844例超重/肥胖儿童,年龄为6~17岁。NAFLD患病率为38.2%(322/844),其中NAFL和NASH患病率分别为28.8%(243/844)和9.4%(79/844)。多因素logistic回归分析显示,腰臀比(waist-to-hip ratio,WHR)增加及低高密度脂蛋白胆固醇血症与NAFL和NASH的发生有关(P<0.05)。受试者操作特征曲线分析显示:WHR和高密度脂蛋白胆固醇联合检测预测NAFL的曲线下面积为0.653 (95%CI:0.613~0.694);二者联合检测预测NASH的曲线下面积为0.771 (95%CI:0.723~0.819)。结论 医院就诊的超重/肥胖儿童NAFLD的患病率较高;WHR和高密度脂蛋白胆固醇与NAFLD的发生有关,二者联合检测对NAFLD的发生具有一定的预测价值。     

磁共振成像定量评估儿童非酒精性脂肪肝的研究进展

随着肥胖及糖尿病患儿增多,儿童非酒精性脂肪肝的发病率越来越高,严重影响儿童的健康成长。儿童非酒精性脂肪肝的病理改变以肝内脂肪浸润为主,因此,肝脏脂肪含量的测定在脂肪肝的诊治中有重要作用。目前,定量评估肝脏脂肪含量的磁共振技术有 Dixon 技术、化学位移成像技术及 MRS 技术等。该文综述定量评估儿童非酒精性脂肪肝的磁共振技术及其相关研究进展。     

Effectiveness of weight loss in the treatment of non-alcoholic steatohepatitis in an obese adolescent

Childhood obesity is the most frequent nutritional disorder in developed countries and has been described as a global epidemic by the World Health Organization. In children, as in adults, obesity is the most significant risk factor for the development of non-alcoholic fatty liver disease. Therefore, it may become the most frequent chronic liver disease in children. However, pediatric publications on this disorder, which can progress to severe liver disease with risk of mortality, are scarce, with small series and few histological studies. The present article describes an obese adolescent who presented severe steatosis and steatohepatitis, which responded to weight loss with clinical and histological normalization. The risk of obesity comorbidity is increasing significantly in the pediatric population.     

The relationship between serum transaminase activities and fatty liver in children with simple obesity

To determine hepatic diseases in obese children, biochemically and histologically, 11 obese patients with abnormal serum transaminase activities were subjected to this study. Fat accumulation in the liver was semiquantitatively graded, and histologically the 11 patients were classified into four groups; fatty liver, fatty hepatitis, fatty fibrosis and fatty cirrhosis. All patients had fat deposition in liver specimens, the grade of which did not significantly correlate with the degree of obesity. The grade of fat deposition in the liver specimens also did not significantly correlate with either serum transaminase activities or GOT/GPT ratio. Five patients were grouped into the fatty liver group, three into the fatty hepatitis group, and the remaining three patients into the fatty fibrosis group. However, no significant differences were found among the three histologically classified groups in terms of serum transaminase activities or GOT/GPT ratio. The usefulness of serum transaminase activities and GOT/GPT ratio was limited in predicting the severity of fat deposition or histological abnormality in pediatric obese patients.     

Mechanisms of lipotoxicity in NAFLD and clinical implications

With the epidemic of childhood obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in pediatrics. NAFLD is strongly associated with insulin resistance and increased level of serum free fatty acids (FFAs). FFAs have direct hepatotoxicity through the induction of an endoplasmic reticulum stress response and subsequently activation of the mitochondrial pathway of cell death. FFAs may also result in lysosomal dysfunction and alter death receptor gene expression. Lipoapoptosis is a key pathogenic process in NAFLD, and correlates with progressive inflammation, and fibrosis. Accumulation of triglyceride in the liver results from uptake and esterification of FFAs by the hepatocyte, and is less likely to be hepatotoxic per se. To date, there are no proven effective therapies that halt NAFLD progression or unfortunately improve prognosis in children. The cellular mechanisms of lipotoxicity are complex but provide potential therapeutic targets for NAFLD. In this review we discuss several potential therapeutic opportunities in detail including inhibition of apoptosis, c-Jun-N-terminal kinase, and endoplasmic reticulum stress pathways.     

Nonalcoholic fatty liver disease (NAFLD) in children

Nonalcoholic fatty liver disease (NAFLD) is common in obese children and is a growing problem, given the increase in prevalence of obesity. NAFLD is also associated with diabetes, insulin resistance, hypercholesterolemia, and hypertriglyceridemia. Although mostly benign, some children with NAFLD develop fibrosis and cirrhosis, which necessitates close monitoring. Chronically elevated plasma liver enzyme levels is the most frequent finding. Ultrasound (US) examination allows confirmation of the diagnosis and it is useful for the follow-up. Gradual and sustained weight reduction is a management option that is worth trying initially. Other modalities of management, although interesting, await evidence as well as information on long-term benefits and effects. Sustained increase of transaminases despite weight reduction is a cause for concern and may require a liver biopsy both to assess severity of liver damage and for prognostic purposes.