Rare and undiagnosed liver diseases: challenges and opportunities.

According to the statement of the European Commission of Public Health, rare diseases (RDs) are a group of ‘life-threatening or chronically debilitating diseases which are of such low prevalence that special combined efforts are needed to address them’ (1). Epidemiological criteria are essential for their definition. In Europe, a disease whose prevalence is lower than one in 2,000 people is considered a RD, while in the USA prevalence of a RD is less than one in 1,500 people, derived from the definition of a disease affecting fewer than 200,000 Americans. The difference in the prevalence thresholds between Europe and the USA reflects the wide variability among individual jurisdictions dependent on the current estimates of the population size in the different countries (2). At present, about 7,000 different diseases are recognized as ‘rare’, and altogether, affect about 400 million people worldwide (3). In a considerable percentage of patients (nearly 30%), the diseases prolong into the adult age or manifest in the adult age. Thus, this is a field of medicine that concerns both pediatrician and adult physicians and spans across all medical and surgical specialties. Most RDs (about 80%) are caused by monogenic defects. However, a perturbed homeostatic response of the cell may activate other disease mechanisms, including autoimmunity and autoinflammation, susceptibility to infectious agents and cancer. In addition, the correlation between genotype and phenotype is often quite variable. In fact, in a number of RDs, affected genes control fundamental development processes resulting in a multifaceted clinical phenotype and multiorgan involvement. According to the Orphanet database, about 25% of rare patients die before 5 years, whereas an additional 37% have a reduced life expectancy, variably dependent on the severity of the RD (4). Too often, the diagnosis represents a big challenge. Because of the limited awareness of these conditions and the scarcity of centers with adequate clinical experience and laboratory skills, the diagnosis is difficult to achieve and is thus often delayed. Notably, the average time for a patient with a rare disease to receive an accurate diagnosis is nearly 5 years (3). Unfortunately, despite repeated costand time-consuming efforts, several (6%) remain undiagnosed (5). Even when a diagnosis is reached, often the treatment options are limited. In spite of the recent progresses, it is estimated that 95% of RDs still lack an FDA approved treatment. It may take 10–12 years for a new drug to be approved for the cure of rare disease patients (6). This long avenue is also partly dependent on the difficulties in conducting clinical trials in rare diseases (small cohorts of widely dispersed patients in both pediatric and adult age, lack of validated biomarkers and qualified endpoints). Therefore, RDs are also often referred to as ‘orphan’ to highlight the concept that effective treatments are lacking as not enough research and drug development efforts are devoted to that problem. It is worth noting that only one in two RDs has a foundation or research support group, thereby limiting the access to grant opportunities (3). The majority of research funding is assigned to the most frequent diseases or as a reaction to particular events. It should be noted however, that funding research on RDs would also benefit the more prevalent diseases, as a result of the novel cellular functions and targets discovered.