Hepatitis C virus RNA quantitation in hepatic veins and peripheral blood in patients with liver cirrhosis: evidence for low level intrahepatic hepatitis C virus replication in advanced liver disease.

BACKGROUND: Very few data exist concerning the level of hepatitis C virus replication within the cirrhotic liver and its relationship to disease severity and progression. AIMS: To quantitate hepatitis C virus RNA in hepatic vein blood and peripheral blood in patients with cirrhosis, to evaluate the correlation of hepatitis C virus levels in paired blood samples, and to compare the results with clinical features. PATIENTS: A series of 25 patients with hepatitis C virus-related liver cirrhosis undergoing hepatic vein catheterization were studied: 11 belonged to Child Pugh class A, 8 to class B and 6 to class C. RESULTS: Hepatitis C virus RNA levels did not differ between hepatic vein blood and peripheral blood (p = 0.26), despite a trend towards higher peripheral hepatitis C virus RNA levels. Hepatitis C virus RNA levels did not differ between patients with genotype 1b and non-1b either in hepatic veins or peripheral blood. Hepatitis C virus loads varied according to the severity of cirrhosis. The patients with more severe liver disease had significantly lower RNA titres than those with less advanced cirrhosis, both in hepatic veins (p = 0.002) and peripheral blood (p = 0.004). No differences in hepatitis C virus load were observed between patients in Child Pugh classes B and C. CONCLUSIONS: The present data show that in patients with cirrhosis hepatitis C virus RNA concentrations do not differ between hepatic blood and peripheral blood and, furthermore, confirm that hepatitis C virus replication is reduced in patients with advanced cirrhosis, compared with patients with less severe liver disease. These findings might indicate that patients with liver cirrhosis maintain an efficient intrahepatic hepatitis C virus replication even in end-stage disease, although hepatitis C virus viraemia decreases according to the severity of liver disease.

Topographic diagnosis and surgical treatment of insulinoma.

AIM: Controversy continues to reign with regard to the need for preoperative localization of insulinomas and to which are the most sensitive and accurate diagnostic imaging modalities. Our aim was to determine the role of diagnostic procedures and suggest which of them are really useful. METHODS: Over a 12-year period 34 patients underwent several preoperative diagnostic procedures to localize the insulinoma: ultrasonography (US) in 20 cases, computed tomography (CT) in 26, magnetic resonance imaging (MRI) in 28, selective angiography in 8, arterial stimulation venous sampling (ASVS) in 23 and Octreoscan in 26. All patients underwent surgical palpation and in 32 cases intraoperative ultrasonography (IOUS) was performed. Twenty-six cases underwent enucleation, six had distal pancreatic resections and two patients had only exploratory laparotomy with liver biopsies. We compared the findings of the diagnostic procedures and analyzed the surgical treatment chosen according to the pancreatic site of the tumor. RESULTS: In 32 (94.1%) of the 34 patients with clinically suspected pancreatic insulinoma the tumor was found at surgery. Preoperative US achieved 5.2% sensitivity, CT 29.1%, selective angiography 28.5% and MRI 76.9%. ASVS achieved 91.3% sensitivity and diagnostic accuracy whereas Octreoscan achieved only 65.3% diagnostic accuracy. Surgical palpation performed before IOUS identified the tumors in 30/34 patients: in the other four cases, one was a false-positive result (a cyst in the pancreatic head), two were true negatives and one was a false negative. Surgical palpation therefore yielded 88.2% diagnostic accuracy. IOUS was performed in 32 cases and localized the tumors in 29/32 cases (sensitivity: 96.6%) with one false-negative result (diagnostic accuracy: 96.8%). The operative mortality was 2.9% and the morbidity 24.6% (30.7% in patients treated by tumor enucleation). CONCLUSIONS: No single diagnostic imaging modality is reliable for localizing insulinoma. We therefore suggest combined MRI, ASVS and IOUS. ASVS provides particularly useful information for planning manual palpation and intraoperative ultrasonography.

Expression of insulin/IGF-I hybrid receptors is increased in skeletal muscle of patients with chronic primary hyperinsulinemia.

The insulin receptor (IR) shares structural and functional homology with the IGF-I receptor (IGF-IR). Hybrid receptors composed of an IR alphabeta-heterodimer and an IGF-IR alphabeta-heterodimer are formed in tissues expressing both molecules. Hybrids behave as IGF-IR rather than IR with respect to ligand binding affinity, receptor autophosphorylation, and hormone internalization and degradation. Factors regulating hybrid formation in vivo are unknown. We recently reported that in skeletal muscle of NIDDM patients, expression of hybrids is increased and correlated with a decrease in IR number and an increase in fasting insulin levels. However, it is not clear whether increased expression of hybrid receptors is a primary defect specifically associated with NIDDM or a secondary event caused by hyperinsulinemia. To address this issue, we used a quantitative microwell-based immunoassay to measure hybrid receptor abundance in skeletal muscle of 11 normal subjects and 12 patients with insulinoma, a state of primary nongenetically determined hyperinsulinemia. Total insulin binding was lower in insulinoma patients than in normal subjects (0.70 +/- 0.18 vs. 4.59 +/- 0.77; P < 0.0001). Total IGF-I binding did not differ between the two groups (0.81 +/- 0.27 and 0.85 +/- 0.10, respectively). The amount of hybrids, expressed as bound/total (B/T), was higher in patients with insulinoma than in normal subjects (0.57 +/- 0.19 vs. 0.36 +/- 0.03; P < 0.0006) and was inversely correlated with total insulin binding (r = -0.64, P < 0.0004). Increased abundance of hybrid receptors was positively correlated with insulin levels (r = -0.82, P < 0.0009) and inversely correlated with insulin-mediated glucose uptake (r = -0.80, P < 0.01). No correlations were observed between insulin-mediated glucose uptake and maximal specific insulin binding (r = 0.19, P = 0.64). These results indicate that insulin-induced IR downregulation may lead to the formation of a higher proportion of hybrid receptors, whose abundance is negatively correlated with in vivo insulin sensitivity. These results, therefore, support a role for insulin in the regulation of hybrid receptors formation and suggest that increased expression of hybrids in NIDDM may be a secondary event caused by hyperinsulinemia rather than a primary defect.

111In-octreotide scintigraphy in metastatic medullary thyroid carcinoma before and after octreotide therapy: in vivo evidence of the possible down-regulation of somatostatin receptors.

We have investigated the presence of somatostatin receptors on the cell surface of metastatic medullary thyroid carcinoma in vivo using 111In-Octreotide scintigraphy. Five patients were studied before and three months after therapy with octreotide (300-600 micrograms/day). After each 111In-Octreotide scintigraphy the target/background (T/B) radioactivity ratio was calculated for each detectable metastases. A total of 14/18 metastases showed a reduction in the T/B ratio after therapy, suggesting saturation or down-regulation of the somatostatin receptors on metastases induced by octreotide therapy. Patients also showed a reduction in serum calcitonin levels after therapy. We conclude that 111In-Octreotide scintigraphy may be useful in medullary thyroid carcinoma to evaluate the rationale for somatostatin therapy and to monitor the effect of treatment.