Improving the lives of adults with liver disease by focusing on children


  • Saul J. Karpen M.D., Ph.D.

    Corresponding author
    1. Texas Children's Liver Center, Department of Pediatrics/Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine, Houston, TX
    • Texas Children's Liver Center, Department of Pediatrics/Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030
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    • fax: 832-825-4893.

  • Potential conflict of interest: Nothing to report.

Among the more complex aspects of caring for patients with liver disease is the patient-to-patient variability in presentation and disease progression, compounded by the short list of effective therapeutics. In large part, we rely upon the patient's liver to engage its own means of adaptation to disease, with care plans dependent upon how well this works. Some patients appear to be genetically preprogrammed to readily adapt to their diseases with slow timelines, often measured in decades, while others progress more rapidly and floridly. Examples of the former include viral hepatitis, and the latter include cholestatic diseases in childhood, which over the course of only a few months, may lead to cirrhosis and end-stage liver disease. There are myriad contributors to an individual's response to disease, but advances over recent years point toward an individual's genetic composition as perhaps the primary determinant of disease response. We are now in an era where application of current methodologies make these genetic determinants discoverable. If we are hoping to understand what makes one person fare well and another poorly when faced with the same disease, it is best to use well-controlled clinical trials in the most informative and well-characterized population. This is a daunting task for many adult liver diseases, given their slow and variable progression and the contributions to survival from sources outside the liver, including diet, lifestyle, medications, and diseases that affect other organs. The focus of this commentary is to propose the concept that the optimal age to understand personalized adaptation to liver disease is best explored during the time when genes involved in adaptation to life and disease are given their first “test drive”—childhood.


NAFLD, nonalcoholic fatty liver disease.

Studies of children with liver disease may point the way toward a clearer understanding of etiology, adaptation, and perhaps treatment of adult diseases. With regards to etiology, single-gene mutations provide extreme examples where disease progression is more rapid and evident in childhood. A ready example is that of hypercholesterolemia due to low-density lipoprotein receptor deficiency, which leads to accelerated atherosclerosis in early childhood. Such studies of a rare disease led the way to a nearly universal focus upon cholesterol dynamics as a main survival marker for adult health. In the liver, the recent identification of single-gene mutations in hepatobiliary transporters as causes for inherited cholestatic syndromes has led to an understanding that mutations and polymorphisms of such genes are contributors to adult diseases such as benign recurrent intrahepatic cholestasis, intrahepatic gallstones, intrahepatic cholestasis of pregnancy, drug-induced liver injury, and others. These studies are in their infancy, but these genes were first identified in childhood liver diseases and may prove to be major determinants of disease modification in adults with cholestatic and bile duct diseases.

The genetic underpinnings of adaptation to liver disease is poorly understood and may, in fact, play a greater role than disease etiology in determining life-span of both adults and children. Most patients would just like us to make them feel better and live longer, perhaps by improving adaptation to disease, especially if the disease itself cannot be eradicated. Recent years have seen a veritable explosion of new understanding of how the liver responds to injury, and that it involves many distinct genes and pathways, each of which is likely modified by the individual's genetic composition. For example, if a patient has a genetically determined means of enhancing detoxification, or quieting the immune response to liver injury, it may positively affect their disease progression and survival from a host of causes. On the other hand, if there are impairments in genes and pathways involved in hepatic necrosis, apoptosis, regeneration, fibrosis, detoxification, cholestasis, inflammation, nutrition, etc., then adaptation would not be optimal, and that person would likely fare more poorly than someone who did not have this genetic component (that is, genetic modifiers). Children with biliary tract and cholestatic diseases may prove to be one of the best populations to explore these adaptive mechanisms, because there is a spectrum of disease progression between patients, and the timelines to determine these stratifications of outcomes are short, on the order of months. For example, if a patient cannot adapt well to cholestasis, as seen in a substantial proportion of children with biliary atresia or parenteral nutrition–associated cholestasis, they will progress to cirrhosis and end-stage liver disease, often within the first 6 months of life. With such a short timeline, survival is the major concern, but this may prove to be the right patient population to understand human adaptation, with insights into disease progression in adult cholestatic diseases, as well as provide new molecular targets for therapies.

Another readily evident disease in which adaptation appears to be a major component of disease progression is fibrosis associated with nonalcoholic fatty liver disease (NAFLD). Certain populations have already been identified in childhood where fibrosis, and even cirrhosis, can occur before these patients enter high school. That fibrosis and cirrhosis occurs in some children with NAFLD and not in others supports exploration into the genetic contribution to disease progression, which is more likely to be rapidly discovered in this population than in adults with NAFLD.

As we identify the molecular targets that mediate hepatic adaptation to cholestasis and NAFLD, it is clear that these populations are uniquely situated to identify the individual genetic makeup that distinguishes those children who do well from those who do not, and provide select subpopulations who may benefit most from targeted therapies. The pediatric population is arguably a purer reflection of the adaptive mechanisms to liver disease without the overlay of years, lifestyle exacerbants, or residua of attempted therapies. Rapid identification of these targets in adult populations is less likely, taking into account the various ages, lifestyle, and comorbidities which would require larger populations to achieve the same aims.

It is evident that the optimal means of understanding pathogenesis and identifying therapeutic targets to help children with liver diseases is the study of such children. The same is true for adult diseases, which are best studied and understood with appropriately-powered adult population studies. It makes sense that detailed studies of those patients with a rapid timeline to disease progression (be it viral hepatitis, NAFLD, cholestasis, or others) will likely uncover which genes and pathways are not working to their fullest capacity, when compared to those that adapt well. I expect the outcomes of these studies in children will trickle up to adults by readily identifying critical adaptation genes, and thus therapeutic targets, which can rapidly be tested in adults. With exploration of pathways involved in adaptation to liver disease, where the liver is central to the metabolic needs of the patient yet is reacting to the disease process, we should be able to home in on potential therapeutic targets. This information can be used to direct a focused screening of chemical libraries to identify candidate pharmaceuticals that appropriately modulate the function of these targets towards improved adaptation. The targets may be in apoptotic pathways, innate immunity, autoimmunity, nuclear receptors, or most likely others not already considered. With shorter timelines for disease progression and response to therapy, limited need for large study populations and minimal comorbidities, it is clear that for many of these disease processes, children will lead the way.