[Occult gastrointestinal hemorrhage. Description of a case with unusual clinical presentation]. / Emorragie gastro-intestinali di origine sconosciuta. Descrizione di un caso con presentazione clinica anomala.

Bleeding from small bowel is a quite rare event and often is a diagnostic challenge to physician and surgeon. We present a case of a patient with an acute massive haemorrhage due to jejunal diverticulosis and with an unusual clinical setting. The site of bleeding was localized by scan with radiotagged erythrocytes, but the diagnosis of jejunal diverticule was evident only at laparotomy. The patient underwent to surgical resection of the affected bowel (40 cm). Although jejunal diverticula are considered a rare source of gastrointestinal haemorrhage, we suggest that this disorder must be considered in all patients with occult gastrointestinal bleeding especially in the elderly.

Bone marrow findings further support the hypothesis that essential mixed cryoglobulinemia type II is characterized by a monoclonal B-cell proliferation.

One-hundred-sixteen consecutive bone-marrow biopsies were taken from 76 patients with essential mixed cryoglobulinemia type II (type II cryo), whose median follow-up was 97 months. Fifty-four out of fifty-six subjects who underwent ELISA and RIBA tests for HCV, were found to be positive. At conventional light microscopic examination, 64/76 patients showed discrete lymphoid infiltrates consisting of small elements with plasmacytoid differentiation and with frequent paratrabecular location. Thirty-nine biopsies were studied by immunohistochemistry that revealed the B-cell nature of the infiltrates (CD20+, CD45RA+, CD79 alpha+, CD3-, CD45RO-), with demonstrable monotypic Ig light-chain restriction in 22 cases. It is worthy of note that the lymphoid elements usually appeared protected against apoptosis, because of the strong expression of the bcl-2 oncogene product, and provided with a very low proliferative capacity, the Ki-67 index being lower that 3%. The latter findings are in keeping with the indolent behaviour of the clonal lymphoid population observed in type II cryo and allow some speculation as to the need for environmental stimuli for its maintenance as well as further mutagenic events for its eventual transformation into an overt lymphoma.

A laboratory and thrombokinetic study of HCV-associated thrombocytopenia: a direct role of HCV in bone marrow exhaustion?

OBJECTIVE: In order to investigate HCV associated thrombocytopenia, 6 patients suffering from this disease, in the absence of splenomegaly and other common causes of peripheral platelet destruction, underwent laboratory and scintigraphic tests. RESULTS: Thrombokinetic studies revealed a significant, nearly linear, delayed splenic accumulation with normal or low-normal values for the average platelet life span, low-normal recovery, and depressed platelet production. Megakariopoiesis was normal or slightly increased. HCV infection of the megakariocytes was found in two patients. Autoantibodies and liver disease were also investigated. CONCLUSIONS: A role of immunological mechanisms in HCV associated thrombocytopenia appears to be ruled out. The authors conclude that tests for HCV infection should be included in the evaluation of thrombocytopenia in adults and a possible direct involvement of HCV cannot be excluded.

Lymphoproliferation in type II mixed cryoglobulinemia.

OBJECTIVE: The role of the hepatitis C virus (HCV) in the etiology of type II mixed cryoglobulinemia (MC) has been well established, but the pathogenetical relationships among the virus, the immune system, the natural history of MC, and lymphoproliferation in the bone marrow and liver need to be further elucidated. METHODS: Eighty-two patients with HCV positive type II MC and 20 subjects with chronic hepatitis C without MC were studied: bone marrow and liver specimens were examined by routine histology and immunohistochemistry, particularly focusing on parameters related to disease behaviour, such as the expression of the bcl-2 oncogene product and the proliferation-associated Ki67 antigen. RESULTS: In most MC patients there were lymphoid infiltrates within the bone marrow showing a monomorphic cytology, frequent immunoglobulin light chain monotypic restriction, expression of the anti-apoptotic bcl-2 oncogene product, and a low proliferative capacity (Ki-67 < 3%). On the other hand, in all non-cryoglobulinemic patients a bone marrow picture of reactive lymphoplasmacytosis was found. In both MC and chronic hepatitis patients, the liver biopsy showed portal infiltrates consisting of T-cells, associated with a significant B-cell component; the latter was particularly abundant in MC, where it was frequently arranged in pseudo-follicles. The B-cell component expressed the bcl-2 oncogene product and CD5 antigen, thus suggesting that the immune system is actively involved in the production of liver damage both in MC and non-cryoglobulinemic patients. It is worth noting that in MC patients (but not in the non-cryoglobulinemic patients) these CD5+/bcl-2+ B-cells frequently also exhibited a monotypic restriction bearing an IgM kappa. CONCLUSION: Our findings in these liver and bone marrow studies further support the role of a lymphoproliferative disorder in the pathology of type II MC: the B cells involved accumulate due to the inhibition of apoptosis, and their low proliferative index justifies the indolent course of the disease. HCV probably interacts with these B-cells, facilitating their clonal expansion.

A pilot study on the effectiveness of cyclosporine in type II mixed cryoglobulinemia.

OBJECTIVE: To evaluate the effect of cyclosporine in the treatment of type II mixed cryoglobulinemia, after the failure of more conventional therapies. METHODS: Two patients with type II mixed cryoglobulinemia associated with chronic HCV infection, purpura, liver disease, and sensitive/motor neuropathy were treated with cyclosporine (2.5 mg/Kg/b.w.), after their failure to respond to treatment with corticosteroid, immunosuppressive drugs, interferon, and plasmapheresis. RESULTS: In both patients an improvement in the clinical manifestations (purpura and peripheral neuropathy), laboratory results (serum transaminases and cryocrit), and liver histology was seen, as well as the disappearance of bone marrow B-cell lymphoproliferation. CONCLUSION: Cyclosporine may be useful in the treatment of type II mixed cryoglobulinemia with prominent autoimmune clinical manifestations, although further studies are needed to better define the selection of patients.

Hepatitis C virus RNA in the bone marrow of patients with mixed cryoglobulinemia and in subjects with noncryoglobulinemic chronic hepatitis type C.

Hepatitis C virus (HCV) infection is associated with most mixed cryoglobulinemia (MC) syndromes. In this study, HCV RNA was detected in the peripheral blood mononuclear cells of 11 (73.3%) of 15 patients with MC and in 5 (71.4%) of 7 noncryoglobulinemic patients with chronic hepatitis type C. All patients with cryoglobulinemia and 3 (42.8%) of the 7 without cryoglobulinemia (P < .05) had HCV RNA in bone marrow cells. Subjects in both groups with HCV-positive bone marrow also had HCV RNA in serum. The majority of patients with MC syndromes were infected with HCV subtypes 1b and 2a. Two patients with MC had different genotypes in serum and cells. Further studies are needed to determine which bone marrow cell population is preferentially infected by HCV and to determine if this phenomenon is involved in inducing the production of cryoglobulins.

Hepatotoxicity of hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors.

The first clinical studies on hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors reported a low incidence of liver toxicity. The personal observation of a case of simvastatin-induced acute cholestatic hepatitis prompted us to evaluate the true incidence of hepatic side effects of these drugs in a large Italian population. One hundred patients taking simvastatin and ninety patients treated with pravastatin were followed-up six months with periodical evaluation of serum lipid levels and liver function test. In 5% of simvastatin-treated patients and 4.5% of pravastatin-treated patients significant liver toxicity was observed, which required drug discontinuation. The mechanism of liver damage was direct, idiosyncratic, but immunological features of drug toxicity could be hypothesized in one patient.

MACOP-B treatment for advanced stage diffuse large cell lymphoma: a multicenter Italian Study.

Seventy-one patients with advanced stage diffuse large cell lymphoma were treated with MACOP-B. Sixty-nine per cent of patients achieved a complete response (CR), 10% a partial remission, while 11% had no response and 10% died because of toxicity. The CR rate was adversely affected by immunoblastic type, poor performance status and bone marrow involvement. Two-year survival for all 71 patients was 55% and 2-year disease-free survival (DFS) for the 49 CRs was 73%. Relapses were lower (P less than 0.05) in patients achieving CR in 8 weeks or less (DFS 83% vs. 59%) and in patients without tumor bulk (DFS 87% vs. 54%). Overall toxicity was acceptable with mucositis proving to be the most frequent severe side-effect. However, treatment-related deaths were unacceptably high in patients over 59 years of age (30% vs. 7%). Thus for the elderly MACOP-B is potentially lethal and must be used cautiously. These preliminary results confirm the effectiveness of MACOP-B. The delay of response and/or the presence of tumor bulk may be important prognostic factors in identifying a subset of poor risk patients with a high incidence of relapse.