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.