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Corresponding author. Address: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Padiglione Marangoni, Ospedale Policlinico, via F Sforza 35, 20122 Milano (MI), Italy. Tel.: +39-02-50320278.
Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, ItalyDepartment of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy
Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, ItalyDepartment of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy
Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, ItalyDepartment of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy
Chronic liver disease (CLD) is a significant health problem affecting more than 4 million people in the United States and leading to over 40,000 deaths annually.1 CLD is often undiagnosed for many years unless there is awareness of subtle clinical signs, behavioral risk factors and/or investigation of abnormal liver function tests. In many patients, by the time overt manifestations of CLD emerge, liver injury has advanced to result in portal hypertension or hepatic decompensation. The taxonomy of CLD in clinical practice is based broadly on categories of etiology such as exposure to toxins, viral infections, cholestatic, autoimmune, metabolic and select genetic disorders.
We read with interest the study by Hakim et al., and the related comment by Pinto e Vairo and Lazaridis, on the application of a personalized medicine approach based on whole exome sequencing (WES) for diagnosing young patients with unexplained liver disease.
By performing WES in 19 patients with severe cryptogenic liver disease, not related to alcohol abuse, but also including fatty liver disease not associated with obesity, Hakim et al. identified and characterized in 5 (25%) inherited variants in ABCB4, PPARG, NDUFB3, and APOB. These variants were selected based on the frequency (rare), predicted impact on protein activity, and localization at genomic loci previously associated with liver disease. Importantly these variants resulted in phenotypes consistent with a loss-of-function of the encoded proteins. These genetic diagnoses had implications for clinical management, treatment, and family counselling of the affected individuals.
Overall, their findings supported the utility of WES for diagnosing patients with unexplained liver disease, including adults with symptoms onset before the age of 40 years.
We recently applied the same WES approach to a cohort of 201 patients with severe liver disease (advanced fibrosis with or without hepatocellular carcinoma), which was attributed to non-alcoholic fatty liver disease (NAFLD).
We used even more strict criteria for variants prioritization based on allelic frequency (<0.001), affected genes (a predefined list of 181 implicated in liver disease, lipid metabolism and hereditary cancer), and predicted impact (mutations already defined as pathogenic or with a very high likelihood of altering protein activity), to define pathogenic mutations. By consulting the Clinvar database reporting variants already defined as pathogenic, we identified a genotype consistent with a genetic diagnosis of Mendelian disease, which predisposed patients to liver disease or cancer in 22 cases (11%). In keeping with the results of Hakim et al.,
Loss-of-function variants in APOB, encoding for apolipoprotein B, are responsible for hypo-betalipoproteinemia, an autosomal dominant condition characterized by fatty liver related to altered very low-density lipoprotein secretion, which may also be associated with malabsorption determining low body mass and damage to the intestinal barrier.
When we selected variants based on the likelihood of them being pathogenic, we confirmed a strong enrichment in multiple genes, including APOB, compared to healthy individuals (Fig. 1). Confirming the genetic diagnoses, carriage of such APOB variants resulted in a circulating lipid profile consistent with hypo-betalipoproteinemia.
Of the 15 patients with APOB mutations with advanced liver disease associated with NAFLD, 7 (47%) were obese, 5 (33%) overweight, and 3 (20%) had normal weight.
Fig. 1Computation plot showing the distribution of likely pathogenic inherited variants enriched in patients with NAFLD-HCC compared to controls in patients with severe liver disease related to NAFLD. HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease. p <0.0001 at Fisher's exact test for the overall enrichment of rare pathogenic variants in patients with NAFLD-HCC vs.controls.
However, it should be noted at the same time that the cumulative rate of carriage of variants in genes associated with liver disease is relatively high in the general population. In addition, carriage of APOB mutations may even protect against cardiovascular disease in the absence of cofactors for hepatotoxicity.
Furthermore, as also reported in the Journal, the list of genes whose mutations cause development of severe fatty liver in adults is rapidly expanding.
Careful evaluation of the phenotype associated with single mutations and family history, coupled with in silico and functional studies leading to the update of public database will therefore be required to accurately interpret the WES results in clinical practice.
In conclusion, we propose that additional studies are carried out to evaluate the impact of WES or more targeted resequencing approaches in selected categories of liver disease patients older than 40 years, due to the possible large impact on liver disease management and screening in family members. In addition, APOB mutations are likely an underdiagnosed factor contributing to the development of advanced fatty liver disease, even in those with increased adiposity, which may even represent a triggering factor for the development of hepatocellular damage.
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