Inhibitor against coagulation factor V after liver transplantation.

A new case of anti-factor V inhibitor is described in a 46-year-old man, who received a liver transplantation for hepatocellular carcinoma, without exposure to bovine thrombin or fibrin glue during the operative course. The inhibition occurred on the 14th postoperative day, while the patient was being treated with oxacillin, azathioprine, and a new immunosuppressive drug, FK506. The inhibition was of short duration (3 days), and no bleeding complication occurred despite a very low plasmatic level of factor V activity and antigen (<5%). Plasma samples drawn after cessation of FK506 disclosed a dose-dependent inhibitory activity when alcoholic solutions of FK506 were exogeneously added; this suggests a possible role of the FK506 drug in the occurrence of this anti-factor V inhibitor.

Increased incidence of oropharyngeal squamous cell carcinomas after liver transplantation for alcoholic cirrhosis.

BACKGROUND: THE aim of this study was to describe the features of posttransplantation tumors observed in a series of liver transplant recipients with special reference to patients receiving a transplant for alcoholic cirrhosis. METHODS: Among 171 consecutive liver transplant recipients, 90 patients who had received a first liver allograft for cirrhosis were studied. After liver transplantation, detection of de novo malignancies was prospectively undertaken and the characteristics of the patients in whom tumors occurred were compared with those in whom tumors did not develop. RESULTS: With a follow-up of 45.2+/-21.2 months, 11 tumors were observed in 90 patients (overall incidence of 12.2%). The incidence of tumors was higher in patients receiving a transplant for alcoholic cirrhosis than in patients receiving a transplant for nonalcoholic cirrhosis (26.7% vs. 5.0%, P<0.01). Squamous cell carcinoma (SCC) of the oropharynx or esophagus and posttransplant lymphoproliferative disorders were mainly observed. SCC (uvula in two cases, tongue in one case, esophagus in one case, pharynx in one case) occurred exclusively in patients transplanted for alcoholic cirrhosis (16.7% vs. 0%, P=0.001). The incidence of posttransplant lymphoproliferative disorders was similar in alcoholics and nonalcoholics (6.7% vs. 5%, NS). Survival was not influenced by the occurrence of SCC. CONCLUSION: The incidence of oropharyngeal SCC could be high in patients receiving a transplant for alcoholic cirrhosis. This could be due to an additional effect of posttransplantation immunosuppression in patients exposed to alcohol and tobacco before transplant. Careful posttransplantation screening of oropharyngeal SCC is warranted after liver transplantation for alcoholic cirrhosis.

Reverse seroconversion of hepatitis B after allogeneic bone marrow transplantation: a retrospective study of 37 patients with pretransplant anti-HBs and anti-HBc.

BACKGROUND: Reverse seroconversion to hepatitis B virus (HBV), i.e., HBV reactivation in patients with pretransplant antibodies to hepatitis B surface antigen (anti-HBs) and to hepatitis B core antigen (anti-HBc), is rarely re-ported after allogeneic bone marrow transplantation. METHODS: To determine this risk, we studied clinical outcome and serological changes in 37 patients with pretransplant anti-HBs and anti-HBc. RESULTS: In 33 cases, no change in HBV markers was observed in the posttransplant period. In four cases, anti-HBs and anti-HBc were lost, and hepatitis B surface antigen, hepatitis B e antigen, and HBV DNA emerged together with acute hepatitis, after cessation of immunosuppression. The actuarial risk of reactivation in the 37 patients was 20.5% (median follow-up 20 months). No reactivation occurred in patients with anti-HBs-positive donors. CONCLUSION: Although few cases of postallogeneic bone marrow transplantation reverse seroconversion to HBV have been reported, this study demonstrates that the actuarial risk is relatively high and suggests that donor vaccination might be proposed prophylactically or that HBs-specific immunoglobulin infusions might be warranted.

Terbinafine-induced prolonged cholestasis with reduction of interlobular bile ducts.

The antifungal drug terbinafine has infrequently been incriminated in the occurrence of acute liver injury. We report a case of prolonged cholestasis that occurred in a 75-year-old woman, following terbinafine administration. Jaundice followed by pruritus appeared after four weeks of therapy and was associated with mixed hepatocellular and cholestatic liver tests abnormalities. Following drug withdrawal, serum bilirubin returned to normal values within three months, but anicteric cholestasis persisted for over six months. A liver biopsy performed after six months showed centrilobular cholestasis, discrete portal fibrosis, and a reduction in the number of interlobular biliary ducts. Terbinafine should be added to the list of drugs that can cause reduction in interlobular bile ducts.

On the use of ion-pair chromatography to elucidate doxorubicin release mechanism from polyalkylcyanoacrylate nanoparticles at the cellular level.

The major hypothesis underlying the remarkable efficiency of polyalkylcyanoacrylate particles loaded with doxorubicin against multidrug resistant tumor cells in vitro, is based on the ion-pair association of doxorubicin with soluble hydrolysis products of polyalkylcyanoacrylate. In an attempt to demonstrate the validity of this hypothesis, we have used ion-pair reversed-phase high-performance liquid chromatography and a laboratory-synthetized compound, i.e., the 2-cyano-2-butylhexanoic acid, as a model for polyalkylcyanoacrylate highly polydispersed degradation products. It is shown that, compared to a counter-ion, like heptane sulfonic acid, 2-cyano-2-butylhexanoic acid exhibits an effective ion-pairing effect at different pH values and organic mobile phase conditions. Moreover, at pH close to physiological conditions and at low mobile phase organic modifier percentage, this effect is experimentally observed, which strongly supports the initial hypothesis.

A histopathological study of the effects of 6-month versus 12-month interferon alpha-2b therapy in chronic hepatitis C.

BACKGROUND/AIMS: Interferon therapy has been shown to have beneficial effects in chronic hepatitis C, but the optimal duration of treatment has not been clearly defined. The aims of this study were: (a) to perform a detailed histological comparison of the effects of a 6-month and a 12-month treatment using the Knodell score as well as a recently proposed grid of analysis, (b) to determine possible histological predictive factors of response to therapy, and (c) to attempt to relate histological and biochemical modifications. METHODS: Liver biopsies obtained before and 18 months after beginning of treatment were therefore compared in 26 patients treated for 6 months, and in 34 patients treated for 12 months. RESULTS: Six months of treatment induced a significant decrease in periportal (p = 0.02) and intralobular (p = 0.004) hepatocyte necrosis. The same items were improved in the 12-month-treated patients but, in addition, portal inflammation (p = 0.01), bile duct lesions (p = 0.03), lymphoid aggregates (p = 0.002) and fibrosis (p = 0.008) were also improved, according to the Knodell score. Low scores for fibrosis, steatosis and cholangiolar proliferation on the pretreatment liver biopsy could be considered predictive factors for alanine aminotransferase normalization at 6 months. There was no relationship between biochemical response and modification of fibrosis. CONCLUSION: Our results suggest that: (a) a decrease in fibrosis might be detected only after a 12-month interferon treatment, and (b) initial fibrosis, cholangiolar proliferation and steatosis are predictive of a lack of biochemical response. The absence of a relation between biochemical response and evolution of fibrosis implies that the evaluation of treatments in chronic hepatitis C should always include a detailed histopathological study.

Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological, and pathological correlations.

Preoperative distinction between focal nodular hyperplasia (FNH) that should be managed conservatively and hepatocellular adenoma (HA) that should be resected remains difficult. The result is controversial management of these patients. The aims of this study were to report the value of modern imaging procedures for noninvasive diagnosis of these lesions, to assess the value of intraoperative frozen section studies, and to propose a management strategy in those patients. Forty-one consecutive women with FNH (35 cases) or HA (6 cases) treated at our institution between 1985 and 1992 were studied. New imaging techniques, including enhanced magnetic resonance imaging (MRI) and color Doppler ultrasonography (US), were prospectively appraised in addition to usual techniques. Histological examination of surgical specimens was obtained in all cases. A sixfold increase in the number of patients with FNH was observed during this study, whereas the number of patients with HA did not change. FNHs were incidental US findings in 74% of the cases. The best imaging procedure in the diagnosis of FNH was enhanced MRI with a sensitivity of 70% and a specificity of 98%. Color Doppler US was a useful adjunct. Intraoperative frozen section studies were performed in 16 patients with 19 tumors with a sensitivity of 89% and a specificity of 100%.(ABSTRACT TRUNCATED AT 250 WORDS)

Serial quantitative determination of hepatitis C virus RNA levels after liver transplantation. A useful test for diagnosis of hepatitis C virus reinfection.

After liver transplantation for hepatitis C virus (HCV)-related cirrhosis, recurrent viral infection is almost constant, resulting in acute graft dysfunction in 30-75% of cases. Acute graft dysfunction in the post-transplant period may also be the result of various causes (such as rejection, CMV infection, sepsis, or technical problems). Therefore, the role of HCV reinfection is often difficult to document. The aim of this study was to assess the diagnostic value of serial HCV RNA quantitation in this setting. Fourteen patients transplanted with follow-up greater than 6 months were studied. HCV RNA was quantitated before and serially after transplantation, using branched DNA technology. In cases of acute graft dysfunction, usual investigations and additional HCV RNA quantitation were conducted. There were 15 episodes of acute graft dysfunction in 12 patients. Six episodes had a hepatitic biochemical pattern, and 5 of them were associated with a concomitant HCV RNA peak. Nine episodes had a mixed, hepatitic, and cholestatic biochemical pattern, and 5 of them were associated with a concomitant peak of HCV RNA. Overall, 10 of 15 (66%) episodes of acute graft dysfunction were associated with HCV RNA peak, which strongly suggests that HCV was the etiologic factor. In 9 of these 10 episodes, no other cause of dysfunction was found, and one had associated CMV disease. In 5 cases, no peak of HCV RNA was observed and the causes of dysfunction were CMV (in 2 cases) and rejection, granulomatosis, and unknown (in 1 case each). Serial quantitations of HCV RNA levels after liver transplantation for cirrhosis C provide a useful tool in the diagnosis of HCV reinfection of the graft.

[Value of a powerful initial immunosuppression after liver transplantation. Prospective study of 60 cases]. / Intérêt d'une forte immunosuppression initiale après transplantation hépatique. Etude prospective de 60 cas.

With usual immunosuppression, the incidence of acute rejection after liver transplantation is higher than 60% in most series. The aim of this prospective study was to assess the value of a powerful initial immunosuppression on acute rejection, mortality and morbidity. REGIMEN. Group 1: patients with normal postoperative renal function (serum creatinaemia < 150 mumol/L) received cyclosporine from day 1 to day 15 by continuous i.v. infusion to reach a whole blood level of 400 to 500 ng/mL; after day 15, cyclosporine was reduced. Group 2: in cases of postoperative renal failure (serum creatinine > or = 150 mumol/L), anti-thymocyte globulins were used for 10 days; cyclosporine was introduced after recovery of renal failure at usual doses. In addition, all patients received steroids and azathioprine according to usual regimens. RESULTS. From January 1989 to June 1992, 60 cases were studied in 59 patients: 45 (75%) entered group 1 and 15 (25%) entered group 2. In group 1, there were 11 acute rejection episodes (24%) and one postoperative death at three months (2.3%). In group 2, two early deaths (within 5 days) were excluded from the study of rejection. Among the 13 remaining cases, there were three episodes of acute rejection (23%) and one hospital death at three months. Overall, there were 14 episodes of acute rejection (24%), 12 of which were steroid-responsive (86%), no chronic rejection, a usual rate of infections (57%), one retransplantation (1.7%) and a hospital mortality of 6.8% (4 of 59 cases). One year survival was 78%, with 5 of 7 late deaths due to recurrent cancer. CONCLUSIONS. Our results suggest that, after liver transplantation, a) high initial cyclosporine dose in patients with normal postoperative renal function is associated with reduced incidence and severity of acute rejection without increased mortality and morbidity, b) antithymocyte globulins are an efficient alternative to cyclosporine in patients with postoperative acute renal failure and saves OKT3 for the treatment of steroid-resistant rejection.

[Liver transplantation associated with combined adjuvant treatment in hepatocellular carcinoma. Feasibility and preliminary results]. / Transplantation hépatique associée à un traitement adjuvant combiné dans le carcinome hépatocellulaire. Faisabilité et résultats préliminaires.

Combined adjuvant therapy was prospectively assessed in 7 patients receiving orthotopic liver transplantation for hepatocellular carcinoma complicating cirrhosis. The protocol included hepatic arterial chemotherapy while waiting for transplant, immediate preoperative liver irradiation, and early postoperative chemotherapy. There were no postoperative deaths, and morbidity included mainly hematologic toxicity of chemotherapy. Two patients died of tumor recurrence 6 and 14 months after transplant. The remaining 5 patients are alive and free of disease with a follow-up of 7 to 26 months. These results show the feasibility of aggressive adjuvant therapy in patients transplanted for hepatocellular carcinoma and suggest a possible effect of such a protocol on the prevention of tumor recurrence.

Multiple nuclear dots antinuclear antibodies are not specific for primary biliary cirrhosis.

Multiple nuclear dots antinuclear antibodies display a specific immunofluorescence pattern on HEp-2 cells. They have been reported to be strongly associated with primary biliary cirrhosis, especially when sicca syndrome was present. To determine whether multiple nuclear dots antinuclear antibodies are specific for primary biliary cirrhosis, we studied the clinical, biochemical, immunological and morphological features of 38 patients between December 1983 and September 1990 who had serum multiple nuclear dots antinuclear antibodies detected in an immunology laboratory of a large medical center. Sufficient information was reliable in 36 patients; the group included 31 women and 5 men (mean age = 57.6 +/- 14.5, range = 30 to 87). Fifteen patients (42%) had primary biliary cirrhosis, 5 patients (14%) had type 1 autoimmune chronic active hepatitis, 4 patients (11%) had liver disease of unknown cause and 12 patients (33%) had various immunological disorders but no liver disease. Two of the patients with primary biliary cirrhosis (13%) had clinical sicca syndrome. Our study demonstrates the following: (a) serum multiple nuclear dots antinuclear antibodies are not specific for liver disease because they can be observed in one third of patients with various immunological disorders without liver involvement, and (b) serum multiple nuclear dots antinuclear antibodies are not specific for PBC because they can also be observed in type 1 autoimmune chronic active hepatitis. Our results also suggest that patent sicca syndrome is abnormally present in patients with primary biliary cirrhosis and multiple nuclear dots antinuclear antibodies.

Idiopathic biliary ductopenia in adults: a report of five cases.

The clinical and pathological findings of five adult cases of idiopathic nonsyndromatic paucity of interlobular bile ducts are reported. Patients were 18-32 years old at the onset of the disease; four presented with pruritus and/or jaundice and one with bleeding of the esophageal varices. Two patients were siblings. Serum alkaline phosphatase counts ranged from 1 to 16 times the upper normal value, and total bilirubin counts ranged from 0.6 to 8.8 mg/dL (10 to 150 mumol/L). Initial liver biopsy showed portal and periportal fibrosis with cholangiolar proliferation and reduction in the number of interlobular bile ducts. Antimitochondrial antibodies were absent, and bile ducts were normal after opacification. The patients were observed for 3-11 years. Repeated liver biopsies in the five patients showed progression of the lesions, with development of biliary type cirrhosis in four. Two of the four patients with cirrhosis died of hepatic failure 3 and 11 years after onset of the disease. In the two other cases, liver transplantation was performed successfully. These cases suggest that chronic cholestasis with marked ductopenia resembling the nonsyndromatic paucity described in infancy and childhood may reveal itself at an adult age. This disorder, possibly familial, may rapidly progress to severe and even fatal liver disease and could be a new indication for liver transplantation.

Cystic dilatation of intrahepatic bile ducts in primary sclerosing cholangitis.

A case of primary sclerosing cholangitis associated with cystic dilatations of intrahepatic bile ducts simulating Caroli's disease is described. The diagnosis of primary sclerosing cholangitis was based upon cholangiogram features, liver histologic examination and the association with chronic ulcerative colitis. It may be suggested that the cystic dilatation of intrahepatic bile duct represents an extreme form of the usual mild dilatations (cholangiectases) described in primary sclerosing cholangitis. We suggest that cystic dilatation of intrahepatic bile ducts could be included among the radiologic features of this disease.

[Ultrasonographic and x-ray computed tomographic aspects of Mirizzi's syndrome]. / Aspects échotomographiques et tomodensitométriques du syndrome de Mirizzi.

The Mirizzi syndrome is due to common hepatic duct obstruction secondary to the impaction of a large gallstone in the neck of the gallbladder or the cystic duct. The sonographic and computed tomography features in 3 cases of Mirizzi syndrome are described and compared with percutaneous transhepatic cholangiography or endoscopic retrograde cholangiography findings. The Mirizzi syndrome was diagnosed preoperatively on sonography in 2 out of 3 cases and on plain computed tomography scans in all 3 cases. However pre or intraoperative visualization of the biliary tract is mandatory in suspected Mirizzi syndrome to detect the presence or absence of cholecystobiliary fistula, in order to adapt the operative strategy.

Amiodarone-induced hepatic phospholipidosis: a morphological alteration independent of pseudoalcoholic liver disease.

In order to study the relationship between amiodarone-induced hepatic phospholipidosis and liver disease, liver biopsies obtained from 13 patients treated with amiodarone for 4 months to 15 years were investigated by light and electron microscopy. Light microscopy showed pseudoalcoholic liver lesions that were probably related to amiodarone in four cases, various alterations (i.e. cirrhosis, three cases; steatosis and fibrosis, two cases; chronic venous congestion, one case; acute hepatitis, one case) that could be explained by another cause than amiodarone in seven cases and normal liver in two cases. In all cases, electron microscopy showed intralysosomal myelin figures suggestive of phospholipidosis. These myelin figures were associated with intralysosomal electron-dense deposits. In the four cases in which analysis by electron microprobe was performed, it demonstrated large amounts of iodine in the electron-dense deposit-containing lysosomes, indicating the accumulation of amiodarone. These results show that hepatic phospholipidosis is constantly observed in amiodarone-treated patients, whether or not pseudoalcoholic liver lesions are present. This phospholipidosis, which could be only a morphological marker of intrahepatic accumulation of the drug, should not therefore be considered grounds for attributing liver disease to the drug.

The usefulness of microscopic bile examination in patients with suspected microlithiasis: a prospective evaluation.

Gallbladder bile collected by duodenal intubation or during surgery was examined microscopically in patients who were free of stones and in patients with proven stones. None of the 16 patients free of stones had cholesterol monohydrate crystals or calcium bilirubinate granules in bile. Among the 17 patients with proven cholelithiasis, 13 with cholesterol stones had cholesterol monohydrate crystals in their bile, but only 2 of the 4 patients with pigment stones had calcium bilirubinate granules. These data confirm that cholesterol monohydrate crystals are sensitive and specific for cholesterol stones, whereas calcium bilirubinate granules lack sensitivity for the diagnosis of pigment stones. From these results, the diagnostic usefulness of microscopic examination of bile collected from the duodenum was studied prospectively in 46 patients with symptoms suggestive of cholelithiasis but in whom stones had not been visualized at cholecystography and ultrasonography. In 15 of them, bile was found to be abnormal: cholesterol monohydrate crystals were seen in 11, cholesterol crystals + calcium bilirubinate granules in 2 and calcium bilirubinate granules in 2. To date, nine of these patients have been operated on: 6 (all with cholesterol monohydrate crystals) had small cholesterol gallstones and 3 (2 with cholesterol monohydrate crystals and 1 with calcium bilirubinate granules) had signs strongly suggestive of the recent migration of gallstones. One patient refused operation, but minute pigment stones were found to be associated with calcium bilirubinate granules at duodenal intubation. In the other 31 patients, bile contained neither cholesterol monohydrate crystals nor calcium bilirubinate granules. They were not operated on and were followed up with repeated investigations for 12 to 24 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic granulomas in Whipple's disease.

Hepatic epithelioid cell granulomas that were negative for periodic acid-Schiff stain after diastase digestion were found in a 32-yr-old man who presented with painless hepatomegaly and slight fever. The patient never complained of intestinal symptoms, which in part explains why the diagnosis of Whipple's disease was made only 3 mo later, at a time when severe neurologic manifestations had appeared. The definitive diagnosis was made on the basis of the characteristic histologic findings in biopsy material obtained from jejunum and abdominal lymph nodes at laparotomy. The patient's condition, especially neurologic manifestations, rapidly improved after antibiotic therapy. It is noteworthy that Whipple's disease is generally not included among the causes of hepatic epithelioid cell granulomas. It is suggested that its possibility should be considered in patients with hepatic granulomas without obvious etiology, even in the absence of intestinal symptoms.