André Geubel

HLA association of amoxicillin-clavulanate--induced hepatitis.

BACKGROUND & AIMS Drug-induced immunoallergic hepatitis typically affects a minority of patients exposed to a particular drug. Its rarity is believed to be due to metabolic or immunologic idiosyncrasy. The presence of an immunologic idiosyncrasy might imply an HLA association. Previous studies reporting an HLA association of drug-induced hepatitis included only small numbers of patients and used serological HLA typing. METHODS We studied 35 patients with biopsy-documented amoxicillin-clavulanate-induced hepatitis. HLA-A and -B were typed using alloantisera and compared with those of 300 controls (volunteer bone marrow donors). HLA-DRB and -DWB were typed by polymerase chain reaction-line probe assay, with 60 volunteer bone marrow donors serving as controls. RESULTS The study group was characterized by a higher frequency of DRB1*1501-DRB5*0101-DQB1*0602 haplotype (57.1% vs. 11.7% in controls, P < 0.000005; after correction for the large number of comparisons, P < 0.0002). Patients with DRB1*1501-DRB5*0101-DQB1*0602 haplotype were more likely than patients without it to have a cholestatic (70% vs. 60%) or mixed (30% vs. 13%) than a hepatocellular pattern of hepatitis (0% vs. 27%) (P < 0.05). CONCLUSIONS Amoxicillin-clavulanate-induced hepatitis is associated with the DRB1*1501-DRB5*0101-DQB1*0602 haplotype. The data support the view that an immunologic idiosyncrasy, mediated through HLA class II antigens, plays a role in the pathogenesis of drug-induced immunoallergic hepatitis. HLA association has a limited impact on the expression of hepatitis.

Changes in size, subclass, and metabolic properties of serum immunoglobulin A in liver diseases and in other diseases with high serum immunoglobulin A.

We have studied the relative contributions of monomeric (m-) and polymeric IgA (p-IgA) and of IgA1 and IgA2 to total serum IgA in healthy adults and patients with liver disease (LD) or with other diseases and high serum IgA. Serum concentration of total secretory component (SC) was also determined. In addition, fractional catabolic rates (FCR) and synthetic rates for both m- and p-IgA were measured in nine controls and nine cirrhotics. Our results support four main conclusions: (a) In healthy adults, intravascular p-IgA contributes to only 4-22% (mean 12%) of serum IgA, because its FCR and synthetic rate are approximately two times higher and four times smaller, respectively, than those of intravascular m-IgA. (b) in LD, biliary obstruction does not result in a significant increase in serum p-IgA unlike in rats and rabbits, indicating that in humans the SC-dependent biliary transport of p-IgA plays a much less significant role in selective removal of p-IgA from plasma than in rats and rabbits. (c) In contrast to biliary obstruction, parenchymal LD results in a significant and preferential increase in serum p-IgA, which in cirrhotics correlates with a selective reduction of the p-IgA-FCR. This supports a role for the human liver in selective removal of p-IgA from plasma, but another mechanism than the SC-dependent biliary transport should be considered. (d) Total SC, p-IgA, and IgA2 in serum are unlinked parameters, not necessarily reflecting mucosal events. A marked increase in serum SC occurs almost selectively in LD. Although a shift to IgA2 is suggested in Crohns disease and alcoholic cirrhosis, a shift to IgA1 frequently associated to a shift to p-IgA occurs in chronic active LD, primary Sicca, and connective tissue diseases.

Adult polycystic liver disease: is fenestration the most adequate operation for long-term management?

OBJECTIVE The aim of this study was to evaluate the immediate and long-term results in a retrospective series of patients with highly symptomatic adult polycystic liver disease (APLD) treated by extensive fenestration techniques. A classification of APLD was developed as a stratification scheme to help surgeons conceptualize which operation to offer to patients with APLD. SUMMARY BACKGROUND DATA Treatment options for APLD remain controversial, with partisans of fenestration techniques or combined liver resection-fenestration. METHODS Clinical symptoms, performance status, liver volume measurement by computed tomography (CT), and morbidity were recorded before surgery and after surgery. Adult polycystic liver disease was classified according to the number, size, and location of liver cysts and the amount of remaining liver parenchyma. Follow-up was obtained by clinical and CT examinations in all patients. RESULTS Ten patients with highly symptomatic APLD were operated on using an extensive fenestration technique (by laparotomy in 8 patients and by laparoscopy in 2 patients, 1 of whom conversion to laparotomy was required). The mean preoperative liver volume was 7761 cm3. There was no mortality. Postoperative morbidity occurred in 50%, mainly from biliary complications, requiring reintervention in two cases. Massive intraoperative hemorrhage occurred in one patient. During a mean follow-up time of 71 months (range, 17 to 239 months), all patients were improved clinically according to their estimated performance status. The mean postoperative liver volume was 4596 cm3, which represents a mean liver volume reduction rate of 43%. However, in type III APLD, despite absence of clinical symptoms, a significant increase in liver volume was observed in 40% of the patients. CONCLUSIONS Extensive fenestration is effective in relieving symptoms in patients with APLD. Hemorrhage and biliary complications are possible consequences of such an aggressive attempt to reduce liver volume. The procedure can be performed laparoscopically in type I APLD. A longer follow-up period is mandatory in type II APLD, to confirm the usefulness of the fenestration procedure. In type III APLD, significant disease progression was observed in 40% of the patients during long-term follow-up. Fenestration may not be the most appropriate operation for long-term management of all types of APLD.

Patterns of hepatitis delta virus reinfection and disease in liver transplantation.

Twenty-seven carriers of the hepatitis B surface antigen who underwent liver transplantation in Italy and Belgium for terminal Hepatitis delta virus (HDV) cirrhosis were investigated. In 22 of the patients, HDV infection recurred. Two patients died of coexisting HDV and hepatitis B virus (HBV) reactivation. Four patients who died of unrelated causes were found to have HDV without signs of HBV reactivation. Five patients (18%) cleared both HBV and HDV after transplantation with no evidence of hepatitis (mean follow-up, 29 months). In many surviving patients. HDV infection recurred early without signs of HBV reactivation. Disease returned in the 11 HDV-infected patients in whom HBV also recurred. Histological hepatitis did not recur during an interim of 12-33 months in the 5 HDV-infected patients in whom HBV did not return. The overall medium-term survival in patients with HDV who underwent transplantation was 77.7%. Liver transplantation offers patients with HDV a hope of cure from disease despite a high risk of reinfection. In the transplantation setting. HDV can cause subclinical infections without any apparent assistance from HBV; these infections become symptomatic only if and when HBV reactivates. Thus, HDV may not be in itself pathogenic but requires cooperation from HBV to cause the appearance of the disease.

Liver injury related to amoxycillin-clavulanic acid: interlobular bile-duct lesions and extrahepatic manifestations

We report eight cases of liver injury related to amoxycillin-clavulanate. Liver biopsy performed in seven patients revealed varying degrees of injury to interlobular bile ducts in all cases. Lesions included irregularity of the nuclei, vacuolization of the cytoplasm, lymphocytic infiltration, destruction and endothelialization of the bile duct epithelium. Ductopenia was not observed. In two patients liver injury was accompanied by prominent extrahepatic manifestations (acute interstitial nephritis in one and acute lacrimal gland inflammation and sialadenitis with prolonged xerostomia in the other). We conclude that interlobular bile-duct lesions of varying severity are a common feature in liver injury related to amoxycillin-clavulanate. Side effects of the drug include acute interstitial nephritis and sialadenitis.

Is early enteral nutrition in acute pancreatitis dangerous? About 20 patients fed by an endoscopically placed nasogastrojejunal tube.

Bowel rest during treatment of acute pancreatitis deprives the gut of nutrients and affects its structure and function. Enteral feeding is usually performed late in the course of acute pancreatitis and therefore cannot prevent intestinal barrier dysfunction and possible bacterial translocation. To assess the effect of early enteral nutrition we performed a prospective study on 21 patients (11 males/10 females) presenting with severe acute pancreatitis (13 biliary, 6 alcoholic, and 2 miscellaneous). Severity was established by a mean Ranson score of 3.57. All but one patient could be fed through a double-lumen nasogastrojejunal tube within 60 h after admission. No significant complication of the technique was observed. We conclude that early jejunal feeding can be used safely in severe acute pancreatitis. Further comparative studies are necessary to demonstrate any superiority to total parenteral nutrition.

Responses to treatment can differentiate chronic active liver disease with cholangitic features from the primary biliary cirrhosis syndrome.

Of 125 patients fulfilling preestablished criteria for severe chronic active liver disease (CALD) and enrolled in a prospective trial of treatment, 15 (12%) presented with morphological features of liver biopsy consistent with the diagnosis of both CALD and primary biliary cirrhosis (PBC) syndrome. Customary clinical, biochemical, and immunoserological studies failed to distinguish fully between these conditions. By contrast, early response to treatment with prednisone and/or azathioprine identified two different groups of patients. Five patients failed to respond, whereas 10 improved and this was followed by resolution of all clinical, biochemical, and morphological evidence of disease activity. Analysis of the initial chemical findings and cumulative bile duct counts from multiple biopsies correlated failure to respond with biochemical and morphological features more consistent with PBC than CALD. Responses to treatment can therefore be utilized when indicated for differentiating CALD with cholangitic features from PBC.

The place of liver transplantation in Caroli's disease and syndrome

Carolis disease (CD) or syndrome (CS) are rare inherited disorders which may cause severe, life‐threatening, cholangitis or which may lead to hepatobiliary degeneration. The typical cystic biliary anomalies are often associated to congenital hepatic fibrosis (CHF) and, less frequently, to cystic renal disease especially autosomic recessive polycystic kidney disease (ARPKD). The place of liver transplantation (LT) in the treatment of CD or CS is evaluated based on our own experience of three successfully transplanted patients, the literature review of 19 patients and the European experience with 110 patients collected in the European Liver Transplant Registry. LT should be proposed as a definitive therapeutic option once severe cholangitis or (suspicion of) malignant transformation is present. The frequently used radiological, endoscopical or surgical biliary drainage procedures carry a high morbidity and mortality rate. In case of concomitant symptomatic CHF and renal failure, combined or sequential hepatorenal transplantation should be carried out, dependant on the evolution of the hepatic and renal disease. In case of associated ARPKD, renal transplantation is often indicated early on because of the more rapid progression of the renal component of the disease.

Benign hepatocellular tumors: MRI after superparamagnetic iron oxide administration.

Objective Our goal was to describe the features of benign hepatocellular tumors on superparamagnetic iron oxide (SPIO)–enhanced MR images and to evaluate the potential role of SPIO administration in the diagnosis of these tumors. Materials and Methods The T1− and T2-weighted SE images were performed before and after SPIO administration in 19 patients with focal nodular hyperplasia (FNH) or adenomas. The lesions were counted and qualitatively assessed. In 32 tumors with a diameter of >10 mm, the contrast-to-noise ratio (CNR) and the liver and tumor enhancement were calculated. Results Thirty-seven tumors were detected on MR images: 29 before and 36 after SPIO administration (p < 0.05). The SPIO-enhanced T1-weighted images provided the highest detection rate and CNR. The central scar was most conspicuous on SPIO-enhanced T2-weighted images. Most FNHs and adenomas lost less signal than the liver, three tumors did not lose signal, and four FNHs showed a signal loss equal to or greater than that of the liver. Conclusion The SPIO-enhanced T1-weighted images increased the CNR and the detection rate of benign hepatocellular tumors. On T2-weighted images, most benign hepatocellular tumors showed a signal decrease after SPIO administration. No significant difference in signal loss was observed between FNH and adenomas.

Preoperative Assessment of Pancreatic Tumors Using Magnetic Resonance Imaging, Endoscopic Ultrasonography, Positron Emission Tomography and Laparoscopy

Background: The appropriate preoperative evaluation of a pancreatic tumor remains a matter of debate. Methods: We retrospectively evaluated an institutional strategy including magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS), positron emission tomography (PET) and laparoscopy (LAP) for detection and staging of pancreatic tumors suspected to be malignant. Results: In a consecutive series of 59 patients screened by MRI, PET, EUS and LAP between July 1998 and November 2002, 48 patients were found to bear pancreatic adenocarcinoma and surgery was performed in 27 of them. For tumor detection, the sensitivity of EUS was superior to MRI and PET (98 vs. 87.5 and 87.5%, respectively, p = 0.13). MRI best assessed loco-regional staging, i.e. arterial involvement. For the detection of distant metastases, the sensitivity of all preoperative examinations taken separately was low. When laparotomy was performed with a curative intent according to all four examinations, occult metastasis or carcinomatosis was discovered in 7/27 patients and the overall predictive value of resectability was thus 74%. Five-year and median survival were significantly better in resected vs. non-resected patients (39% and 26 months vs. 0% and 8 months, p = 0.0006). Conclusions: MRI can be recommended has the first examination in patients bearing pancreatic tumors, complemented by EUS if the findings of MRI are non-conclusive. For detection of distant metastasis, only the combination of all preoperative examination was proved to be more accurate than a single technique.