Non-alcoholic steatohepatitis in children

Pediatr Transplantation 2004: 8: 613–618. DOI: 10.1111/j.1399-3046.2004.00241.x Printed in Singapore. All rights reserved Non-alcoholic steatohepatitis in children Kerkar N. Non-alcoholic steatohepatitis in children.
Pediatr Transplantation 2004: 8: 613–618. Ó 2004 Blackwell Munksgaard Department of Pediatric Liver Transplant andHepatology, Mount Sinai School of Medicine, New Abstract: Obesity has emerged as a significant new health problem in the pediatric population. Non-alcoholic steatohepatitis (NASH) is an entityin the spectrum of non-alcoholic fatty liver disease (NAFLD) rangesfrom fat in the liver – simple steatosis, NASH/ steatohepatitis – fat withinflammation and/or fibrosis to advanced fibrosis and cirrhosis when fatmay no longer be present. NASH is associated with obesity, diabetes,insulin resistance (IR), and hypertriglyceridemia. While majority ofindividuals with risk factors like obesity and IR have steatosis only aminority develop steatohepatitis, possible mechanisms have been dis-cussed. Clinical experience with pediatric NASH is limited. Childrengenerally present in the prepubertal age group, have a male predomin-ance with a higher incidence in children of Hispanic origin. Body massindex (BMI) of 25–29.9 is considered to be overweight and that ‡30obese. Acanthosis nigricans as a marker of IR should be looked for. AsNASH is a diagnosis of exclusion, other causes of chronic liver diseasemust be excluded. Increased echogenicity in the liver is noted on ultra-sound. Liver biopsy is considered the gold standard in establishing thediagnosis. Histopathological lesions thought to be necessary for diag-nosis of NASH include steatosis (macrovesicular > microvesicular),mixed mild lobular inflammation and hepatocyte ballooning. A system ofgrading depending on degree of steatosis and/or inflammation and sta-ging depending on the extent of fibrosis has also been proposed.
Although there is no consensus for the treatment for NASH, effort needsto be made to prevent development of fibrosis, which results in cirrhosisand portal hypertension. Slow, consistent weight loss has been shown tobe effective in childhood NAFLD, based on improvement of serumaminotransferases or liver sonogram. A low glycemic index diet has beenshown to be more effective than a low fat diet in lowering BMI. Familybased behavioral intervention may also enhance success with diet.
Several pharmacological agents have been used including ursodeoxy-cholic acid, vitamin E, betaine, n-acetyl cysteine, and insulin sensitizingagents like metformin, rosiglitazone, and pioglitazone. Transplantation Key words: children – insulin resistance – for overt NASH is rare, accounting for <1% of liver transplantations in the USA. The disease can recur after liver transplantation. A strongassociation exists between the presence of steatosis in a donor liver and Nanda Kerkar MD, The Mount Sinai Medical Center, poor graft function. As a result, cadaveric donor livers with macro- One Gustave L. Levy Place, PO Box 1104, New York,NY 10029-6574, USA vesicular 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 inboth pretransplantation and post-transplantation patients.
Abbreviations: ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate aminotransferase; BMI, body massindex; GPC, gastric parietal cell antibody; HOMA, homeostasis model assessment; IR, insulin resistance; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NHANES, National Health and Nutrition ExaminationSurvey; QUICKI, quantitative insulin sensitivity check index; SMA, smooth muscle antibody.UDCA, ursodeoxycholic acid.
NASH, an entity in the spectrum of NAFLD is serum antioxidants (vitamin E, b-carotene, and of increasing importance to medical practitioners vitamin C) and elevated glycolated hemoglobin because of rise in prevalence and potential to progress to end-stage liver disease. NAFLD The association between diabetes and NASH ranges from fat in the liver – simple steatosis, in adults can vary between 2 and 50%, and a fat with inflammation and/or fibrosis – steato- recent review concluded that up to a third of hepatitis/NASH to advanced fibrosis and cirrho- adults have diabetes or fasting hyperglycemia at sis when fat may no longer be present. Steatosis the time of diagnosis of NASH (8). Apart from may be macrovesicular or microvesicular. In age, diabetes is a strong independent predictor of microvesicular steatosis, the hepatocytes contain fibrosis in NASH (9). In a recent pediatric study, numerous fat-filled globules, but the nucleus impaired glucose tolerance was detected in 25% remains central; in macrovesicular steatosis, of the 55 obese children (4–10 yr of age) and there are one or two large globules of fat that 21% of 112 obese adolescents (11–18 yr of age); displace the nucleus to an eccentric position. In silent type 2 diabetes was identified in 4% of NASH, the steatosis is predominantly macrove- obese adolescents (10). Impaired glucose toler- sicular. Two decades ago, Ludwig et al. (1), used ance was associated with IR while beta-cell the term NASH for the first time to describe Ôthe function was still relatively well preserved.
pathological and clinical features of non-alco- Unfortunately, data regarding liver function tests holic disease of the liver associated with patho- logical features most commonly seen in alcoholic IR means a smaller than expected response to liver disease itselfÕ. The first report of steatohep- a given dose of insulin. The gold standard for atitis in children was 3 years later (2).
determining IR has been the euglycemic hype-rinsulinemic clamp test where glucose and insulinare infused simultaneously at doses titrated to maintain euglycemia (11). The higher the IR, the smaller will be the amount of glucose required to NASH has not yet been determined. Based on maintain euglycemia. However, this technique is biopsies of apparently normal potential donors too complicated for routine clinical practice.
for live-donor transplant, autopsy studies of Mathematical modeling of the physiological automobile accident and car crash victims as balance of glucose and insulin produced the well as hospital-based studies, about 2–3% of HOMA, which provided equations for estima- lean individuals and 15–20% of obese individuals ting IR (HOMA-IR) and beta-cell function from have steatohepatitis (3). NASH is associated with simultaneous fasting measures of insulin and obesity, diabetes, IR and hypertriglyceridemia glucose levels (12). Following logarithmic and which are the main features of the metabolic reciprocal transformation, better correlation with the clamp method was noted. The most recently Obesity has emerged as a significant new proposed derivation, QUICKI is calculated as health problem in the pediatric population.
follows: 1/[log (insulin) +_log (glucose)] [(insulin Increase in affluence, with accompanying chan- expressed in mU/mL and glucose in mg/dL)] ges in lifestyle; have led to reduced physical (13). Mather et al. (14), have shown that meas- activity and increased intake of easily available calorie-rich foods resulting in increased obesity.
provide estimates of IR comparable with the BMI is calculated using the formula (weight in kg)/(height in m2 ). In general, BMI of 25–29.9 is It is clear that while the majority of individuals considered to be overweight and that ‡30 obese.
with risk factors like obesity and IR have steatosis, only a minority will develop steatohep- that over 20% of children aged 12–17 yr were atitis. A two-hit hypothesis has been proposed.
found to be overweight (>85th percentile of The first hit is IR resulting in steatosis (15). The BMI for age) and 8–17% were obese (>95th second appears to be oxidative stress, which percentile of BMI for age) in different ethnic produces lipid peroxidation and activates inflam- groups. Studies have shown that 24–25% of matory cytokines like TNF-a resulting in NASH.
children referred to obesity centers have elevated Ob/ob mice are genetically obese, hyperlipidemic, ALT (5, 6). Strauss et al. (7), studied the develop type 2 diabetes and fatty liver spontane- children/adolescents enroled in the NHANES study and reported a much lower prevalence (6% NAFLD. Li et al. (16), showed that probiotics of overweight adolescents and 10% of obese and antibodies to TNF-a inhibit inflammatory adolescents) of elevated ALT. Decreased levels of activity and improve NAFLD in ob/ob mice.
Non-alcoholic steatohepatitis in children Treatments that reduce Kupffer cell exposure to having cancer (24). Blood pressure should be lipopolysaccaride from endogenous intestinal checked at each visit and occurrence of sleep flora may improve NAFLD in leptin deficient apnea elicited. While the weight is usually over mice. Patients with NASH have been shown to the 90th percentile, NASH can occur in children have a higher prevalence of small intestinal with weights appropriate for their age. Acanth- osis nigricans as a marker for hyperinsulinism was noted in a third of children with NASH (25).
noted to have higher TNF-a levels than control Children with hyperinsulinism as part of a subjects (17). A role for genetic factors has been syndrome like Bardet–Biedel syndrome and the suggested by two reports of family clustering (18, Leptin is an adipocyte-derived anti-obesity In adults, the ratio of AST to ALT is usually hormone that in rodents prevents ÔlipotoxicityÕ <1 in NASH and often >2 in alcoholic hepatitis by limiting triglyceride accumulation and also (26). Apart from measuring the liver enzymes, regulates matrix deposition (fibrosis) during serum triglyceride and markers of IR need to be wound healing. Serum leptin levels were raised assessed. As NASH is a diagnosis of exclusion, other causes of chronic liver disease for example, with controls (20). In a multivariate analysis, metabolic diseases including Wilson disease, a-1 serum leptin, c-peptide, and age were selected as antitrypsin deficiency, viral hepatitis and drug/ independent predictors of severity of hepatic alcohol ingestion must be excluded. In a study of steatosis, but serum leptin alone was not an 112 patients with NAFLD, presence of type 2 independent predictor of hepatic inflammation diabetes or ALT greater than twice normal increased the risk of NASH by fourfold; the combined presence of both increased the risk by complex. On the one hand, appropriate fatty acid 30-fold (27). A third of 84 adults with NAFLD oxidation is required to prevent accumulation of were noted to be positive for ANA and/or SMA fat in the liver, while on the other, excessive fatty (28). In a pediatric study, seven of 14 children acid oxidation is probably responsible for the with NAFLD were found to be positive for ANA generation of oxidative stress. Children with and/or SMA in six and GPC in one; four of the inherited defects in mitochondrial b-oxidation six children with fibrosis were noted to be develop steatosis but they do not get to NASH, strongly suggesting that intact mitochondrial fat Increased echogenicity in the liver is noted on oxidation is required for progression to inflam- ultrasound. Liver biopsy is the gold standard in mation and fibrosis (22). Drugs like amiodarone, establishing the diagnosis of NASH. This was perhexiline, stilbesterol, tamoxifen, and methot- illustrated in a recent study that showed that rexate have been associated with NASH.
while the severity of hepatic steatosis can beaccurately detected radiologically when there ismoderate or severe (>33%) fatty infiltration of the liver documented by a liver biopsy, radiolo- Clinical experience with pediatric NASH is gical modalities (US, CT, and MRI) were unable limited. Children generally present in the prepu- to detect or characterize NASH or distinguish it bertal age group. There appears to be a male from steatosis alone (29). Nuclear magnetic predominance and a higher incidence in children resonance spectroscopy is considered to be a of Hispanic origin. While there are no charac- good non-invasive method of quantifying fat.
teristic symptoms, abdominal pain, malaise or A liver core biopsy of 10–30 mm · 1.2–2 mm tiredness, and history of drug ingestion may be biopsy is estimated to represent 1/50 000 of the elicited at presentation (23). Some children are organ. No single microscopic finding is diagnos- completely asymptomatic; others have non-liver- tic of NASH. Histopathological lesions thought related symptoms, the elevated transaminases to be necessary for diagnosis of NASH include having been noted incidentally during blood tests. On being directly questioned, children mixed mild lobular inflammation and hepatocyte admit to being bullied at school because of their ballooning, typically in zone 3. Although usually weight and also to feeling depressed. In a recent present, features like perisinusoidal fibrosis, study, obese children/adolescents were more glycogenated nuclei, lipogranulomas, and fat likely to have impaired health-related quality of cysts, are not necessary for diagnosis (30). A life than healthy children/adolescents and were system of grading from 1 to 3 depending on the similar to children/adolescents diagnosed as degree of steatosis and/or inflammation and staging from 1 to 4 depending on the extent of occurring metabolite of choline, at a dose of fibrosis has also been proposed. Of children who 20 g/day, was shown to have caused improve- have had a liver biopsy, the incidence of steato- ment in aminotransferases and histology follow- hepatitis and fibrosis appears to be quite high. In ing 1 yr of treatment in a small pilot study (42).
a series of 36 children, 21 had steatohepatitis, 16 Betaine acts by increasing s-adenosylmethionine levels, which in turn protects the liver fromethanol induced triglyceride deposition in rats (43). An open-label pilot trial of antioxidanttherapy with vitamin E, a-tocopherol, at 400– Although there is no consensus for the treatment for NASH, effort needs to be made to prevent aminotransferases (44). Vitamin E is a potent development of fibrosis, which results in cirrhosis antioxidant particularly effective against mem- and portal hypertension. As the pathogenesis of brane lipid peroxidation. N-acetylcysteine, a this condition is not clear, treatment has been glutathione pro-drug which is thought to protect largely empirical. Conditions associated with the liver against oxidative stress has shown NAFLD like obesity, diabetes, IR, hyperlipide- improvement in transaminases when given to mia, drugs have been the focus of attention.
Prognosis in NASH is dependent not only on Metformin, a biguanide reduces hyperinsuline- severity and number of risk factors but also on mia and improves hepatic IR. It has been shown to reverse fatty liver in obese, leptin deficient The key principle of obesity therapy is to eat mice (46) and has been used in the treatment of fewer calories than are expended in order to NASH in adults (47). Metformin has also been consume endogenous fat stores as fuel. The used successfully in juvenile acanthosis nigricans American Gastroenterological Association has (48) and in children with type 2 diabetes mellitus made a medical position statement based on (49). Thiazolidinediones like rosiglitazone and pioglitazone have improved transaminases, stea- Institute of Health’s Expert panel on the tosis and IR in adults with NASH (50, 51).
Atorvastatin has been used to successfully treat overweight and obesity in adults (31). Slow, consistent weight loss has been shown to beeffective improvement of serum aminotransferases orliver sonogram (25, 32) In adult patients with A strong association exists between the presence high degree of fatty infiltration, rapid weight of steatosis in a donor liver and poor graft loss may lead to the development of pericellular function (53). As a result, cadaveric donor livers and portal fibrosis, bile stasis, and focal necro- with macrovesicular steatosis >40% are not sis (33, 34). However, gradual weight loss has used routinely. A scarcity of cadaveric donor shown improvement both in liver biochemistries organs has increased the use of living-related and histology (35). The rate and degree of donors. Assessment of steatosis is always a weight loss required for normalization of liver necessary part of living donor evaluation; pros- histology has not been established. A low pective donors who are at high risk (increased glycemic index diet has been shown to be more BMI) should have liver biopsy even if results of effective than a low fat diet in lowering BMI (36). Family-based behavioral intervention may Transplantation in the care of patients with also enhance success with diet (37). Apart from a good diet, children need to have a regular co-morbid conditions like obesity, diabetes, and hyperlipidemia. At present transplantation for overt NASH is rare, accounting for <1% of liver used. UDCA at a dose of 10–15 mg/kg/day has transplantations in the USA. After the develop- been shown to improve liver biochemistry in ment of cirrhosis from NASH, the histological NASH (38–40). UDCA, an epimer of chenode- features of steatosis and various necroinflamma- oxycholic acid appears to replace endogenous hepatotoxic bile acids and has membrane stabil- disappear. In the face of end-stage Ôburned-outÕ izing or cytoprotective effects. There is however, liver disease disease and the absence of any a single report of lack of efficacy of UDCA when serological markers characteristic of the disease, used alone without accompanying diet/exercise the possibility of NASH can only be inferred by regime in obese children (41). Betaine, a naturally the overall clinicopathological picture. It is Non-alcoholic steatohepatitis in children possible that the contribution of NASH to liver 10. Sinha R, Fisch G, Teague B, et al. Prevalence of impaired transplantation may well have been underesti- glucose tolerance among children and adolescents with marked mated in the past and will most likely continue to obesity. N Engl J Med 2002: 346: 802–810.
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