[Fulminant liver failure: etiopathogenesis and therapy]. / Insufficienza epatica fulminante: eziopatogenesi e terapia.

Fulminant hepatic failure (FHF) is a clinical syndrome characterized by the development of encephalopathy within eight weeks from the onset of the first symptoms, in the absence of previous hepatic disease. It is an uncommon but not rare disease, often fatal but potentially reversible. This article looks at the diverse aetiologies, clinical features, and current medical management, including orthotopic liver transplantation, and auxiliary orthotopic or eterotopic liver transplantation, that are the most recently adopted surgical procedures. Clinical experience with bio-artificial liver support systems of two of the most active research Groups in this field, concludes the paper.

[Acute and fulminant liver failure: experimental models]. / Insufficienza epatica acuta e fulminante: modelli sperimentali.

Fulminant hepatic failure (FHF) is a complex clinical syndrome, with an invariably high mortality rate, that follows many possible and different infectious, pharmacologic and surgical liver injuries. The appearance of the syndrome is similar whatever the etiology, but the mechanisms which lead to the development of FHF are greatly varied. In order to understand the possible pathways which drive to FHF, experimental animal models have been used for a long time. Six requirements should be fulfilled by any FHF animal model: 1) reversibility; 2) reproducibility; 3) death from liver failure; 4) the presence of a therapeutic window; 5) the need of large laboratory animal; 6) minimal hazard to personnel involved in the study. In the present paper a number of models are reported and described, and advantages and disadvantages are discussed. It is concluded that with respect to the aforementioned criteria, no available experimental model is yet as satisfactory as expected.

[In vitro experimentation of a new model of radial flow bioreactor containing isolated hepatocytes]. / Sperimentazione in vitro di un nuovo modello di bioreattore a flusso radiale contenente epatociti isolati.

Hepatocyte based artificial liver support systems are under investigation to support acute liver failure patients. The main purpose of such systems is to serve as a bridge to liver transplantation, or to promote spontaneous liver recovery. Limitation in mass-transfer capacity makes hollow-fiber bioreactors unsuited for long-term functioning of hybrid devices. We developed a novel radial-flow bioreactor in which the fluid perfuses the module from the center to the periphery, after having diffused through a space occupied by a three-dimensional structure filled with the hepatocytes. Five grams of freshly isolated porcine hepatocytes were seeded into uncoated, woven-non woven, hydrophilic polyester fabric, overlaid by two polyethersulfone membranes. Liver cells were perfused with 37 degrees C-warm, oxygenated, serum-free tissue culture medium, in which NH4Cl and Lidocaine were added at the final concentration of 1 mM and 60 micrograms/ml, respectively. Ammonium chloride removal, urea synthesis, monoethylglycinexylide (MEGX), pO2, pCO2, and pH were measured throughout the 14 day duration of the study. In a separate set of experiments, a scaled-up version of the radial flow bioreactor containing 150 grams of cells was perfused for 7 h with recirculating human plasma and MEGX production was monitored. During the 2 weeks of the study, an increasing production of urea was paralleled by constant ammonium removal. MEGX concentration after Lidocaine addition increased throughout the 14 days of perfusion with tissue culture medium, as well as after 7 hour perfusion with human plasma. Under transmission and scanning electron microscopy cells appeared attached to the polyester and one to each other, displaying ultrastructural features typical of functioning hepatocytes. Our study showed that liver cells were metabolically active when perfused into the radial-flow bioreactor. This configuration allowed close contact between media, or plasma, and cells at a physiological flow rate, by equalizing the concentration of the perfusing components, including O2, throughout the module. Our results suggest a potential use of this system for temporary extracorporeal liver support in acute hepatic failure patients.

Pancreatic beta-cell replication in streptozotocin-diabetic rats: the effect of liver compensatory growth on intraportally engrafted islets.

Early studies showed that compensatory liver growth after anterior portal branch ligation (aPBL) may restore normoglycemia in streptozotocin (STZ)-diabetic rats, in which a subtherapeutic islet mass was previously transplanted into the liver. We hypothesized that this effect could be related to islet regeneration at the graft site. This study was designed to characterize the proliferative response of the intraportally transplanted islets, shortly after aPBL. Male Wistar-Furth rats were used as syngeneic islet donors and/or recipients. STZ-diabetic rats were divided in four groups: groups 1 and 2 underwent selective 250-islet transplantation (Tx) into the posterior liver lobes, followed by aPBL 10 days later; rats were killed 24 h (n = 9) and 48 h (n = 10) after aPBL, respectively; groups 3 and 4 underwent selective 250-islet Tx into the posterior liver lobes, followed by sham aPBL 10 days later; rats were killed 24 h (n = 3) and 48 h (n = 3) after aPBL, respectively. Two hours before killing, all animals were injected with 5'-bromo-2'-deoxyuridine (BrdU; 50 mg/kg, i.v.). Liver sections were immunostained for insulin and BrdU, and both hepatocyte and islet cell labeling index (LI) were calculated. Islet cell LI was 2.30+/-1.18% in group 1, 2.23+/-1.00% in group 2, 0.43+/-0.29% in group 3, and 0.39+/-0.21% in group 4 (group 1 vs. group 3: p<0.02; group 2 vs. group 4: p<0.01). Hepatocyte LI was 2.50+/-2.14% in group 1, 15.0+/-7.6% in group 2, 0.12 +/-0.04 in group 3, and 0.11+/-0.03% in group 4, respectively (group 1 vs. group 2: p<0.02; group 1 vs. group 3: p<0.001; group 2 vs. group 4: p<0.001). Our study showed that intraportally transplanted islets undergo a concurrent proliferative response after aPBL, although with a lower extent and a different timing when compared with the liver-cell response.

Growth of intraportally transplanted islets under liver regeneration stimulus and restoration of normoglycemia in streptozocin-diabetic rats.

BACKGROUND: Limitation of beta-cell growth after intraportal islet transplantation plays an important role in graft failure. To induce transplanted beta-cell proliferation, we studied the effect of compensatory liver growth in diabetic rats that had a subtherapeutic islet mass previously injected into the liver. METHODS: Syngeneic rats were used as islet donors or recipients; diabetes was induced by streptozocin. Three groups of streptozocin-treated rats were studied. In group 1, 250 islets were selectively transplanted into the posterior liver lobes and 10 days later anterior portal branch ligation (PBL) was performed (n = 18); in group 2, 250 islets were transplanted into the posterior lobes and 10 days later sham PBL was performed (n = 13); in group 3, rats underwent a sham transplantation and PBL (n = 6). Nonfasting blood glucose levels and body weight were monitored. Six rats in groups 1 and 2 were killed 48 hours after PBL, liver sections were stained for proliferating cell nuclear antigen, and islet cell labeling index was calculated. The remaining rats were killed 30 days later. Liver compensatory growth or atrophy was calculated and morphometric determination of beta-cell area was assessed on insulin-immunostained sections of the liver. RESULTS: In group 1 rats killed 48 hours after PBL, islet cell labeling index was significantly higher than in group 2 (p < 0.0001). After PBL, we observed normalization of nonfasting blood glucose levels in 10 of 12 rats. At 30 days, posterior liver lobes showed compensatory growth (218.5% +/- 18.6%) accompanied by atrophy of the anterior lobes; morphometric study of liver-engrafted islets showed a significant increase of individual beta-cell area, compared with group 2 (p < 0.0001). In groups 2 and 3, normoglycemia was not achieved. CONCLUSIONS: In streptozocin-diabetic rats, normoglycemia was restored after transplantation of a sub-therapeutic islet mass, followed by PBL-induced liver regeneration. Histologic and morphometric results indicating islet cell proliferation suggest that compensatory liver growth might have induced a hypertrophic/hyperplastic response in the intraportally transplanted beta-cells.

Treatment of hypercholesterolemia in the Watanabe rabbit using allogeneic hepatocellular transplantation under a regeneration stimulus.

Numerous studies have reported successful allotransplantation of hepatocytes. However, none have shown long-term correction of a liver-related metabolic defect. In this study, we used a method of regional hepatocyte transplantation and subsequent induction of transplanted cell proliferation by regeneration response in the transplant-bearing liver lobes. New Zealand White rabbits were used as cell donors and Watanabe heritable hyperlipidemic (WHHL) rabbits were used as cell recipients (2 x 10(8) cells/rabbit). All recipient rabbits were maintained on daily cyclosporine. Two weeks after baseline serum cholesterol determination, group I WHHL rabbits (n = 7) received an infusion of cells into the right lateral liver lobe, and a loose ligature was placed around the portal venous branch supplying the anterior lobe. After 1 week, to allow engraftment, the portal venous branch was ligated, which resulted in the atrophy of the affected liver parenchyma and induction of hyperplasia in the transplant-bearing liver tissue. Group II rabbits (n = 6) were transplanted with New Zealand White hepatocytes without portal branch ligation (PBL) and group III rabbits (n = 4) were subjected to sham transplantation (saline) and PBL. The experimental period extended to 150 days after transplantation. All WHHL rabbits transplanted with normal hepatocytes showed reduction in serum cholesterol and low-density lipoprotein (LDL) levels. Group I (PBL-stimulated) recipients demonstrated a more pronounced and sustained effect than group II animals (P < 0.05). Group III controls showed only a slight, typical for aging decrease in serum cholesterol. Group I recipient livers perfused with LDL labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (DiI) showed much higher numbers of DiI-LDL-positive hepatocytes than those of group II recipients. In conclusion, a liver regeneration stimulus enhanced the population of transplanted hepatocytes and their functional effect in a large animal model of inborn error of liver metabolism.

[Benign obstruction of the common bile duct: what is the current role of transduodenal sphincteroplasty?]. / Ostruzione benigna del coledoco: è ancora attuale la papillosfinteroplastica transduodenale?

This paper is a critical review of the clinical records of 20 patients who underwent a Transduodenal Sphincteroplasty (PSP), from October 1990 to January 1992 at our Department (General Surgery). The age was 64.9 (14.2) years (mean and standard deviation), but 14 (70%) of those patients were older than 60 (range: 63 to 89) and 9 (45%) were in the 8th up to 9th decade of their lives. In 16 patients PSP was performed at the same time as cholecystectomy. Common bile duct (CBD) exploration was decided in 11 patients only on the basis of the intraoperative cholangiographic findings (evidence of CBD stones and/or benign stenosis of the Papilla of Vater) as demonstration of the permanent role of this examination in biliary surgery. Among the patients who underwent PSP some time after cholecystectomy, one had a lesion of the choledochus, sustained when he was cholecystectomized 15 days before. Because of the fact that recovery was prompt and definitely uneventful, PSP together with the infusion of somatostatin (SMTN) can be considered a useful approach to the treatment of the biliary fistula.

[Transduodenal sphincterotomy and type II Mirizzi syndrome]. / Papillosfinteroplastica transduodenale e sindrome di Mirizzi di tipo II.

This paper describes the clinical course of a 76-year-old woman surgically treated in our department (General Surgery) for obstructive jaundice in Mirizzi syndrome (II). Ultrasonography and ERCP failed to demonstrate the pathological situation at the level of the biliary tree. When laparotomy was decided because of the progressive worsening of the general clinical conditions of the patient, intraoperative cholangiography showed the presence of a cholecystocholedochal fistula with multiple residual stones eroded into the common bile duct. Surgical management consisted of partial cholecystectomy, removal of the stones, choledochoplasty and exploration of the distal part of the common bile duct by a transduodenal sphincteroplasty. The post-operative period was uneventful and the patient was discharged from our department nine days after surgery. Even though the surgical approach to Mirizzi syndrome generally includes procedures other than papillosphincteroplasty+partial cholecystectomy, our experience seems to substantiate the efficacy of the previously mentioned treatment under suitable conditions.

Abdominal aortic aneurysmectomy associated with a native iliac kidney. Case report.

Abdominal aortic aneurysm (AAA) repair associated with a pelvic kidney is extremely rare. To date only 14 cases have been reported in the literature. The main problem during aortic cross clamping is kidney preservation. The purpose of this article is to record and additional case of AAA repair associated with a native pelvic kidney. The preservation has been successfully achieved by a distal aortic double clamping.

Conservative management of traumatic chylothorax: a case report.

A case is presented of a right traumatic chylothorax, secondary to thoracic trauma with bilateral posterior eleventh rib fracture, treated by total parenteral nutrition and pleural drainage, with resolution within 2 weeks. On the basis of this clinical report and of a review of the literature, it is concluded that adequate conservative management should be initially the treatment of choice. Surgical treatment should be reserved to the cases in which clinical improvement does not occur within 2 weeks, and should consist of supradiaphragmatic thoracic duct ligation. Thoracoscopic fibrin glue injection has recently been described as a possible alternative treatment.

Effect of intravenous and intraperivenous injections of sclerosants (sodium tetradecyl sulfate and hydroxy polyethoxy dodecan) on the rat femoral vein.

The sclerosant effect of injected tetradecyl sulfate of sodium (STS) and hydroxy polyethoxy dodecan (HPD) was studied in the rat femoral vein. Intravenous (i.v.) and intravenous plus perivenous (i.v. + p.v.) injections of both sclerosants and physiologic saline were compared as to vein lumen occlusion, fibrosis, phlogosis, and damage to the artery and surrounding nervous and muscular tissues. The study was carried out in 30 rats treated by STS, in 30 treated by HPD, and 15 animals were injected with saline. The neurovascular bundle and adjacent muscle were removed at 48 h, 7 and 30 days and examined histologically. I.v. injections of STS produced a solid occlusion of the vein in a significant number of cases, after 30 days (P less than 0.01). A statistically significant number of solid occlusions of the femoral vein resulted after i.v. + p.v. injection of STS and HPD, at 48 h, 7 and 30 days (P less than 0.05; P less than 0.01). There was no significant difference between STS and HPD after i.v. + p.v. injection. After i.v. + p.v. we recorded a marked inflammation of muscle with signs of focal necrosis, at 48 h and 7 days. Our study indicated that i.v. + p.v. injection of STS and HPD provided a high degree of efficacy as regards vein occlusion. On the other hand, i.v. + p.v. injection induced a severe inflammation and necrosis of the tissues surrounding the sclerosed vein. Extrapolating our results to the endoscopic sclerotherapy for esophageal variceal bleeding, we conclude that paravariceal injection of sclerosants is a dangerous procedure, even though efficacious to reduce variceal hemorrhage, owing to the high risk of iatrogenic ulcers and esophageal perforation caused by muscular and mucosal necrosis.

The origin of bile ductular-like structures after transplantation of regenerating hepatocytes into the spleen of syngeneic rats.

Normal and 24-h regenerating hepatocytes were transplanted into the spleen of 70% partially hepatectomized, syngeneic rats, which were sacrificed after 2, 4, 6, 10, and 12 months from the transplant. Altogether 50 rats served as recipients. Histological examination of splenic sections showed a small number of surviving hepatocytes both in normal hepatocytes recipients and in the regenerating hepatocytes recipients. In the latter group marked bile ductular proliferation was present from 4 to 12 months after transplantation. This experimental evidence supports the theory that intrahepatic bile duct cells can originate from hepatocytes.