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.     

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.     

儿童非酒精性脂肪肝最新研究动态

目的 近年来,随着儿童肥胖及超重发生率的增加,儿童非酒精性脂肪肝成为儿童最常见的肝病之一,相关的研究也不断深入拓展.虽然二次打击及多重打击学说已被广范接受,但是遗传因素、环境因素及饮食结构等对于儿童非酒精性脂肪肝发病也起着至关重要的作用.对于儿童非酒精性脂肪肝的临床诊断,目前还没有一个十分满意的方法,但是无创诊断技术是学者们努力的方向,并且有了一些新的评分方法;对于儿童非酒精性脂肪肝的治疗,也没有特别有效的药物,目前仍然是以改变生活方式为主.本文主要对儿童非酒精性脂肪肝的相关知识及观点的最新研究动态进行总结,并对其诊断、评分方法及治疗等进行讨论.     

Non-alcoholic fatty liver disease and childhood obesity

Obesity has emerged as a significant global health problem in the pediatric population. Pediatric liver disease is a serious complication of childhood obesity. 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 in ammation 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. Children get NAFLD, and the incidence of this pediatric liver disease is rising as childhood obesity becomes increasingly prevalent. Although much remains to be learned about pediatric NAFLD, it is already evident that children with NASH risk progressive liver damage, including cirrhosis. Liver biopsy is required for definitive diagnosis, and other causes of fatty liver in childhood must be excluded. Gradual weight loss through increased regular exercise and a low-fat, low-refined carbohydrate diet appears to be effective. Drug treatments are being developed. The important message is that childhood obesity poses important health problems, including but not limited to potentially severe chronic liver disease. Early diagnosis of children who are only overweight is a worthy goal so that strategies to limit obesity can be instituted as early as possible. Identification of genetic risks is important, but management will invariably require changes in environmental factors. In addition to individual treatment, a multifaceted, societal initiative is required for solving the childhood obesity epidemic.     

Nonalcoholic fatty liver disease in children living in the obeseogenic society

Background  

The problem of obesity in children has grown considerably in recent years in the United States as well as the rest of the world. This has resulted in a marked increase in the prevalence of nonalcoholic liver disease in the pediatric age group. Nonalcoholic fatty liver disease (NAFLD) is currently the most common hepatic disorder seen in pediatric hepatology practice.     

肥胖儿童非酒精性脂肪肝病及代谢综合征发病情况分析

目的 研究肥胖儿童中非酒精性脂肪肝病(NAFLD)与代谢综合征(MS)的发生情况,并探索两者之间的关系.方法 对308例在本院内分泌科住院的9～14岁肥胖儿童进行腰围、体块指数、血脂、肝功能、肝脏B超、糖耐量试验及胰岛素释放试验等各项检查,根据诊断标准分别计算发生NAFLD[包括单纯性非酒精性脂肪肝(SNAFL)、非酒精性脂肪肝炎(NASH)]和MS的患病率,并将308例肥胖患儿分为无肝脏损害的肥胖儿童组(OCWLD组),SNAFL组和NASH组,比较各组胰岛素、胰岛素抵抗(IR)指标及MS的发病率和MS组成成分的发病率.结果 (1)308例中发生NAFLD的达到203例(65.9%),其中发生SNAFL者140例(45.5%),发生NASH者63例(20.5%).(2)308例中发生MS 76例(24.7%),这76例中合并有NAFLD的64例(84.2%).NAFLD组中MS 64例(31.5%),高于OCWLD组的12例(11.4%),差异有统计学意义,但SNAFL组中MS 41例(29.3%),与NASH组的23例(36.5%)比较差异无统计学意义.(3)就单个MS的组成成分来说,OCWLD组与SNALF组比较仅在高血压的发病率上差异有统计学意义,而OCWLD组与NASH组比较在高血压、高血脂、高血糖的发病率上差异均有统计学意义;SNALF组与NASH组比较在高血脂的发病率上差异有统计学意义.随OCWLD向SNAFL和NASH发展,空腹胰岛素水平逐渐上升,IR也越加明显.但NAFLD患儿与MS患儿比较各IR指标差异无统计学意义.结论 肥胖儿童中NAFLD和MS的发生率均已相当高,MS患儿合并NAFLD的比例很高,IR是NAFLD和MS共同的发病基础,且随着NAFLD患儿病情的进展,MS成分指标越来越严重,IR也越来越严重.     

上海市闵行区儿童青少年非酒精性脂肪肝病7年患病率横断面调查

背景：儿童非酒精性脂肪肝病（NAFLD）导致成年后心血管病发病风险明显增加,而目前我国儿童青少年一般人群NAFLD患病率研究十分有限,长期变化趋势亦不明确。目的：描述儿童青少年NAFLD患病流行趋势。设计：横断面调查。方法：以上海市闵行区2014至2020年参加健康体检的住校学生为调查对象。将ALT水平高于一般人群性别和年龄别P97.5水平定义为疑似NAFLD,依此估计疑似NAFLD患病率（简称患病率）。根据全国标准分别以BMI和腰围定义一般性肥胖和腹型肥胖。通过计算平均年度变化百分比（AAPC）及其95%CI行描述NAFLD患病率逐年变化幅度,趋势性检验Logistic回归分析,并校正BMI和腰围。主要结局指标：NAFLD患病率。结果：NAFLD总体患病率为5.1%,从2014年至2020年上升了2.5倍（2.1%到7.4%）,NAFLD患病率逐年上升（Ptrend<0.001）,AAPC为0.9%（95%CI：0.1%~1.7%）,且男孩高于女孩（6.3% vs 3.7%）。在体重正常人群中NAFLD患病率为1.9%,7年中呈逐年上升趋势（Ptrend<0.001）。调整BMI和腰围后,NAFLD患病率逐年上升的趋势仍显著（Ptrend<0.001）。结论：上海儿童青少年人群NAFLD患病率呈现每年上升近1.0%的趋势,调整BMI和腰围因素后,NAFLD患病率逐年上升的趋势仍然存在。提示除肥胖外,儿童人群防控NAFLD需进一步关注其他可干预危险因素的作用。     

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.     

Non-alcoholic fatty-liver disease in pediatric populations

The increasing prevalence of obesity is not only observed in adults. Children are affected by obesity and related diseases, such as chronic liver disease, more frequently than in the past. Nonalcoholic fatty-liver disease is an important cause of chronic liver disease and in the near future will become important worldwide. Considering this phenomenon, it is important for gastroenterologists and hepatologists to be aware of the presence of nonalcoholic fatty-liver disease in pediatric populations and to treat it adequately. This practice will have important benefits for future generations. This review discusses the most important aspects in epidemiology, diagnostics and treatment of nonalcoholic fatty-liver disease in children.     

Decreased prevalence of nonalcoholic fatty liver disease in black obese children

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is a common cause of pediatric liver disease. Studies suggest decreased prevalence in blacks, females, and younger children. However, the proportion of black subjects in these studies was small, and children under 12 were not included. We propose that abnormal alanine aminotransferase (ALT) is more common in whites than blacks, males than females, and children over 12 compared with younger children in a prospective study. METHODS: We enrolled 181 consecutive asymptomatic obese children attending general pediatric clinics who denied recent fever or known liver disease. Obesity was defined as body mass index (BMI) z score of greater than 1.64 (95th percentile for age and sex). Elevated ALT was defined as greater than 40 U/L. BMI z score, race, sex, age, and parental obesity were compared using the chi-square test and Fisher's exact test. RESULTS: The population included 81 males and 100 females, 147 non-Hispanic black, 33 non-Hispanic white, and 1 Hispanic white. Elevated ALT occurred in 14 (8%) subjects. White children were significantly more likely to have abnormal ALT (odds ratio [OR] = 4.0, P < .02). Very obese children (BMI z score >2.3) were more likely to have abnormal ALT compared with mildly obese children (OR = 4.0, P < 0.05). Sex, age, hepatomegaly, acanthosis nigricans, and parental obesity did not significantly predict elevated ALT. CONCLUSION: Eight percent of asymptomatic, obese children had an elevated ALT suggestive of NAFLD. White and very obese children are more likely to be affected. Sex and age are not good clinical predictors of NAFLD. We suggest that all obese children be screened for NAFLD.     

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.     

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.     

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.     

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.     

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.     

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.     

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］     

Type 2 diabetes in children is frequently associated with elevated alanine aminotransferase

BACKGROUND: Nonalcoholic fatty liver disease, a cause of chronic liver disease in obese adults also occurs in obese children. In susceptible populations, fatty liver progresses to nonalcoholic steatohepatitis and eventually to fibrosis and cirrhosis. Nonalcoholic steatohepatitis is associated with elevation of alanine aminotransferase, although the aminotransferases can also be normal. The prevalence of nonalcoholic fatty liver disease in type 2 diabetes is unclear in adults and unknown in children. OBJECTIVES: The aim of this study was to estimate the prevalence of elevated serum aminotransferases as a marker of nonalcoholic fatty liver disease in pediatric type 2 diabetes and to identify correlates of aminotransferase elevation. METHODS: A chart review was completed on 115 children with type 2 diabetes at a pediatric diabetes clinic. The prevalence of elevated alanine aminotransferase was calculated from the 42% of patients with available aminotransferase measurements and correlations with fasting lipids, hemoglobin A-1c, body mass index, age and diabetes therapy were sought. RESULTS: The prevalence of elevated alanine aminotransferase was 48%. There was no association between elevations and other variables. Among subjects with elevated alanine aminotransferase, 39% were one to two times above normal, 26% were two to three times normal and 35% were greater than three times above normal. Several patients experienced improvement in aminotransferase elevations after using insulin-sensitizing medications. CONCLUSIONS: There is a high prevalence of elevated serum aminotransferases among children with type 2 diabetes unrelated to age, body mass index, glycemic control, blood lipids or diabetic therapy. The significance of this abnormality and its relationship to nonalcoholic fatty liver disease requires further evaluation.     

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。