• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Gut. Author manuscript; available in PMC Nov 1, 2010.
Published in final edited form as:
PMCID: PMC2792743
NIHMSID: NIHMS154507

THE NATURAL HISTORY OF NONALCOHOLIC FATTY LIVER DISEASE IN CHILDREN: A FOLLOW-UP STUDY FOR UP TO 20-YEARS

Abstract

Objectives

The long-term prognosis of nonalcoholic fatty liver disease (NAFLD) in children remains uncertain. We aimed at determining the long-term outcomes and survival of children with NAFLD.

Design

Retrospective longitudinal hospital-based cohort study.

Patients

Sixty-six children with NAFLD (mean age 13.9±3.9 years) were followed-up for up to 20 years with a total of 409.6 person-years of follow-up.

Results

The metabolic syndrome was present in 19 (29%) children at the time of NAFLD diagnosis with 55 (83%) presenting with at least one feature of the metabolic syndrome including obesity, hypertension, dyslipidemia and/or hyperglycemia. Four children with baseline normal fasting glucose developed type II diabetes 4-11 years after NAFLD diagnosis. A total of 13 liver biopsies were obtained from five patients over a mean of 41.4±28.8 months showing progression of fibrosis stage in four children. During follow-up, two children died and two underwent liver transplantation for decompensated cirrhosis. The observed survival free of liver transplantation was significantly shorter in the NAFLD cohort as compared to the expected survival in the general United States population of the same age and sex (log-rank test, p<0.00001), with a standarized mortality ratio of 13.6 (95% CI 3.8, 34.8). NAFLD recurred in the allograft in the two cases transplanted, with one case progressing to cirrhosis and requiring re-transplantation.

Conclusions

Children with NAFLD may develop end-stage liver disease with the consequent need for liver transplantation. NAFLD in children seen in a tertiary care center may be associated with a significantly shorter survival as compared to the general population.

Keywords: NAFLD, NASH, children, prognosis, long-term survival

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the preadolescent and adolescent age groups in most of the Western World. An autopsy study found that 9.6% of the American population aged 2 to 19 years have NAFLD, and this figure increased to 38% among those who were obese.1 Similar high figures have been reported among children from other countries in Europe and Asia.2-4 Insulin resistance is almost a universal finding in pediatric NAFLD, and consequently, several of the clinical features associated with insulin resistance such as obesity, diabetes mellitus, and dyslipidemia are common comorbidities in children who suffer from NAFLD.5-14

NAFLD includes a wide spectrum of liver damage ranging from simple, uncomplicated steatosis to steatohepatitis to advanced fibrosis and cirrhosis.15,16 Several studies on long-term prognosis in the adult population demonstrate that simple steatosis follows a relatively benign clinical course17,18 whereas steatohepatitis associated with increased fibrosis may progress to end-stage liver disease and its resulting complications.18,19

Data on prognosis of NAFLD in children remain scant. Some series have reported well-documented cases of cirrhotic stage disease in children1,20 and other series have reported cases of children with NAFLD who developed cirrhosis in young adulthood.21,22 However, the natural history and prognosis of NAFLD in children remains unknown. Studies of children with NAFLD who underwent long-term follow-up are necessary to better determine the natural history and long-term prognosis of NAFLD in the pediatric population. Thus, we conducted this cohort study aimed at determining the long-term prognosis of children with NAFLD and compare their survival with expected survival of the general population of the United States of the same age and sex.

MATERIAL AND METHODS

Study Design and Patient Population

This was a retrospective longitudinal hospital-based cohort study. The study was approved by the Mayo Institutional Review Board and all patients or responsible guardian gave written informed consent for participation in medical research. Pediatric patients with NAFLD were identified using our Mayo computerized master diagnosis index which is a database of medical records of every single patient seen at Mayo Clinic. Each unit medical record contains all inpatient and outpatient medical information for each individual patient seen at Mayo Clinic since 1907. This has led to the creation of a unified medical index system, the Rochester Epidemiology Project (REP) by which the details of the medical care provided to Mayo patients can be studied.23 The REP Mayo computerized master diagnosis indexes all medical diagnoses made at each health encounter by health care providers at Mayo.23 All diagnoses made in outpatient office or clinic visits, hospitalizations, emergency room visits, nursing home care, surgical procedures, autopsies, and death certificates are recorded in the database. Thus, the REP Mayo diagnosis index makes it possible to identify a group of patients with certain characteristics and follow them longitudinally assessing long-term outcomes such as mortality and causes of death.

Patients with a diagnosis of NAFLD were identified by searching the REP master diagnostic index using Hospital Adaptation of International Classification of Diseases (HICDA) codes for fatty liver, hepatic steatosis or steatohepatitis (5710-42-42, 5710-43-1, 5710-43-0, 5470-42-0 to 4, 2790-44-1). For the purpose of this study we used the definition of child as an individual under the age of 21 years as proposed by the National Institute of Health (http://grants.nih.gov/grants/funding/children/children.htm). Patients had their first medical evaluation for their liver disease at our institution during a 15-year period from 1/1/1985 to 12/31/1999. The date 1/1/1985 was chosen since the first case of pediatric NAFLD was reported in the mid 1980's;20 the date 12/31/1999 was chosen to have a 15-year ascertainment period and a follow-up of more than 5 years for the last patient enrolled. The diagnosis of NAFLD required 1) confirmation of diffuse fatty infiltration of the liver in imaging studies regardless of aminotransferases levels; 2) average daily ethanol consumption of less than 10 grams; and 3) appropriate exclusion of other liver diseases based on standard clinical, laboratory, imaging and/or liver biopsy features. Laboratory tests to rule out other liver diseases included viral hepatitis panel (for hepatitis A, B and C performed either at the time of first evaluation or during the follow up), ceruloplasmin levels, alpha-1-antitrypsin levels and phenotype, autoantibodies (nuclear antibody [ANA], smooth muscle antibody [SMA], antibody to the liver/kidney microsome type 1, and antimitochondrial antibody), and standard metabolic/inborn error panel (lactate/piruvate ratio, urine and serum organic acids and aminoacids).

The REP master diagnostic index identified a total of 130 cases. After an extensive review of the medical records of these patients, a total of 66 children with unequivocal NAFLD as defined by our diagnostic criteria detailed above were identified. A complete medical history and physical examination, and a complete laboratory evaluation were performed in all patients at the time of first medical evaluation in our institution and repeated at regular intervals thereafter. Laboratory evaluation included liver biochemistries (serum aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase activity, γ-glutamyl transferase [GGT], total bilirubin, albumin levels, and prothrombin time), fasting blood glucose, fasting lipid profiles (triglyceride, total cholesterol, HDL-cholesterol, and LDL-cholesterol levels), and specific laboratory tests to ruled other liver diseases as described before. All patients underwent abdominal imaging with ultrasonography, CT scan, and/or magnetic resonance imaging confirming the presence of fatty infiltration of the liver.

The body mass index (BMI) based on body weight (kilograms) divided by the square of height (meters) was calculated in every case. BMI percentile was determined according to age and sex based on data from the Center for Disease Control and Prevention.24 Obesity was defined by a BMI >95th percentile for age and sex.24 Abnormalities in the fasting levels of triglycerides and HDL-cholesterol were adjusted according to age, sex, and race or ethnic group (>95th percentile for triglycerides; <5th percentile for HDL-cholesterol) as recommended.25 Diabetes mellitus was diagnosed based on standard criteria as recommended by the American Diabetes Association.26 Hypertension was defined as a systolic or diastolic value that exceeded the 95th percentile for age, sex and height.27 Hypercholesterolemia was defined as a fasting total cholesterol level ≥ 200 mg/dL.28 High LDL-cholesterol was defined by a LDL-cholesterol level ≥ 130 mg/dL.28

In addition, patients were classified as having the metabolic syndrome if they met three or more of the following five criteria for age and sex as proposed:29 BMI above the 97th percentile (which correspond to a z-score of 2.0 or more); triglyceride level above the 95th percentile; HDL cholesterol level below the 5th percentile; systolic or diastolic blood pressure above the 95th percentile; and impaired glucose tolerance. As oral glucose tolerance test was not performed, we used a fasting glucose value of at least 100 mg/dl to replace impaired glucose tolerance as recently proposed by the International Diabetes Federation.30

Liver Histology

A baseline liver biopsy was performed in 29 patients at time of diagnosis and follow-up liver biopsies in 5 of these patients. Since there are no established guidelines of when to perform a liver biopsy in patients with NAFLD, the decision to perform a baseline liver biopsy in our patient population was made on an individual basis by the treating Gastroenterologist, and in most (82%) cases was performed due to persistently abnormal liver enzymes. Liver biopsy features including grade of steatosis, inflammatory infiltrate, and ballooning, presence of Mallory hyaline, and stage of fibrosis were graded according to the scoring system proposed by Kleiner et al.31

Statistical Analysis

Continuous variables are presented as mean ± standard deviation (SD), and discrete variables are expressed as the number (percentage) of patients with a condition. Comparisons between patients with and without liver biopsy were performed with 2-sample t-tests for continuous variables and chi-square tests for categorical variables. Survival curves were created using the Kaplan-Meier method. The starting point for survival analysis was date of diagnosis of NAFLD. Patient follow-up was extended up to April 2008. The end-points for survival analysis were death or liver transplantation. For survival comparison we calculated the expected number of deaths for a cohort with the same age and sex distribution and the same amount of observation time (exposure to death) as the 66 children with NAFLD. The estimates were made using mortality data for United States from the U.S. Center for Health Statistics as previously detailed.32 We used the relationship between the log-rank test and the Poisson distribution. The p-value calculated (from the one sample logrank test) depends on the assumption that the number of deaths follows a Poisson distribution with an expected value equal to the expected number of deaths.32 The standardized mortality ratio (SMR) was calculated using the Ederer method based on age and sex to derive the expected number of events.33

RESULTS

Clinical Features at Presentation

The main demographic and clinical features are summarized in Table 1. There was a slightly higher proportion of boys than girls, and two thirds were obese. Most patients had symptoms or signs at presentation. The features of the metabolic syndrome were common with more than half having a BMI >97th percentile. Fifty-five (83.3%) children presented with at least one feature of the metabolic syndrome whereas overt metabolic syndrome (i.e., ≥3 features) was present in 19 (28.8%) children. Other features that worse the cardiovascular risk profile such as hypercholesterolemia and high LDL-cholesterol were also common. The main laboratory data gathered at the time of NAFLD diagnosis are summarized in Table 2. ALT and AST levels were each within the normal range in few patients. The AST/ALT ratio was greater than 1 in 29% of children. GGT was elevated in 88% of patients while serum alkaline phosphatase was above the normal value for age and sex in few patients. Serum total bilirubin, albumin and prothrombin time were essentially within the normal range in all patients. Positive autoantibodies in low titers were found in 20% of patients including ANA in 15.4%, and SMA in 10% of patients.

Table 1
Demographic and clinical features at presentation (n = 66)
Table 2
Laboratory features at presentation (n = 66)

Liver Histology

The main liver biopsy features are summarized in Table 3. Some degree of fibrosis was present in 59% of children including mild fibrosis (stage 1-2) in 11, septal/bridging fibrosis (stage 3) in 4, and cirrhotic-stage disease in 2. The mean NAFLD activity score was 3.5 ± 1.02. Portal based injury was seen in 9 (31%) children but associated with zone 3 injury in most. Interface hepatitis or other features suggestive of autoimmune hepatitis were not present in any case. As summarized in table 4, patients undergoing liver biopsy had significantly higher levels of ALT and lower levels of total cholesterol and triglycerides; otherwise patients undergoing liver biopsy were similar to those who were not biopsied.

Table 3
Liver biopsy features (n = 29)
Table 4
Comparison of major variables between patients with or without liver biopsy

Long-Term Follow-Up

The mean follow-up of the total cohort was 6.4 ± 4.5 (range 0.05 to 20) years, for a total of 409.6 person-years. During this time, treatment recommendations included lifestyle modifications consisting of an exercise program along with diet modifications tailored to individual need and preference alone or in 8 (12.1%) patients in combination with either ursodeoxycholic acid or vitamin E. One-year after initiation of the prescribed lifestyle modification, 49% of children were able to lose at least 10% of their baseline weight, and 86% of them showed significant improvement or normalization of aminostrasferases. Neither ursodeoxycholic acid nor vitamin E treatment appeared to impact further the liver enzymes levels although their effect independent of weight loss could not be assessed due to the very small number of patients on either treatment. At the time of last follow-up, however, most patients (76%) had re-gained weight, and in 46% of them aminotransferases returned to baseline values. Interestingly, 4 children developed type II diabetes 4, 6, 7 and 11 years after the diagnosis of NAFLD. Other complications that occurred during follow-up were cholecystitis requiring cholecystectomy (6 patients), morbid obesity requiring bariatric surgery (2 patients), contraceptive induced liver injury (1 patient) and bilateral oophorectomy and hysterectomy for endometriosis (1 patient).

A total of 13 liver biopsies were obtained from 5 patients over a mean period of 41.4 ± 28.8 months (Table 5). Grade of steatosis and lobular inflammation either worsened or remained the same in all patients. Progression of fibrosis stage was documented in 4 cases. One patient without fibrosis at presentation developed stage 1 fibrosis at 19 months, and cirrhosis (stage 4 fibrosis) at 57 months. Another patient presented without fibrosis, but progressed to stage 1 fibrosis at 39 months, and to stage 3 fibrosis at 82 months. Two other patients without fibrosis at presentation progressed both to stage 1 fibrosis, one at 28 months and the other at 7 months. There was no improvement in any of those histological features in any case.

Table 5
Follow-up liver biopsy (n = 5)

Long-Term Survival

During follow-up, 2 patients underwent liver transplantation, and 2 additional patients died. The observed number of events in the total person-years of follow up was 4/409.6 = 9.8 per thousand. The observed number of events in the NAFLD cohort was significantly higher than the expected number of events in the United States population of same age and sex (4 vs. 0.29416, p<0.00001) with a SMR of 13.6 (95% confidence intervals, 3.8, 34.8). The observed survival free of liver transplantation in the NAFLD cohort as compared to the expected survival of the general United States population of the same age and sex is illustrated in Figure 1.

Figure 1
Kaplan-Meier survival curve of children with NAFLD (n=66) as compared to the general United States population of same age and sex. The observed survival free of liver transplantation was significantly shorter in the NAFLD cohort as compared to the expected ...

The 2 patients who underwent liver transplantation were those 2 who presented with cirrhosis on liver biopsy. The first case was a Hispanic female diagnosed with cirrhotic-stage NASH at 11 years of age, when she presented with a BMI of 26.9 kg/m2, hypercholesterolemia and hypertriglyceridemia. She was found with grade 3 esophageal varices and developed recurrent variceal bleeding requiring variceal band ligation in multiple occasions. She underwent liver transplantation at 20 years of age due to end-stage liver disease and hepatopulmonary syndrome. In the post-transplant period, she was diagnosed with recurrent NASH at 9 months, stage1 fibrosis at 2 years and 3 months, and stage 2 fibrosis at 3 years and 3 months post liver transplantation. She is currently alive. The second case was a white female diagnosed with cirrhotic-stage NASH at 18.9 years of age when presented with a BMI of 33.6 kg/m2, and low HDL-cholesterol. She developed severe hypoxemia from hepatopulmonary syndrome without any other liver complication requiring liver transplantation at 25 years of age. She was found with macrovesicular steatosis on protocol liver biopsy as early as 14 days post liver transplantation, with well-established NASH at 6 weeks post liver transplantation, and with bridging fibrosis at 1 year. She was diagnosed with cirrhotic stage NASH in the graft and hepatopulmonary syndrome 2 years post liver transplantation, requiring re-transplantation 2.3 years after the first liver transplant procedure. Finally, she died from multiple organ failure at age 27 years. The 2 deaths recorded were both non-liver related, and none of these two cases had liver biopsy performed at any time.

DISCUSSION

The study is the first to describe the long-term survival of children with NAFLD who underwent a follow-up of up to 20-years. The study demonstrates that NAFLD in children is a disease of progressive potential. Some children presented with cirrhosis, other progressed to advanced fibrosis or cirrhosis during follow-up, and some developed end-stage liver disease with the consequent need of liver transplantation. The study shows that NAFLD in children is associated with a significantly shorter long-term survival as compared to the expected survival of the general population of the same age and sex; our children with NAFLD had a 13.8-fold higher risk of dying or requiring liver transplantation than the general population of same age and sex. The two deaths recorded were not liver-related, but the inclusion of these two cases among the 4 cases reaching the outcome of death or liver transplantation is appropriate as the comparison was done to overall mortality in the general population of same age and sex regardless of the causes of death.

The study also provides interesting data regarding the progressive potential of NAFLD to more advanced disease. Four of the five children with repeated liver biopsy did not have fibrosis on diagnosis liver biopsy, but two developed mild (stage 1) fibrosis, and the other two developed advanced (stage 3-4) fibrosis. The progression of liver damage in these patients over a relatively short period of time highlights the importance of identifying those children with NAFLD who are at risk of having a more progressive liver disease. In some recent series, presence and severity of fibrosis was consistently associated with a higher BMI or larger waist circumference.10,12,14 Older age and higher levels of AST and insulin have been found associated with fibrosis in some series10,12 However, further studies are needed to accurately identify those children who are more likely to progress to end stage liver disease.

Interestingly, the two patients in our cohort who underwent liver transplantation had hepatopulmonary syndrome as the main indication for transplant. However, whether or not there is an association between progression to cirrhosis and development of severe hepatopulmonary syndrome requiring liver transplantation in pediatric NAFLD remains uncertain, and further studies in this area are needed. It is also intriguing that both cases undergoing liver transplantation in our series developed recurrent NASH, with cirrhotic stage disease in one patient who required re-transplantation. Recurrence of NASH post liver transplantation in children has been documented in two isolated cases34,35 both male patients of age 13 and 16 years who developed decompensated liver disease from NAFLD. Both cases had a history of hypothalamic/pituitary dysfunction in one case associated with hepatopulmonary syndrome. These two cases34,35 extended prior observations of the development of severe liver disease from NAFLD in patients with hypothalamic/pituitary dysfunction.36

Similar to other pediatric series of NAFLD, most of our children were diagnosed in the second decade of life, girls and boys were affected almost equally with a slight male predominance, and most were symptomatic at presentation.

Alike adults with NAFLD, a high proportion of our children were obese and had associated several features of the metabolic syndrome. Unlike adults, almost a third of our children had portal-based injury on liver biopsy, but most of them had pericentral/perisinusoidal injury as well. Two of our children had type II diabetes prior to the diagnosis of NAFLD, whereas four patients developed type II diabetes within 11 years after NAFLD was diagnosed. Therefore, children with NAFLD should be closely monitored for development of type II diabetes later in life.

We found a high proportion of children (27.3%) with HDL-cholesterol below the 5th percentile for their age and sex which has not been reported in pediatric NAFLD before. Similar to adults with NAFLD,37 20% of our children tested positive for low titer of ANA and/or SMA. Interestingly, the vast majority (88%) of our children had elevated GGT with alkaline phosphatase levels within the normal range in most of them. To our knowledge, this high proportion of children with elevated GGT levels has not been described in any other series of pediatric NAFLD. Recently, higher serum levels of GGT have been associated with several cardiovascular disease risk factors or components of the metabolic syndrome.38-41 GGT is located on the external surface of most cells and mediates the uptake of glutathione, an important component of intracellular antioxidant defenses. GGT could be informative in children with NAFLD because its expression is enhanced by oxidative stress and it could be released by several conditions inducing cellular stress and insulin resistance; both insulin resistance and oxidative stress are key components in the development of NAFLD.42

The main strengths of our study are the inclusion of children with the whole spectrum of NAFLD from simple steatosis to cirrhosis along with the long-term follow-up of up to 20 years. The cases were well documented with all children having the diagnosis of NAFLD confirmed by radiological findings, and in almost half of them with liver histology. However, our study has some limitations. First, our patients were seen in a referral tertiary care medical center, and although the results may be extrapolated to other similar medical centers, the results most likely may not apply to children with NAFLD from the community. In this regard, larger community- or population-based studies are necessary to determine the prognosis of NAFLD in children from the general population. Second, most of our children (80%) were white, and thus, whether or not the long-term prognosis of pediatric NAFLD is any different among the different ethnic groups needs to be investigated. Finally, since liver biopsy is not part of the standard of care to confirm the diagnosis of NAFLD, only about a half of our children underwent liver biopsy, and thus, we were not able to determine the prognostic significance of the individual histological features.

In summary, our study demonstrates that NAFLD in children is associated with a significantly shorter survival as compared to survival of the general population of same age and sex. NAFLD in children may progress to cirrhosis and end-stage liver disease with the consequent need for liver transplantation, but NAFLD with severe NASH may recur in the allograft. Further studies are needed to identify those children with NAFLD who are at a higher risk for disease progression who would be expected to benefit the most from medical therapy.

ACKNOWLEDGEMENTS

Dr. P.C. was supported by a grant from the Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok. Dr. S.T was supported by a medical research scholarships from Faculty of Medicine, Chulalongkorn University, Bangkok.

Abbreviations

NAFLD
nonalcoholic fatty liver disease
AST
aspartate aminotransferase
ALT
alanine aminotransferase
ANA
antinuclear antibody
ASMA
antismooth muscle antibody

Footnotes

Statements:

The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in Gut editions and any other BMJPGL products to exploit all subsidiary rights, as set out in our license (http://gut.bmjjournals.com/ifora/licence.dtl).”

STATE OF COMPETING INTEREST

None to declare.

REFERENCES

1. Schwimmer JB, Deutsch R, Kahen T, et al. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118:1388–1393. [PubMed]
2. Tominaga K, Kurata JH, Chen YK, et al. prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci. 1995;40:2002–2009. [PubMed]
3. Franzese A, Vajro P, Argenziano A, et al. Liver involvement in obese children. Ultrasonography and liver enzymes levels at diagnosis and during follow-up in an Italian population. Dig Dis Sci. 1997;42:1428–1432. [PubMed]
4. Chan DF, Li AM, Chu WC, et al. Hepatic steatosis in obese Chinese children. Int J Obes Relat Metab Disord. 2004;28:1257–1263. [PubMed]
5. Baldridge AD, Perez-Atayde AR, Grame-Cooke F, et al. Idiopathic steatohepatitis in childhood: A multicenter retrospective study. J Pediatr. 1995;127:700–704. [PubMed]
6. Franzese A, Vajro P, Argenziano A, et al. Liver involvement in obese children. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. Dig Dis Sci. 1997;42:1428–1432. [PubMed]
7. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatric Gastroenterol Nutr. 2000;30:48–53. [PubMed]
8. Demir H, Kocak N, Gurakan F, et al. Obesity: a cause of steatohepatitis in children. Am J Gastroenterol. 2000;95:1366–1367. [PubMed]
9. Manton ND, Lipsett J, Moore DJ, et al. Nonalcoholic steatohepatitis in children and adolescents. Med J Aust. 2000;173:476–479. [PubMed]
10. Schwimmer JB, Deutsch R, Rauch JB, et al. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr. 2003;143:500–505. [PubMed]
11. Schwimmer JB, McGreal N, Deutsch R, et al. Influence of gender, race, and ethnicity on suspected fatty liver in obese adolescents. Pediatrics. 2005;115:e561–5. [PubMed]
12. Nobili V, Marcellini M, Devito R, et al. NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology. 2006;44:458–65. [PubMed]
13. Patton HM, Sirlin C, Behling C, et al. Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research. J Pediatr Gastroenterol Nutr. 2006;43:413–427. [PubMed]
14. Manco M, Marcellini M, Devito R, et al. Metabolic syndrome and liver histology in paediatric non-alcoholic steatohepatitis. Int J Obes (Lond) 2008;32:381–387. [PubMed]
15. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–1231. [PubMed]
16. Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–74. [PubMed]
17. Dam-Larsen S, Franzmann M, Andersen IB, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53:750–755. [PMC free article] [PubMed]
18. Ekstedt M, Franzen LE, Mathiensen UI, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–873. [PubMed]
19. Adams LA, Lymp JF, Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–121. [PubMed]
20. Kinugasa A, Tsunamoto K, Furukawa N, et al. Fatty liver and its fibrous changes found in simple obesity of children. J Pediatr Gatroenterol Nutr. 1984;3:408–414. [PubMed]
21. Molleston JP, White F, Teckman J, et al. Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroenterol. 2002;97:2460–2462. [PubMed]
22. Suzuki D, Hashimoto E, Kaneda K, et al. Liver failure caused by non-alcoholic steatohepatitis in an obese young male. J Gastroenterol Hepatol. 2005;20:327–329. [PubMed]
23. Melton LJ., 3rd History of the Rochester Epidemiology Project. Mayo Clin Proc. 1996;71:266–74. [PubMed]
24. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: United States. Adv Data. 2000;8(314):1–27. [PubMed]
25. NGHS Coordinating Center . NHLBI Growth and Health Study (NGHS) data monitoring report. Maryland Medical Research; Baltimore: 1998.
26. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2005;28(Suppl 1):S37–S42. [PubMed]
27. Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: a working group report from the National High Blood Pressure Education Program. Pediatrics. 1996;98:649–658. [PubMed]
28. National Cholesterol Education Program Report of the Expert Panel on Blood Cholesterol in Children and Adolescents. Pediatrics. 1998;101:141–147.
29. Weiss R, Dziura J, Burgert TS, et al. Obesity and the Metabolic Syndrome in Children and Adolescents. N Engl J Med. 2004;350:2362–2374. [PubMed]
30. Zimmet P, Alberti G, Kaufman F, et al. The metabolic syndrome in children and adolescents. Lancet. 2007;369:2059–2061. [PubMed]
31. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21. [PubMed]
32. Therneau T, Offord J. Expected Survival Based On Hard Rates (Update) Department of Health Science Research. Section of Biostatistics, Mayo Clinic; Rochester, MN: 1999. (Technical Report Series No.63).
33. Ederer F. The Relative Survival Rate: a statistical methodology. National Cancer Institute Monograph. 1961;6:101–21. [PubMed]
34. Jonas MM, Krawczuk LE, Kim HB, et al. Rapid recurrence of nonalcoholic fatty liver disease after transplantation in a child with hypopituitarism and hepatopulmonary syndrome. Liver Transpl. 2005;11:108–110. [PubMed]
35. Jankowska I, Socha P, Pawlowska J, et al. Recurrence of non-alcoholic steatohepatitis after liver transplantation in a 13-yr-old boy. Pediatr Transplant. 2007;11:796–798. [PubMed]
36. Adams LA, Feldstein A, Lindor KD, et al. Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. Hepatology. 2004;39:909–914. [PubMed]
37. Adams LA, Lindor KD, Angulo P. The prevalence of autoantibodies and autoimmune hepatitis in patients with nonalcoholic Fatty liver disease. Am J Gastroenterol. 2004;99:1316–1320. [PubMed]
38. Lee DH, Ha MH, Kim JH, Christiani DC, Gross MD, Steffes M, Blomhoff R, Jacobs DR., Jr Gamma-glutamyltransferase and diabetes--a 4 year follow-up study. Diabetologia. 2003 Mar;46(3):359–64. Epub 2003 Mar 1. [PubMed]
39. Nakanishi N, Nishina K, Li W, Sato M, Suzuki K, Tatara K. Serum gamma-glutamyltransferase and development of impaired fasting glucose or type 2 diabetes in middle-aged Japanese men. J Intern Med. 2003 Sep;254(3):287–95. [PubMed]
40. Kim DJ, Noh JH, Cho NH, Lee BW, Choi YH, Jung JH, Min YK, Lee MS, Lee MK, Kim KW. Serum gamma-glutamyltransferase within its normal concentration range is related to the presence of diabetes and cardiovascular risk factors. Diabet Med. 2005 Sep;22(9):1134–40. [PubMed]
41. Kang YH, Min HK, Son SM, Kim IJ, Kim YK. The association of serum gamma glutamyltransferase with components of the metabolic syndrome in the Korean adults. Diabetes Res Clin Pract. 2007;77:306–13. [PubMed]
42. Day CP. From fat to inflammation. Gastroenterology. 2006;130:207–210. [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...