ABSTRACT
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe rare liver disease that affects between 1/50,000 and 1/100,000 children. In physiological conditions, bile is produced by the liver and stored in the gallbladder, and then it flows to the small intestine to play its role in fat digestion. To prevent tissue damage, bile acids (BAs) are kept in phospholipid micelles. Mutations in phosphatidyl choline transporter ABCB4 (MDR3) lead to intrahepatic accumulation of free BAs that result in liver damage. PFIC3 onset usually occurs at early ages, progresses rapidly, and the prognosis is poor. Currently, besides the palliative use of ursodeoxycholate, the only available treatment for this disease is liver transplantation, which is really challenging for short-aged patients. To gain insight into the pathogenesis of PFIC3 we have performed an integrated proteomics and phosphoproteomics study in human liver samples to then validate the emerging functional hypotheses in a PFIC3 murine model. We identified 6246 protein groups, 324 proteins among them showing differential expression between control and PFIC3. The phosphoproteomic analysis allowed the identification of 5090 phosphopeptides, from which 215 corresponding to 157 protein groups, were differentially phosphorylated in PFIC3, including MDR3. Regulation of essential cellular processes and structures, such as inflammation, metabolic reprogramming, cytoskeleton and extracellular matrix remodeling, and cell proliferation, were identified as the main drivers of the disease. Our results provide a strong molecular background that significantly contributes to a better understanding of PFIC3 and provides new concepts that might prove useful in the clinical management of patients.
ABSTRACT
Coronavirus disease-2019 (COVID-19) is a global public health emergency with numerous clinical facets, including acute kidney injury and acute cerebrovascular disease. Further knowledge of its various pathogenic mechanisms is essential, including coagulation disorders. Monoclonal gammopathy is characterized by the overproduction of a monoclonal immunoglobulin caused by clonal proliferation. Using a postmortem study of ultrasound-guided percutaneous core biopsies, the aim of this report is to present our observations on the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection pathology associated with monoclonal gammopathy. The clinical presentation was acute renal failure. Pathological findings revealed kappa light chain cast nephropathy. SARS-CoV-2 immunohistochemistry was positive in some renal tubular cells. Another notable finding was the presence of a high density of alveolar megakaryocytes, which probably explained the final outcome (acute cerebrovascular disease). Immunohistochemical study for SARS-CoV-2 does not verify the pathogenic effect of the virus and thus its contribution to the acute kidney injury.
