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Intestinal failure (IF) is a condition in which severe intestinal malabsorption mandates artificial nutrition through a parenteral route. Causes of severe protracted IF include short bowel syndrome, congenital diseases of enterocyte development, and severe motility disorders (total or subtotal aganglionosis or chronic intestinal pseudo-obstruction syndrome). IF can result in nutritional failure, defined as the long-term failure to nourish a child by natural or artificial means. Today, IF-associated liver disease is the most common cause of parenteral nutrition (PN) failure, but catheter-related sepsis and extensive vascular thrombosis may also jeopardize the health of those receiving PN. For a child with nutritional failure, intestinal transplantation, often in the form of a composite visceral graft, offers the only chance for long-term survival. The management of IF requires a multidisciplinary approach. There have been a number of recent advances in both medical and surgical treatments of IF. In particular, new intestinal lengthening techniques and the use of PN formulas rich in fish oil both have resulted in decreased rates of severe complications of IF and its treatments. In addition, better awareness of the risks and benefits of intestinal transplantation have resulted in better patient selection, and ultimately in improved patient survival, hence restricting the indication to transplantation only to patients with nutritional failure and no other chance to survive.

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While the prevalence of most diseases caused by single-gene mutations is low and defines them as rare conditions, all together, monogenic diseases account for approximately 10 in every 1000 births according to the World Health Organisation. Orthotopic liver transplantation (LT) could offer a therapeutic option in monogenic diseases in two ways: by substituting for an injured liver or by supplying a tissue that can replace a mutant protein. In this respect, LT may be regarded as the correction of a disease at the level of the dysfunctional protein. Monogenic diseases that involve the liver represent a heterogeneous group of disorders. In conditions associated with predominant liver parenchymal damage (i.e., genetic cholestatic disorders, Wilson's disease, hereditary hemochromatosis, tyrosinemia, α1 antitrypsin deficiency), hepatic complications are the major source of morbidity and LT not only replaces a dysfunctional liver but also corrects the genetic defect and effectively cures the disease. A second group includes liver-based genetic disorders characterised by an architecturally near-normal liver (urea cycle disorders, Crigler-Najjar syndrome, familial amyloid polyneuropathy, primary hyperoxaluria type 1, atypical haemolytic uremic syndrome-1). In these defects, extrahepatic complications are the main source of morbidity and mortality while liver function is relatively preserved. Combined transplantation of other organs may be required, and other surgical techniques, such as domino and auxiliary liver transplantation, have been attempted. In a third group of monogenic diseases, the underlying genetic defect is expressed at a systemic level and liver involvement is just one of the clinical manifestations. In these conditions, LT might only be partially curative since the abnormal phenotype is maintained by extrahepatic synthesis of the toxic metabolites (i.e., methylmalonic acidemia, propionic acidemia). This review focuses on principles of diagnosis, management and LT results in both paediatric and adult populations of selected liver-based monogenic diseases, which represent examples of different transplantation strategies, driven by the understanding of the expression of the underlying genetic defect.