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Neonatal and infantile cholestasis (NIC) can represent the onset of a surgically correctable disease and of a genetic or metabolic disorder worthy of medical treatment. Timely recognition of NIC and identification of the underlying etiology are paramount to improve outcomes. Upon invitation by the Italian National Institute of Health (ISS), an expert working grouped was formed to formulate evidence-based positions on current knowledge about the diagnosis of NIC. A systematic literature search was conducted to collect evidence about epidemiology, etiology, clinical aspects and accuracy of available diagnostic tests in NIC. Evidence was scored using the GRADE system. All recommendations were approved by a panel of experts upon agreement of at least 75% of the members. The final document was approved by all the panel components. This position document summarizes the collected statements and defines the best-evidence diagnostic approach to cholestasis in the first year of life.

Results of recent studies have shown that disease models using human induced pluripotent stem (iPS) cells have recapitulated the pathophysiology of genetic liver diseases, viral hepatitis and hepatic fibrosis. The utilization of human iPS cells as a model of liver diseases has several substantial advantages compared with primary hepatocytes and cancer cell lines, such as the potential for unlimited expansion and similarity of biological characteristics to normal liver cells. In this review, we have focused on modeling liver diseases using human iPS cells and discussed the experimental evidence that supports the utility of such disease models, including that in our recent studies. Genetically modified or patient-derived human iPS cells can mimic congenital liver disease phenotypes. Human iPS-derived hepatic cells can be infected with the hepatitis viruses. The co-culture of human iPS-derived hepatocytes and mesenchyme partially mimics the process of liver fibrosis. Human iPS cell-derived hepatic cells and the co-culture system of such cells will contribute to the progress of studies on the pathophysiology of genetic and non-genetic liver diseases and development of novel therapeutic strategies for treating liver diseases.

The presence of the homozygous &lsquo, Pi*Z&rsquo, variant of alpha-1 antitrypsin (AAT) (&lsquo, Pi*ZZ&rsquo, genotype) predisposes to liver fibrosis development, but the role of iron metabolism in this process remains unknown. Therefore, we assessed iron metabolism and variants in the Homeostatic Iron Regulator gene (HFE) as the major cause of hereditary iron overload in a large cohort of Pi*ZZ subjects without liver comorbidities. The human cohort comprised of 409 Pi*ZZ individuals and 254 subjects without evidence of an AAT mutation who were recruited from ten European countries. All underwent a comprehensive work-up and transient elastography to determine liver stiffness measurements (LSM). The corresponding mouse models (Pi*Z overexpressors, HFE knockouts, and double transgenic [DTg] mice) were used to evaluate the impact of mild iron overload on Pi*Z-induced liver injury. Compared to Pi*Z non-carriers, Pi*ZZ individuals had elevated serum iron, transferrin saturation, and ferritin levels, but relevant iron overload was rare. All these parameters were higher in individuals with signs of significant liver fibrosis (LSM &ge, 7.1 kPa) compared to those without signs of significant liver fibrosis. HFE knockout and DTg mice displayed similar extent of iron overload and of fibrosis. Loss of HFE did not alter the extent of AAT accumulation. In Pi*ZZ individuals, presence of HFE mutations was not associated with more severe liver fibrosis. Taken together, Pi*ZZ individuals display minor alterations in serum iron parameters. Neither mild iron overload seen in these individuals nor the presence of HFE mutations (C282Y and H63D) constitute a major contributor to liver fibrosis development.

Crigler‐Najjar syndrome type I (CNSI) is a rare monogenic disease characterized by severe neonatal unconjugated hyperbilirubinemia with a lifelong risk of neurological damage and death. Liver transplantation is the only curative option, which has several limitations and risks. We applied an in vivo gene targeting approach based on the insertion, without the use of nucleases, of a promoterless therapeutic cDNA into the albumin locus of a mouse model reproducing all major features of CNSI. Neonatal transduction with the donor vector resulted in the complete rescue from neonatal lethality, with a therapeutic reduction in plasma bilirubin lasting for at least 12 months, the latest time point analyzed. Mutant mice, which expressed about 5–6% of WT Ugt1a1 levels, showed normal liver histology and motor‐coordination abilities, suggesting no functional liver or brain abnormalities. These results proved that the promoterless gene therapy is applicable for CNSI, providing therapeutic levels of an intracellular ER membrane‐bound enzyme responsible for a lethal liver metabolic disease.

A psychiatric involvement is frequently present in Wilson’s disease. Psychiatric symptoms are sometimes the first and only manifestation of Wilson’s disease. More often a psychiatric involvement is present beside a neurologic or hepatic disease. We describe the case of a 18 years-old male patient who shows a clinic and laboratoristic pattern of cirrhosis and an history of subchronic hallucinatory psychosis, behavioral symptoms and mood disturbances with depressed mood. He hadn’t familiar history of liver or psychiatric disease. Laboratory and imaging tests confirmed the diagnosis of Wilson’s disease with psichiatric involvement. After liver transplantation copper metabolism and liver function normalised and we noticed no recurrency of the psichiatric illness. Very few cases of psychiatric improvement after orthotopic liver transplantation (OLT) has been described until now.