Urinary nitrite/nitrate concentrations and total antioxidant capacity in patients with chronic hepatitis C in therapy with interferon and ribavirin.

In this study we tried to elucidate the role of nitric oxide (NO) in chronic hepatitis C in relation to antioxidant status, since the mechanisms by which hepatitis C virus (HCV) causes cell damage and the factors underlying its resistance to therapy are not well understood. Before and after one and six months of therapy with alpha-interferon and ribavirin, we measured nitrite/nitrate urinary levels, total antioxidant capacity and selenium serum concentrations in 14 patients with chronic hepatitis C and in 9 healthy subjects. Before therapy, mean urinary nitrite/nitrate levels of patients were not different from those of healthy subjects, but after a 6-month treatment with alpha-interferon and ribavirin, these NO metabolites were higher in virologically negative patients (responders). Moreover, while no changes in selenium were observed in all patients, total antioxidant capacity was significantly higher in non-responders and well correlated with hyperuricemia (due to cell damage) observed in these subjects. Instead, uric acid decreased as free molecule in serum in responders, while we found the excretion of high NO levels as nitrite/nitrate. Our data allow us to hypothesize a role for NO as predictive of the success of therapy, since nitrite/nitrate increase in the urine of some patients precedes disappearance of the virus observed at the end of therapy.

[Visceral leishmaniasis: a rarely diagnosed disease in northern Italy. Report of a case]. / Leishmaniosi viscerale: una malattia raramente diagnosticata nel nord Italia. Descrizione di un caso.

Fever, splenomegaly and pancytopenia may arise from a large range of infectious, hematologic or systemic diseases, and therefore represent a difficult diagnostic challenge. A possible cause of this syndrome is visceral leishmaniasis, an infectious disease due to intracellular protozoa of the genus Leishmania, which is endemic in many countries of both the Old and New World, but is quite uncommon in northern Italy. In particular, no "native" case of visceral leishmaniasis has so far been observed in the province of Verona. We present a case where the final diagnosis of visceral leishmaniasis was made in a 79-year-old man, who lived in Verona and had not traveled outside northern Italy for the previous 10 years. Clinical peculiarities, diagnostic difficulties and therapeutic regimens are discussed. We conclude that visceral leishmaniasis must be taken into consideration in the differential diagnosis of febrile splenomegalies even in geographical areas, such as northern Italy, where the infection is not endemic, and in patients without a suspicious travel history.

[Costal osteolytic lesions and multiple hepatic neoformations in a patient with inflammatory pseudotumor]. / Lesioni litiche costali e neoformazioni epatiche multiple in un caso di pseudotumore infiammatorio.

Inflammatory pseudotumor is a rare disease, that is regarded as a benign reactive inflammatory process, although its etiology and pathogenesis are still unknown. The liver is one of the organs most frequently involved, but inflammatory pseudotumors have been reported in many other sites in the body. Inflammatory pseudotumor of the liver presents as a solitary or, less frequently, multiple space-occupying lesion, which the common imaging techniques do not clearly distinguish from primitive or metastatic hepatic malignancies. Biopsy of the lesion is therefore necessary for diagnosis. The case of inflammatory pseudotumor described here presented with radiologic features of multiple solid space-occupying lesions in the liver, associated with multiple osteolytic lesions in the ribs. Such an association, very suggestive of malignancy, has not yet been reported for inflammatory pseudotumors. Optimum management of this disease has not yet been standardized. The majority of patients are treated by hepatic resection, although spontaneous regression has also been described. In our case, rapid improvement of both hepatic and costal lesions was observed, although the patient did not receive any specific treatment.

Serum level of soluble intercellular adhesion molecule 1 in patients with chronic liver disease related to hepatitis C virus: A prognostic marker for responses to interferon treatment.

Intercellular adhesion molecule 1 (ICAM-1) is a marker of inflammation and tissue damage. Levels of soluble ICAM-1 (sICAM-1) were measured in 71 patients with chronic C hepatitis treated with interferon (IFN)-alpha-2a, at baseline and at every 3 months of therapy, and in 42 normal control subjects. The levels of sICAM-1 were significantly higher in the patient than in the control subject group, particularly among cirrhotics. Baseline sICAM-1 levels were similar in responders and nonresponders. By contrast, the concentration of sICAM-1 decreased significantly only in responders during the first 3 months of therapy. The probability of response to treatment, analyzed by Kaplan-Meier analysis, was much higher in the group showing a decrease of sICAM-1 than in the patients who did not show such a decrease. In conclusion, a "longitudinal" evaluation of serum levels of sICAM-1 in the first period of treatment is particularly useful in the identification of patients with high significant probability of response to treatment.

Pulmonary mucosa-associated lymphoid tissue lymphoma and myasthenia gravis. A case report.

We describe a low-grade, MALT-lymphoma with multiple, unusually large opacities involving both the lungs in a woman suffering from myasthenia gravis. Unlike other autoimmune diseases, myasthenia gravis has never been associated with MALT-lymphoma thus far. After cyclophosphamide treatment, a complete detersion of the pulmonary opacities was obtained.

[Pulmonary mucosa-associated lymphoid tissue lymphoma in a patient with myasthenia gravis]. / Linfoma polmonare del tessuto linfoide associato alla mucosa in una paziente affetta da miastenia grave.

Mucosa-associated lymphoid tissue lymphomas are a subgroup of non-Hodgkin's lymphoma. The lung is the most frequent non-gastrointestinal organ they affect. Pulmonary mucosa-associated lymphoid tissue lymphoma usually appears as a solitary mass often accidentally discovered on chest radiography. Diffuse, bilateral involvement is rare. The association of mucosa-associated lymphoid tissue lymphoma with autoimmune diseases has been reported, and a pathogenetic role has been suggested for the autoimmune process in its development. Optimum management has not yet been standardized. The case described here is a mucosa-associated lymphoid tissue lymphoma with multiple, unusually large opacities involving both lungs. The patient, a 55-year-old woman, also suffered from myasthenia gravis, an autoimmune disease characterized by an autoaggressive process against the acetylcholine receptors. Whereas other autoimmune diseases such as rheumatoid arthritis, polymyositis, and fibrosing alveolitis have been correlated with mucosa-associated lymphoid tissue lymphoma, an association between this lymphoma and myasthenia gravis has not yet been reported. Complete resolution of the pulmonary opacities was obtained with cyclophosphamide treatment. It continues at 15 months after the suspension of therapy.

Serum laminin and type III procollagen in chronic hepatitis C. Diagnostic value in the assessment of disease activity and fibrosis.

Laminin P1 (pepsin-resistant fragment of laminin) and aminoterminal peptide of type III procollagen are measurable in serum and are now considered useful serum markers of fibrogenesis and inflammation in chronic liver diseases. However, very few studies thus far have focused on assessing the diagnostic value of these markers in detecting fibrosis and necro-inflammatory activity in chronically diseased liver. The aim of the present study was therefore to investigate the correlations of laminin and type III procollagen with liver histology and to compare their diagnostic value in detecting the degree of liver fibrosis and necro-inflammatory activity in a homogeneous group of 99 patients suffering from chronic hepatitis C, and lacking other factors which can directly affect the serum levels of the two markers. Both these serum markers were measured by radioimmunoassay, employing commercially available kits. The three main aspects of liver pathology, i.e. portal-periportal activity, lobular activity and fibrosis, were histologically evaluated and semiquantitatively expressed by numerical scores. The results of this study show that laminin and type III procollagen were both positively correlated with the histological scores for portal-periportal activity and with those for fibrosis, whereas no significant correlation was observed between each of the two serum markers and the histological scores for lobular activity. The sensitivity and specificity of laminin and type III procollagen in detecting histological aspects of fibrosis and disease activity in liver, computed at various cut-off levels, showed overlapping trends for the two markers; however, the diagnostic value was in general rather low, whatever the cut-off considered. We therefore conclude that the 'static' measurement of both serum laminin and type III procollagen is of limited value for individual diagnosis of liver damage.

Serum laminin P1 in chronic viral hepatitis: correlations with liver histological activity and diagnostic value.

Laminin is a major basement membrane-associated, non-collagenous glycoprotein of the extracellular matrix and is deposited in the space of Disse during sinusoidal capillarisation. Laminin P1, a pepsin-resistant fragment originating from the central portion of the cross-shaped laminin molecule, is detectable in serum and has been related to liver fibrosis and portal hypertension. In this study we investigated the behaviour of serum laminin P1, measured by radioimmunoassay, in a homogeneous group of 95 patients suffering from chronic viral hepatitis, types C or B, in order to determine the relationships between serum laminin P1 and each of the main histological aspects of the disease process (i.e. portal-periportal activity, lobular activity and fibrosis), which were assigned numerical scores. Moreover, we computed, at several cut-off levels, the sensitivity, specificity and positive and negative predictive values of laminin P1 in detecting both necroinflammatory activity and fibrosis in the liver. The results show that serum laminin P1 levels parallel the severity of liver disease, the highest laminin concentrations being observed in cirrhotic patients. They suggest also that serum laminin P1 should be considered a marker of the liver disease process as a whole, rather than a marker exclusively linked to fibrosis. Nevertheless, the usefulness of serum laminin P1 measurement, as investigated in this study, seems too limited to be recommended for routine clinical practice.

Cryoglobulinemia in hepatitis C virus chronic active hepatitis: effects of interferon-alpha therapy.

We investigated the prevalence of mixed cryoglobulinemia (MC) in 100 cases of chronic hepatitis C virus (HCV) infection and the effect of a 6-month treatment with interferon-alpha (IFN-alpha). Cryoglobulins were detected on admission in 36 of 100 patients and appeared during observation in a further 18 cases. Cryocrit ranged from 0.5% to 20%. Patients with MC were older and had a higher incidence of cirrhosis than those without MC. Immunologic characterization of the cryoprecipitate showed the presence of type II in 84% of cases and type III in 16%. The patients received IFN-alpha (6 MU three times per week) for 6 months. Fifty-seven were responders (i.e., reached normal aminotransferase levels), 26 of these relapsed within 2 months after IFN withdrawal, and 30 did not relapse. After IFN-alpha treatment, cryoglobulinemia disappeared in 11 of the 21 evaluable responders, but in none of the 15 nonresponder patients (p < 0.003). The clearance of MC was associated in all cases with clearance of HCV RNA. The delayed appearance of cryoglobulinemia in responders seems to be associated with a higher probability of relapse.

Long-term variations of serum laminin and procollagen III peptide in chronic HCV hepatitis after alpha-interferon therapy.

Twenty-three out of 40 patients affected by chronic HCV hepatitis responded (i.e. aminotransferases returned to normal) after 6-month treatment with 6 MU tiw of recombinant alpha-interferon 2a (IFN); in 11 (Group 1), the remission was maintained for a mean observation time of 33.15 months (range 20-50) after withdrawal of therapy; 12 (Group 2) relapsing after IFN withdrawal, were treated again obtaining in 10 a second response. Seventeen did not respond (Group 3). Serum markers of connective tissue metabolism (laminin and aminoterminal peptide of type III procollagen -NPIIIP-) were assayed in all patients before treatment and every 6th month, to evaluate long-term effects of IFN therapy. In non-responders, NPIIIP after treatment was not different from baseline, while laminin significantly increased at 6 and 12 months; in responders, NPIIIP decreased significantly after therapy, maintaining values lower than baseline on long-term observation. Laminin decreased significantly six months after the end of therapy and remained lower than baseline in all sustained responders. In this group, the drop in laminin was progressive, whereas in Group 2, laminin showed only a slight decrease on long-term control. Our data show that these serum markers persistently decrease in sustained responders to IFN, while in relapsed cases, prolonged therapy is needed to obtain minor effects on laminin; on the contrary, in non-responders, NPIIIP remains unchanged and laminin significantly increases, suggesting a persistence of active fibrogenesis.

Excessive tea consumption can inhibit the efficacy of oral iron treatment in iron-deficiency anemia.

Intestinal absorption of non-heme food iron may be inhibited by tea, which, on the contrary, does not exert any appreciable effect on heme iron assimilation. Therefore, while an iron-deficiency anemia cannot develop in non-vegetarian subjects as a consequence of tea consumption only, it is possible that tea could inhibit the therapeutic effect of oral iron drugs, which are usually non-hemic ferrous salts, in iron-deficient subjects. This view is supported by the case we describe here, a young woman affected by hypermenorrhea and iron-deficiency anemia, who did not respond to oral iron treatment until she stopped her long-established habit of consuming large quantities of tea. We also believe that oral iron drugs should never be taken together with a cup of tea; therefore we think it useful to advise our iron-deficient patients clearly not to combine tea with the oral consumption of non-hemic ferrous salts.

Decreased activity of scavenger enzymes in human hepatocellular carcinoma, but not in liver metastases.

To investigate the role of oxygen free radicals in hepatocellular carcinoma we assayed tissue scavenger enzymes (superoxide dismutase and selenium-dependent glutathione peroxidase) in liver homogenate, plasma concentrations of vitamins A and E and the serum selenium level from 19 control patients, 23 cases of hepatocellular carcinoma and 18 cases of metastases to liver from different carcinomas. In hepatocellular carcinoma tissue the enzyme activities were all significantly lower than in control liver and in metastases-bearing liver; the enzyme activities of the latter tissues were not different from control liver. In contrast, normal liver adjacent to the hepatocellular carcinoma had decreased activity of superoxide dismutase. Serum selenium concentrations were significantly decreased in patients with hepatocellular carcinoma and those with liver metastases, while vitamin A was significantly decreased only in the former. These findings suggest that hepatocellular carcinoma develops in liver with severe impairment of cellular antioxidant systems, since, in patients with liver metastases from different cancers, despite low selenium concentrations, cellular scavenger enzymes have normal activities.

alpha-Interferon in the treatment of chronic viral hepatitis: effects on fibrogenesis serum markers.

Forty patients with chronic viral hepatitis or active cirrhosis (33 anti-HCV positive) entered a recombinant human alpha 2A interferon randomized trial. Twenty-one subjects were treated with 6 million units (MU) three times per week for 6 months. Nineteen were not treated. Six months later in 12 patients of the treated group (60% of the evaluable 20) with normalized serum aminotransferases levels (responders), fibrogenesis serum markers (NPIIIP and laminin) were significantly lower than baseline. In the untreated patients and in non-responders NPIIIP and laminin were unchanged. Semi quantitative histological evaluation (allotting scores for inflammation, necrosis and fibrosis) confirmed a significant improvement of necro-inflammation in the responders. These data suggest that alpha-IFN treatment may decrease stimuli for fibrogenesis by reducing liver inflammation and necrosis, thus preventing evolution to cirrhosis.

Trigeminal neuropathy in a case of mesenteric localized Castleman's disease.

Peripheral neuropathy of the limbs has so far been observed in very few patients with localized Castleman's disease, generally of the plasma-cell type. In the present case report, of a plasmacellular type localized within the mesenterium, a 25-year-old woman exhibited a clinical picture of right trigeminal neuropathy (together with more common constitutional symptoms and laboratory findings), which promptly disappeared after surgical removal of the mesenteric mass. To our knowledge, a similar impairment of cranial nerves, and specifically of the trigeminal, has never been reported in patients with the localized form of Castleman's disease.

Plasma osteocalcin levels in liver cirrhosis.

Osteocalcin, a recently identified protein, is produced by osteoblasts in the bone tissue. Its plasma level is a good marker of bone metabolism and is reduced in the presence of 'osteodystrophia', commonly found in cholostatic liver diseases. We assayed plasma osteocalcin levels in 20 cirrhotic patients and compared the values with those of 22 healthy controls. In the same patients we also measured the liver function, clotting and mineral metabolism indexes and calcitonin plasma levels. Osteocalcin levels were significantly lower in liver disease patients than in controls (5.53 ng/ml S.D. 2.57 vs 7.79 ng/ml S.D. 2.23; p less than 0.01) and calcitonin plasma levels were much higher in cirrhotics (130.18 pg/ml S.D. 212.30 vs 28.9 pg/ml S.D. 13.09; p less than 0.05). We think that the low osteocalcin levels observed in cirrhotics may be a consequence of "hepatic osteodystrophy" due to low vitamin D and calcium plasma levels.

Hepatic fibrosis and its serum markers: a review.

Hepatic fibrosis is characterized by a progressive increase in extracellular matrix in the liver, formed by collagens, proteoglycans and glycoproteins, qualitatively similar but quantitatively different from that in normal liver. A great number of matrix-related substances have been investigated in serum in order to identify reliable serum markers of liver fibroplasia. Among the various cleavage products of collagen precursor, the NPIIIP collagen is at present considered the most reliable serum marker of active fibrogenesis in liver, useful in monitoring the progression of fibrosis and in assessing the therapeutic efficacy of antifibrotic drugs. Lam-P1 and type IV collagen are now regarded as putative markers of basement membrane formation and sinusoids capillarization, an important pathological process in fibrosing disease, related to the impairment of hepatic circulation. Other serum-measured matrix-related substances, e.g. enzymes involved in collagen metabolism, fibronectin and proteoglycans, have not proved to reflect liver fibroplasia reliably. In spite of the availability of useful serum markers, the assessment of hepatic fibrosis is still based on liver biopsy.

Serum copper and ceruloplasmin in early and in advanced hepatocellular carcinoma: diagnostic and prognostic relevance.

To evaluate the prognostic value of serum copper (S-Cu) and ceruloplasmin and their pathophysiologic significance in human hepatocellular carcinoma (HCC), we studied 49 patients with HCC (20 of which were submitted to partial hepatectomy) compared with 110 patients with liver cirrhosis. In HCC both S-Cu and ceruloplasmin were higher than in cirrhosis; moreover, S-Cu was correlated with the extension of HCC, evaluated by instrumental data and by surgical inspection. In cirrhotic patients, mean S-Cu was 122.9 micrograms/dl (SD, 29.3), in early HCC, 153.0 micrograms/dl (SD, 34.5), and in advanced HCC, 193.1 micrograms/dl (SD, 37.7). Variance analysis gave F = 59.4. In HCC patients S-Cu was positively correlated with ceruloplasmin and with fibrinogen. Survival, evaluated by Mantel's test stratified for surgical therapy, was longer in patients with S-Cu levels lower than 175 micrograms/dl and in those at an earlier stage. We therefore conclude that S-Cu has a relevant diagnostic value in detecting HCC also in early stage and allows prognostic evaluation as regards survival.

Fibronectin is related to prealbumin in plasma of decompensated cirrhotics.

In a group of 23 patients with advanced liver cirrhosis we have found a statistically significant positive correlation (r = 0.746; p less than 0.0001) between fibronectin and prealbumin levels measured in plasma by immunonephelometric methods and found significantly lower than in healthy controls (p less than 0.001). On the contrary, no correlation of fibronectin neither to albumin nor to the presence of an enlarged spleen was observed. Since the sensitivity of prealbumin as an index of liver function is believed to be higher than that of albumin, our results support the view that the decreased fibronectin in advanced cirrhotics is mainly due to their liver failure, an enlarged spleen playing only a minor role.