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We report on a small bowel transplant patient, donor/recipient seropositive (D+/R+) for cytomegalovirus (CMV), with a clinical course complicated by CMV disease. Anti-CMV prophylaxis was given for 100 days. Immunosuppression consisted of alemtuzumab, tacrolimus, mycophenolate mofetil and prednisolone. Five months posttransplant, CMV tissue invasive disease of the upper gastrointestinal tract was evident without the presence of viremia, tested by quantitative polymerase chain reaction (PCR). Complete viral load suppression was achieved with intravenous ganciclovir, followed by valganciclovir for secondary prophylaxis. Mycophenolate mofetil and prednisolone were discontinued. Shortly thereafter the patient presented with recurrent CMV and candida esophagitis. While on ganciclovir and caspofungin, the patient developed CMV tissue invasive disease of the ileal graft, with persistent absence of viremia. Foscarnet and CMV immunoglobulin were added. Viral load declined to undetectable levels; however, clinical improvement did not occur due to occurrence of graft rejection. Despite infliximab and high dose prednisolone, graft rejection was progressive, requiring surgical explantation of the graft. This case highlights the importance of additional diagnostic tools such as endoscopy including PCR analysis of tissue samples. Extension of primary antiviral prophylaxis interval up to 6 months and prolonged retreatment for recurrent CMV disease may be useful to avoid severe CMV-related complications.

α1-Antitrypsin deficiency is an inherited condition that causes liver disease and emphysema. The normal function of this protein, which is synthesized by the liver, is to inhibit neutrophil elastase, a protease that degrades connective tissue of the lung. In the classical form of the disease, inefficient secretion of a mutant α1-antitrypsin protein (AAT-Z) results in its accumulation within hepatocytes and reduced protease inhibitor activity, resulting in liver injury and pulmonary emphysema. Because mutant protein accumulation increases hepatocyte cell stress, we investigated whether transplanted hepatocytes expressing wild-type AAT might have a competitive advantage relative to AAT-Z–expressing hepatocytes, using transgenic mice expressing human AAT-Z. Wild-type donor hepatocytes replaced 20%–98% of mutant host hepatocytes, and repopulation was accelerated by injection of an adenovector expressing hepatocyte growth factor. Spontaneous hepatic repopulation with engrafted hepatocytes occurred in the AAT-Z–expressing mice even in the absence of severe liver injury. Donor cells replaced both globule-containing and globule-devoid cells, indicating that both types of host hepatocytes display impaired proliferation relative to wild-type hepatocytes. These results suggest that wild-type hepatocyte transplantation may be therapeutic for AAT-Z liver disease and may provide an alternative to protein replacement for treating emphysema in AAT-ZZ individuals.

Hereditary systemic amyloidosis is a genetically and clinically heterogeneous group of diseases caused by deposits of insoluble proteins within tissues. The majority of cases are due to a mutation ...

Ghrelin is a 28-amino acid peptide hormone secreted from the stomach that acts as a gut-brain peptide with potent stimulatory effects on food intake. The aim of the present study was to investigate the effects of peripheral ghrelin (1 and 10 nmol/rat) injected intraperitoneally (i.p.) on food intake and neuronal activity in the hypothalamus and brain stem, as assessed by c-Fos-like-immunoreactivity (c-FLI), using a confocal laser scanning microscope (cLSM) as a sensitive microscopic technique to detect c-FLI-positive neurons. Cumulative food intake was significantly increased 5.3- and 3.7-fold for the 4-h period after i.p. injection of ghrelin at both doses. The number of c-FLI-positive neurons in the paraventricular nucleus of the hypothalamus (PVN) was significantly increased after peripheral administration of ghrelin (1 nmol i.p.; median: 41.8) compared with i.p. saline (median: 17.5). As described before, c-fos expression was increased in the arcuate nucleus of the hypothalamus (ARC). In the nucleus of the solitary tract (NTS) or the area postrema (AP), there was no significant change in the density of c-FLI-positive neurons. Our data suggest that an activation of the arcuate-paraventricular axis may be part of the brain circuits involved in the orexigenic effect of peripheral ghrelin.

Bilirubin is the degradation product of the heme moiety of hemoglobin and other hemoproteins. Bilirubin is potentially toxic, requiring a multistep detoxification and excretion process, which can be affected by a multitude of inherited and acquired diseases. This chapter discusses these physiological processes, focusing on inherited disorders that can cause hyperbilirubinemia through perturbation of one or more of these steps.

AIM: To investigate the side effects of a zinc sulphate therapy in a cohort of Polish pediatric patients with Wilson’s disease. METHODS: We retrospectively analyzed a cohort of 53 pediatric patients with Wilson’s disease treated at the Children’s Memorial Health Institute in Warsaw, Poland between the years 1996 and 2011 with zinc sulphate. Patients were diagnosed with Wilson’s disease according to the scoring system of Ferenci, with 49 cases confirmed by mutation analysis. Data about the dosage scheme of zinc sulphate, side effects and efficacy and toxicity of the treatment were collected and recorded in the patient’s medical chart at each visit to the hospital. RESULTS: Mean age of diagnosis for the entire cohort was 10 years (range, 2.5-17 years). Duration of treatment with zinc sulfate was 83.3 wk (range, 8-344 wk). Side effects, all of gastrointestinal origin, were observed in 21 patients (40% - 9 males and 12 females), irrespective of the duration of therapy. Thirteen out of 21 patients were over the age of 10 years. The most common ATP7B mutation was p.H1069Q. Esophagogastroduodenoscopy, performed in 7 patients (33.3%) suffering from persistent and severe abdominal pain, revealed gastrointestinal ulcerations or erosions with negative Helicobacter pylori tests in all subjects investigated. The above mentioned 7 patients were treated with proton pump inhibitors. Three of those experienced resolution of symptoms, whereas proton-pump inhibitors failed to alleviate symptoms of the remaining four children and conversion of therapy to D-penicillamine was needed. CONCLUSION: Zinc sulphate appears to cause significant gastrointestinal side effects, which children on therapy for Wilson’s disease should be closely monitored for.

Thoracic splenosis (TS) is autoimplantation of ectopic splenic tissue in the thoracic cavity that occurs following splenic injury. Most cases of TS are asymptomatic and are diagnosed during the course of an evaluation of incidentally discovered pulmonary lesions. Some cases may be difficult to diagnose, especially if features suggesting TS are not recognized. This may lead to an extensive workup and unnecessary invasive diagnostic procedures including thoracotomy. Multiple, asymptomatic, left-sided pleura-based lesions associated with a history of thoracoabdominal injury and splenectomy are the key points that should alert one to suspect TS, which can then simply be confirmed with a (99m)Tcsulfa colloid radionuclide scan. If TS is suspected and radionuclide imaging studies are performed, further extensive investigations, such as bronchoscopy, biopsy, thoracoscopy, and thoracotomy, are not required as the radionuclide scan is definitive for diagnosis. Most cases are asymptomatic, so further treatment is rarely required; all cases are managed conservatively. We emphasize that all physicians, radiologists, pathologists, and interventionalists should recognize key features that suggest the diagnosis of TS, order appropriate imaging when it is suspected, and avoid unnecessary invasive diagnostic procedures including thoracotomy.

1407 TTR MUTATIONS IN GERMAN PATIENTS WITH FAMILIAL AMYLOID POLYNEUROPATHY Y. Avsar, T. Todorov, A. Zibert, I. Kabar, V. Cicinnati, S. Beckebaum, C. Roecken, A. Barreiros, H.H.-J. Schmidt. Department of Transplantation Medicine, University Hospital Munster, Munster, Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Department of Gastroenterology and Hepatology, Johannes Gutenberg University Mainz, Mainz, Germany E-mail: yesim.avsar@gmx.net

Background and Aims: Preparative hepatic irradiation (HIR), together with mitotic stimulation of hepatocytes, permits extensive hepatic repopulation by transplanted hepatocytes in rats and mice. However, whole liver HIR is associated with radiation-induced liver disease (RILD), which limits its potential therapeutic application. In clinical experience, restricting HIR to a fraction of the liver reduces the susceptibility to RILD. Here we test the hypothesis that repopulation of selected liver lobes by regional HIR should be sufficient to correct some inherited metabolic disorders. Methods: Hepatocytes (10 7 ) isolated from wildtype F344 rats or Wistar-RHA rats were engrafted into the livers of congeneic dipeptidylpeptidase IV deficient (DPPIV 2 ) rats or uridinediphosphoglucuronateglucuronosyltransferase-1A1-deficient jaundiced Gunn rats respectively by intrasplenic injection 24 hr after HIR (50 Gy) targeted to the median lobe, or median plus left liver lobes. An adenovector expressing hepatocyte growth factor (10 11 particles) was injected intravenously 24 hr after transplantation. Results: Three months after hepatocyte transplantation in DPPIV 2 rats, 30–60% of the recipient hepatocytes were replaced by donor cells in the irradiated lobe, but not in the nonirradiated lobes. In Gunn rats receiving median lobe HIR, serum bilirubin declined from pretreatment levels of 5.1760.78 mg/dl to 0.9660.30 mg/dl in 8 weeks and remained at this level throughout the 16 week observation period. A similar effect was observed in the group, receiving median plus left lobe irradiation. Conclusions: As little as 20% repopulation of 30% of the liver volume was sufficient to correct hyperbilirubinemia in Gunn rats, highlighting the potential of regiospecific HIR in hepatocyte transplantation-based therapy of inherited metabolic liver diseases.