The development of colorectal cancer in ulcerative colitis is a function of disease duration, wit... more The development of colorectal cancer in ulcerative colitis is a function of disease duration, with the risk approaching 14% at 25 years. Colitic cancer has become an issue in the last decades, as the availability of effective immune suppressors has reduced resort to curative colectomies. Scrutiny of the available drug options for ulcerative colitis has generated solid evidence of a chemopreventive role of mesalamines. Recent studies on the thiopurines azathioprine and mercaptopurine have unraveled the ability of these drugs to reduce inflammation and influence adaptive immunity by enhancing apoptosis. This evidence, speaking in favor of a chemopreventive role of thiopurines, has not been supported until recently by clinical studies. By contrast, endoscopic and clinical data in our hands have continued to suggest such a role: of a cohort of ulcerative colitis patients treated with azathioprine for 17 years, those on active treatment had no mucosal inflammation on endoscopy and overall none in this cohort developed cancer. This retrospective data have now been validated by cutting-edge information from a prospective nationwide study from an independent group which found a significant chemopreventive effect of azathioprine in those with extended long-standing colitis. Combination of our single-center experience with the data from this large study strongly indicates that the immune modulatory properties of thiopurines can translate into clinically meaningful anti-cancer activity in colitis. These results are likely to influence the medical choices of inflammatory bowel disease caregivers in the decades to come.
... staining using a specific monoclonal antibody (Dakopatts Corp., Copenaghen, Denmark), avidin ... more ... staining using a specific monoclonal antibody (Dakopatts Corp., Copenaghen, Denmark), avidin biotin complex technique (7), and in situ hy-bridization for human cytomegalovirus (Enzo Diag-nostic ... 3. Guthrie W, McLean H. Dissecting aneurysms of arteries other than the aorta. ...
The extracellular signal-regulated kinase 5 (ERK5 or BMK1) is involved in tumour development. The... more The extracellular signal-regulated kinase 5 (ERK5 or BMK1) is involved in tumour development. The ERK5 gene may be amplified in hepatocellular carcinoma (HCC), but its biological role has not been clarified. In this study, we explored the role of ERK5 expression and activity in HCC in vitro and in vivo. ERK5 expression was evaluated in human liver tissue. Cultured HepG2 and Huh-7 were studied after ERK5 knockdown by siRNA or in the presence of the specific pharmacological inhibitor, XMD8-92. The role of ERK5 in vivo was assessed using mouse Huh-7 xenografts. In tissue specimens from patients with HCC, a higher percentage of cells with nuclear ERK5 expression was found both in HCC and in the surrounding cirrhotic tissue compared with normal liver tissue. Inhibition of ERK5 decreased HCC cell proliferation and increased the proportion of cells in G0/G1 phase. These effects were associated with increased expression of p27 and p15 and decreased CCND1. Treatment with XMD8-92 or ERK5 sile...
SERPINB3 is a cysteine-proteases inhibitor up-regulated in a significant number of cirrhotic pati... more SERPINB3 is a cysteine-proteases inhibitor up-regulated in a significant number of cirrhotic patients carrying hepatocellular carcinoma (HCC) and recently proposed as a prognostic marker for HCC early recurrence. SERPINB3 has been reported to stimulate proliferation, inhibit apoptosis and, similar to what reported for hypoxia, to trigger epithelial-to-mesenchymal transition (EMT) and increased invasiveness in liver cancer cells. This study has investigated whether SERPINB3 expression is regulated by hypoxia-related mechanisms in liver cancer cells. Exposure of HepG2 and Huh7 cells to hypoxia up-regulated SERPINB3 transcription, protein synthesis and release in the extracellular medium. Hypoxia-dependent SERPINB3 up-regulation was selective (no change detected for SERPINB4) and operated through hypoxia inducible factor (HIF)-2α (not HIF-1α) binding to SERPINB3 promoter, as confirmed by chromatin immuno-precipitation assay and silencing experiments employing specific siRNAs. HIF-2α-me...
Although possible implications of nitric oxide in the pathophysiology of liver cirrhosis have bee... more Although possible implications of nitric oxide in the pathophysiology of liver cirrhosis have been extensively studied, until now few articles have addressed the assessment of nitric oxide production in primary biliary cirrhosis. This study was directed to evaluate circulating nitrosyl-hemoglobin levels as well as neutrophil elastase and soluble adhesion molecule concentrations in this condition, by assuming these parameters as possible markers of either inflammatory response or neutrophil activation. Laboratory investigations were performed in 30 patients with primary biliary cirrhosis, in 13 patients with postviral and/or alcoholic cirrhosis, and in a group of eight subjects with chronic hepatitis. Although no difference was detected with respect to chronic hepatitis subjects, higher levels of nitrosyl-hemoglobin adducts were found in primary biliary cirrhosis patients than in postviral or alcoholic cirrhotics and in normal subjects (3.55+/-1.75 arbitrary units vs 1.95+/-0.57 and 0.84+/-0.34, p = 0.0004 and p < 0.0001, respectively). Similarly, more elevated concentrations of neutrophil elastase (213.7+/-192.0 microg/L vs 51.1+/-34.3 and 38.0+/-11.5, p < 0.0001 and p < 0.0001, respectively) as well as of soluble forms of intercellular adhesion molecule 1 and endothelial-leukocyte adhesion molecule 1 were shown in primary biliary cirrhosis patients than in subjects with cirrhosis of other etiologies and in controls. Highly enhanced nitric oxide production in primary biliary cirrhosis could be related to the development of strong inflammation and at least partially to neutrophil activation, thus suggesting a putative role of these cellular mediators in the development of liver damage owing to their ability to synthesize and release a wide variety of important factors, including elastase and nitric oxide.
Carcinoids are tumors derived from neuroendocrine cells and often produce functional peptide horm... more Carcinoids are tumors derived from neuroendocrine cells and often produce functional peptide hormones. Approximately 54.5% arise in the gastrointestinal tract and frequently metastasize to the liver. Primary hepatic carcinoid tumors (PHCT) are extremely rare; only 95 cases have been reported. A 65-year-old man came to our attention due to occasional ultrasound findings in absence of clinical manifestations. His previous medical history, since 2003, included an echotomography of the dishomogeneous parenchymal area but no focal lesions. A computed tomography s c a n p e r fo r m e d i n 2 0 0 5 s h o w e d an enhanced pseudonodular-like lesion of about 2 cm. Cholangiomagnetic resonance imaging identified the lesion as a possible cholangiocarcinoma. No positive findings were obtained with positron emission tomography. Histology suggested a secondary localization in the liver caused by a low-grade malignant neuroendocrine tumor. Immunohistochemistry was positive for anti chromogranin antibodies, Ki67 antibodies and synaptophysin. Octreoscan scintigraphy indicated intense activity in the lesion. Endoscopic investigations were performed to exclude the presence of extrahepatic neoplasms. Diagnosis of PHCT was established. The patient underwent left hepatectomy, followed by hormone therapy with sandostatine LAR. Two months after surgery he had a lymph nodal relapse along the celiac trunk and caudate lobe, which was histologically confirmed. The postoperative clinical course was uneventful, with a negative follow-up for hematochemical, clinical and radiological investigations at 18 mo post-surgery. Diagnosis of PHCT is based principally on the histopathological confirmation of a carcinoid tumor and the exclusion of a non-hepatic primary tumor. Surgical resection is the recommended primary treatment for PHCT. Recurrence rate and survival rate in patients treated with resection were 18% and 74%, respectively.
is associated with more severe liver damage and an increased risk of fulminant disease. HDV is a ... more is associated with more severe liver damage and an increased risk of fulminant disease. HDV is a single-stranded RNA virus that encodes a single protein, the delta antigen, which is expressed in two forms, small (S-HDAg) and large (L-HDAg). Here we show that although HDV ribonucleoproteins are mainly detected in the nucleus, they are also present in the cytoplasm of cells infected with HDV or transfected with HDV cDNA. Making use of an heterokaryon assay, we demonstrate that HDV ribonucleoproteins shuttle continuously between the nucleus and the cytoplasm. In the absence of HDV RNA, both forms of the delta antigen are retained in the nucleus, whereas in the absence of the delta antigen, HDV RNA is predominantly detected in the cytoplasm. Coexpression of HDV RNA and S-HDAg (which binds to the viral RNA and contains a nuclear localization signal) results in nuclear accumulation of the viral RNA. This suggests that HDV RNA mediates export of viral particles to the cytoplasm whereas the delta antigen triggers their reimport into the nucleus.
We describe the case of a 19-year-old boy with acute leukaemia who developed primary hepatic zygo... more We describe the case of a 19-year-old boy with acute leukaemia who developed primary hepatic zygomycosis. The patient presented with febrile neutropenia and severe abdominal tenderness. Despite the administration of antibiotics and liposomal Amphotericin-B (L-AmB), the CT scan demonstrated an increase in the size of liver lesions. A wide surgical resection was carried out and liver specimens demonstrated a branching, filamentous fungus that was identified as Rhizomucor pusillus by both phenotypic and molecular methods. The patient was treated with L-AmB combined with posaconazole, and deferasirox was subsequently added given the potential synergistic effect of this iron chelator in combination with L-AmB. Three months after surgical intervention, an allogeneic stem-cell transplantation was successfully carried out. The present case confirms that an early surgical management combined with antifungal agents is crucial to optimise the outcome of patients with zygomycosis and the use of deferasirox is a promising alternative.
Treatment with hepatitis B virus immune globulins (HBIG) or lamivudine has reduced the rate of he... more Treatment with hepatitis B virus immune globulins (HBIG) or lamivudine has reduced the rate of hepatitis B recurrence after liver transplantation to approximately 50%. To further decrease hepatitis B recurrence, 33 hepatitis B virus (HBV)-related cirrhotic patients were treated with lamivudine before liver transplantation and with lamivudine together with low-dose HBIG (46 500 IU the first month followed by 5,000 lU/monthly) after surgery. While on lamivudine, serum HBV DNA level decreased significantly in all patients and in 11 (33%) the Child-Pugh score improved. Twenty-six patients were transplanted. Among the 25 who survived for longer than 12 months, only one (4%) experienced a hepatitis B recurrence over an average follow-up of 31 months, a rate significantly lower (P = 0.0002) than the 50% recurrence rate among a historical control group of 12 patients. However, low-level HBV replication was detected sporadically throughout the follow-up in 64% of patients. Over the medium-term, combined prophylaxis with lamivudine and HBIG significantly decreases the risk of hepatitis B recurrence after liver transplantation. Though low-level HBV infection recurred in two thirds of patients, the pathogenic expression of HBV was prevented.
We determined the prevalence of hepatitis C virus markers and the clinical course in patients tra... more We determined the prevalence of hepatitis C virus markers and the clinical course in patients transplanted for terminal type C or non-A, non-B cirrhosis. Hepatitis C virus infection recurred in 16 of 17 patients (94%) with type C cirrhosis (seropositive for hepatitis C virus prior to ...
Background/Aims: Interferon (IFN) with ribavirin combination therapy (CT) was proposed for the tr... more Background/Aims: Interferon (IFN) with ribavirin combination therapy (CT) was proposed for the treatment of hepatitis C recurring in liver transplants. We assessed the efficacy of two protocols of CT in transplanted patients with recurrent severe hepatitis C virus (HCV) hepatitis.
detected in a-smooth muscle actin-positive myofibroblasts lining fibrotic septa in human cirrhoti... more detected in a-smooth muscle actin-positive myofibroblasts lining fibrotic septa in human cirrhotic livers. Conclusions: Intracellular generation of ROS, through activation of specific signaling pathways, is a critical event for directional migration of HSC/MFs and MSCs. Ó
The histopathology of hepatitis delta virus disease was studied in carriers of HBsAg with chronic... more The histopathology of hepatitis delta virus disease was studied in carriers of HBsAg with chronic hepatitis delta antigen-positive hepatitis and in serial biopsies of patients with acute hepatitis delta virus hepatitis that progressed to chronicity. There was no histologic feature distinctive of hepatitis delta virus from other types of viral hepatitis. Biopsy specimens of patients with chronic disease exhibited portal and periportal inflammation with piecemeal necrosis, conforming to a picture of aggressive hepatitis often accompanied by cirrhosis. Characteristic was a marked intralobular infiltration by mononuclear cells and a degenerative eosinophilic change of the hepatocytic cytoplasms conducive to the formation of acidophilic bodies. Liver specimens from patients with hepatitis delta virus hepatitis exhibited aspects of focal, confluent and bridging necrosis. The disease progressed to chronicity irrespective of the original histological features. The expression of intrahepatic hepatitis delta antigen was reduced in the phase of the acute hepatitis but increased in parallel with the development of chronic active liver disease. In late-stage cirrhosis, expression of hepatitis delta antigen was usually low.
The course of chronic hepatitis B was studied in 30 patients who had antibody to hepatitis e anti... more The course of chronic hepatitis B was studied in 30 patients who had antibody to hepatitis e antigen and hepatitis B virus DNA in the serum and hepatitis B core antigen in the liver. Over a 2-year period, no patient experienced a sustained spontaneous remission of disease, and follow-up liver histology revealed worsening of the disease in four patients. After 2 years of observation, 24 patients were allocated randomly to one of two groups: 12 patients served as untreated controls and 12 received recombinant human alpha-interferon-2a in a dose of 9 million units intramuscularly three times weekly for 16 weeks. Patients who remained viremic after 16 weeks received 3 million units three times weekly for an additional 8 weeks. Abnormal amino-transferases and serum hepatitis B virus DNA persisted without appreciable changes in all untreated patients. Hepatitis B virus DNA rapidly became undetectable and serum aminotransferases fell to normal in eight treated patients. After the end of treatment, hepatitis B virus DNA became detectable once again in seven patients, in six of whom a peak of aminotransferases (range: 256 to 850 units per liter) ensued; subsequently, hepatitis B virus DNA disappeared, and serum aminotransferases again fell to normal in two of the seven. Overall, hepatitis B virus DNA was no longer detectable in serum and liver histology improved in three treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Therapy of chronic hepatitis delta with standard interferon therapy has met with limited efficacy... more Therapy of chronic hepatitis delta with standard interferon therapy has met with limited efficacy. This study was designed to examine the efficacy and safety of peginterferon with or without ribavirin. Thirty-eight serum hepatitis B surface antigen-and HDV RNA-positive patients with alanine aminotransferase (ALT) more than 1.5 times the upper normal limit received peginterferon alpha-2b (1.5 g/kg) alone as monotherapy (n ؍ 16) or in combination with ribavirin (n ؍ 22), for 48 weeks. Thereafter, all the patients were maintained on peginterferon for 24 weeks and followed for 24 weeks off therapy. The primary end point studied was the virological and biochemical response at the end of follow-up. HDV RNA was determined by single or nested polymerase chain reaction assays. Twenty-seven patients (71%), 11 receiving monotherapy and 16 receiving the combination treatment, completed the follow-up. At the end of treatment, a virological response was observed in 3 of the patients treated with peginterferon (19%) and in 2 of the patients treated with combination therapy (9%), and a biochemical response was observed in 6 (37.5%) and 9 patients (41%), respectively. In nonresponders, ALT diminished from a mean of 174 ؎ 53 to 86 ؎ 41 IU/L. At the end of follow-up, serum HDV RNA was negative in 8 patients (21%), and a biochemical response was detected in 10 patients (26%). Treatment was discontinued in 25% of the patients, and dosing was modified in 58%. In conclusion, a prolonged course of peginterferon alpha-2b resulted in clearance of serum HDV RNA and ALT normalization in a fifth of patients with chronic hepatitis D, while ribavirin had no effect on the viral clearance rate. Overall tolerance of therapy was poor. (HEPATOLOGY 2006;44:713-720.) See Editorial on Page 536 Abbreviations: HDV, hepatitis delta virus; ALT, alanine aminotransferase; HBV, hepatitis B virus; IFN, interferon; RBV, ribavirin; PEG-IFN, pegylated interferon; anti-HD, antibody to hepatitis delta antigen; HBsAg, hepatitis B surface antigen; anti-HBe, antibody to hepatitis B e antigen. From the
This study aims to determine the presence of the components of the metabolic syndrome in primary ... more This study aims to determine the presence of the components of the metabolic syndrome in primary nonalcoholic steatohepatitis (NASH) and to assess the role of liver disease in the genesis of peripheral hyperinsulinemia. Nineteen patients (18 men and 1 woman; mean age, ؎ SD, 38 ؎ 10 years; body mass index [BMI], 26 ؎ 2 kg/m 2 ) with histologic evidence of NASH were enrolled; 19 age-and sex-matched normal subjects were investigated as controls. Plasma glucose, insulin, and C-peptide levels were measured during an oral glucose tolerance test, and a frequently sampled intravenous glucose tolerance test (FSIGT), analyzed by minimal modeling technique, was performed. Compared with controls, the NASH group had lower insulin sensitivity (3.84 ؎ 2.44 vs. 7.48 ؎ 3.01 10 -4 ؋ min -1 /U/mL; P ؍ .0003) and higher total insulin secretion (21 ؎ 13 vs. 10 ؎ 3 nmol/L in 240 minutes; P ؍ .001). Hepatic insulin extraction was similar in both groups (69.8% ؎ 16.1% vs. 70.2% ؎ 18.3%; P ؍ .854). According to the results of the oral glucose tolerance test, no patient was classified as diabetic, 5 were classified as glucose intolerant, and 1 was classified as having impaired fasting glycemia. Nine patients (47%) had at least the 2 minimum criteria required to define the metabolic syndrome according to the European Group for the Study of Insulin Resistance (EGIR). In conclusion, hyperinsulinemia and insulin resistance occur frequently in patients with NASH; these conditions do not stem from a reduced hepatic insulin extraction but from an enhanced pancreatic insulin secretion compensatory to reduced insulin sensitivity. The derangement of insulin regulation, often associated with the metabolic syndrome, may play a causal role in the pathogenesis of NASH. (HEPATOLOGY 2002;35:367-372.) See Editorial on Page 497 Abbreviations: NASH, nonalcoholic steatohepatitis; EGIR, European Group for the Study of Insulin Resistance; BMI, body mass index; FSIGT, frequently sampled intravenous glucose tolerance test; SI, insulin sensitivity index. From the
European Journal of Gastroenterology & Hepatology, 2004
Hepatocellular carcinomata are relatively rare in the western hemisphere, but they are much more ... more Hepatocellular carcinomata are relatively rare in the western hemisphere, but they are much more common in South-East Asia and sub-Saharan Africa due to high endogenous levels of hepatitis B and C. Ectopic liver tissue usually is found incidentally (frequently at cholecystectomy), but it may also be found due to neoplastic changes or compressive effects. Ectopic liver tissue has an increased neoplastic potential over orthotopic liver, which we postulate is due to compromised vascular supply and biliary drainage. These lesions may be susceptible to surgical resection, although long-term follow-up data are poor. Ectopic or accessory liver tissue is a rare condition. Most commonly, it is found incidentally, but it may also be found as a result of neoplasia or compressive effects. These lesions appear to have an increased potential for the development of hepatocellular carcinoma in the absence of malignancy in the mother liver. Due to their anatomical features, these carcinomata appear to be susceptible to curative resection, although long-term follow-up data are poor. These carcinomata have been reported more frequently from South-East Asia than from Western countries; however, the common risk factors for hepatocellular carcinoma, such as infection with hepatitis B or C and cirrhosis, appear to be less implicated than in carcinomata of the orthotopic liver. In ectopic or accessory liver tissue, development of hepatocellular carcinoma may be the result of compromised vascular supply or biliary drainage.
Patients with the clinical syndrome of visceral larva migrans as a result of Toxocara species, ha... more Patients with the clinical syndrome of visceral larva migrans as a result of Toxocara species, have typical lesions in the liver consisting of granulomas that contain numerous eosinophils and often Charcot-Leyden crystals. This syndrome is rarely taken into account in patients with cholestatic syndrome, especially when hypereosinophilic reaction is absent. We report the case of a 47-year-old immunocompetent woman who presented with abdominal pain, in whom multiple focal liver lesions were discovered. She had come in contact with dogs. Diagnosis of toxocariasi was done. A good clinical response has been obtained by treating with thiabendazole. We present the findings of various imaging studies of the patient. This report shows that visceral larva migrans may be the cause of a chronic liver disease and should be suspected also in patients without fever and hypereosinophilia with cryptogenic cholestatic and focal liver lesions.
The development of colorectal cancer in ulcerative colitis is a function of disease duration, wit... more The development of colorectal cancer in ulcerative colitis is a function of disease duration, with the risk approaching 14% at 25 years. Colitic cancer has become an issue in the last decades, as the availability of effective immune suppressors has reduced resort to curative colectomies. Scrutiny of the available drug options for ulcerative colitis has generated solid evidence of a chemopreventive role of mesalamines. Recent studies on the thiopurines azathioprine and mercaptopurine have unraveled the ability of these drugs to reduce inflammation and influence adaptive immunity by enhancing apoptosis. This evidence, speaking in favor of a chemopreventive role of thiopurines, has not been supported until recently by clinical studies. By contrast, endoscopic and clinical data in our hands have continued to suggest such a role: of a cohort of ulcerative colitis patients treated with azathioprine for 17 years, those on active treatment had no mucosal inflammation on endoscopy and overall none in this cohort developed cancer. This retrospective data have now been validated by cutting-edge information from a prospective nationwide study from an independent group which found a significant chemopreventive effect of azathioprine in those with extended long-standing colitis. Combination of our single-center experience with the data from this large study strongly indicates that the immune modulatory properties of thiopurines can translate into clinically meaningful anti-cancer activity in colitis. These results are likely to influence the medical choices of inflammatory bowel disease caregivers in the decades to come.
... staining using a specific monoclonal antibody (Dakopatts Corp., Copenaghen, Denmark), avidin ... more ... staining using a specific monoclonal antibody (Dakopatts Corp., Copenaghen, Denmark), avidin biotin complex technique (7), and in situ hy-bridization for human cytomegalovirus (Enzo Diag-nostic ... 3. Guthrie W, McLean H. Dissecting aneurysms of arteries other than the aorta. ...
The extracellular signal-regulated kinase 5 (ERK5 or BMK1) is involved in tumour development. The... more The extracellular signal-regulated kinase 5 (ERK5 or BMK1) is involved in tumour development. The ERK5 gene may be amplified in hepatocellular carcinoma (HCC), but its biological role has not been clarified. In this study, we explored the role of ERK5 expression and activity in HCC in vitro and in vivo. ERK5 expression was evaluated in human liver tissue. Cultured HepG2 and Huh-7 were studied after ERK5 knockdown by siRNA or in the presence of the specific pharmacological inhibitor, XMD8-92. The role of ERK5 in vivo was assessed using mouse Huh-7 xenografts. In tissue specimens from patients with HCC, a higher percentage of cells with nuclear ERK5 expression was found both in HCC and in the surrounding cirrhotic tissue compared with normal liver tissue. Inhibition of ERK5 decreased HCC cell proliferation and increased the proportion of cells in G0/G1 phase. These effects were associated with increased expression of p27 and p15 and decreased CCND1. Treatment with XMD8-92 or ERK5 sile...
SERPINB3 is a cysteine-proteases inhibitor up-regulated in a significant number of cirrhotic pati... more SERPINB3 is a cysteine-proteases inhibitor up-regulated in a significant number of cirrhotic patients carrying hepatocellular carcinoma (HCC) and recently proposed as a prognostic marker for HCC early recurrence. SERPINB3 has been reported to stimulate proliferation, inhibit apoptosis and, similar to what reported for hypoxia, to trigger epithelial-to-mesenchymal transition (EMT) and increased invasiveness in liver cancer cells. This study has investigated whether SERPINB3 expression is regulated by hypoxia-related mechanisms in liver cancer cells. Exposure of HepG2 and Huh7 cells to hypoxia up-regulated SERPINB3 transcription, protein synthesis and release in the extracellular medium. Hypoxia-dependent SERPINB3 up-regulation was selective (no change detected for SERPINB4) and operated through hypoxia inducible factor (HIF)-2α (not HIF-1α) binding to SERPINB3 promoter, as confirmed by chromatin immuno-precipitation assay and silencing experiments employing specific siRNAs. HIF-2α-me...
Although possible implications of nitric oxide in the pathophysiology of liver cirrhosis have bee... more Although possible implications of nitric oxide in the pathophysiology of liver cirrhosis have been extensively studied, until now few articles have addressed the assessment of nitric oxide production in primary biliary cirrhosis. This study was directed to evaluate circulating nitrosyl-hemoglobin levels as well as neutrophil elastase and soluble adhesion molecule concentrations in this condition, by assuming these parameters as possible markers of either inflammatory response or neutrophil activation. Laboratory investigations were performed in 30 patients with primary biliary cirrhosis, in 13 patients with postviral and/or alcoholic cirrhosis, and in a group of eight subjects with chronic hepatitis. Although no difference was detected with respect to chronic hepatitis subjects, higher levels of nitrosyl-hemoglobin adducts were found in primary biliary cirrhosis patients than in postviral or alcoholic cirrhotics and in normal subjects (3.55+/-1.75 arbitrary units vs 1.95+/-0.57 and 0.84+/-0.34, p = 0.0004 and p < 0.0001, respectively). Similarly, more elevated concentrations of neutrophil elastase (213.7+/-192.0 microg/L vs 51.1+/-34.3 and 38.0+/-11.5, p < 0.0001 and p < 0.0001, respectively) as well as of soluble forms of intercellular adhesion molecule 1 and endothelial-leukocyte adhesion molecule 1 were shown in primary biliary cirrhosis patients than in subjects with cirrhosis of other etiologies and in controls. Highly enhanced nitric oxide production in primary biliary cirrhosis could be related to the development of strong inflammation and at least partially to neutrophil activation, thus suggesting a putative role of these cellular mediators in the development of liver damage owing to their ability to synthesize and release a wide variety of important factors, including elastase and nitric oxide.
Carcinoids are tumors derived from neuroendocrine cells and often produce functional peptide horm... more Carcinoids are tumors derived from neuroendocrine cells and often produce functional peptide hormones. Approximately 54.5% arise in the gastrointestinal tract and frequently metastasize to the liver. Primary hepatic carcinoid tumors (PHCT) are extremely rare; only 95 cases have been reported. A 65-year-old man came to our attention due to occasional ultrasound findings in absence of clinical manifestations. His previous medical history, since 2003, included an echotomography of the dishomogeneous parenchymal area but no focal lesions. A computed tomography s c a n p e r fo r m e d i n 2 0 0 5 s h o w e d an enhanced pseudonodular-like lesion of about 2 cm. Cholangiomagnetic resonance imaging identified the lesion as a possible cholangiocarcinoma. No positive findings were obtained with positron emission tomography. Histology suggested a secondary localization in the liver caused by a low-grade malignant neuroendocrine tumor. Immunohistochemistry was positive for anti chromogranin antibodies, Ki67 antibodies and synaptophysin. Octreoscan scintigraphy indicated intense activity in the lesion. Endoscopic investigations were performed to exclude the presence of extrahepatic neoplasms. Diagnosis of PHCT was established. The patient underwent left hepatectomy, followed by hormone therapy with sandostatine LAR. Two months after surgery he had a lymph nodal relapse along the celiac trunk and caudate lobe, which was histologically confirmed. The postoperative clinical course was uneventful, with a negative follow-up for hematochemical, clinical and radiological investigations at 18 mo post-surgery. Diagnosis of PHCT is based principally on the histopathological confirmation of a carcinoid tumor and the exclusion of a non-hepatic primary tumor. Surgical resection is the recommended primary treatment for PHCT. Recurrence rate and survival rate in patients treated with resection were 18% and 74%, respectively.
is associated with more severe liver damage and an increased risk of fulminant disease. HDV is a ... more is associated with more severe liver damage and an increased risk of fulminant disease. HDV is a single-stranded RNA virus that encodes a single protein, the delta antigen, which is expressed in two forms, small (S-HDAg) and large (L-HDAg). Here we show that although HDV ribonucleoproteins are mainly detected in the nucleus, they are also present in the cytoplasm of cells infected with HDV or transfected with HDV cDNA. Making use of an heterokaryon assay, we demonstrate that HDV ribonucleoproteins shuttle continuously between the nucleus and the cytoplasm. In the absence of HDV RNA, both forms of the delta antigen are retained in the nucleus, whereas in the absence of the delta antigen, HDV RNA is predominantly detected in the cytoplasm. Coexpression of HDV RNA and S-HDAg (which binds to the viral RNA and contains a nuclear localization signal) results in nuclear accumulation of the viral RNA. This suggests that HDV RNA mediates export of viral particles to the cytoplasm whereas the delta antigen triggers their reimport into the nucleus.
We describe the case of a 19-year-old boy with acute leukaemia who developed primary hepatic zygo... more We describe the case of a 19-year-old boy with acute leukaemia who developed primary hepatic zygomycosis. The patient presented with febrile neutropenia and severe abdominal tenderness. Despite the administration of antibiotics and liposomal Amphotericin-B (L-AmB), the CT scan demonstrated an increase in the size of liver lesions. A wide surgical resection was carried out and liver specimens demonstrated a branching, filamentous fungus that was identified as Rhizomucor pusillus by both phenotypic and molecular methods. The patient was treated with L-AmB combined with posaconazole, and deferasirox was subsequently added given the potential synergistic effect of this iron chelator in combination with L-AmB. Three months after surgical intervention, an allogeneic stem-cell transplantation was successfully carried out. The present case confirms that an early surgical management combined with antifungal agents is crucial to optimise the outcome of patients with zygomycosis and the use of deferasirox is a promising alternative.
Treatment with hepatitis B virus immune globulins (HBIG) or lamivudine has reduced the rate of he... more Treatment with hepatitis B virus immune globulins (HBIG) or lamivudine has reduced the rate of hepatitis B recurrence after liver transplantation to approximately 50%. To further decrease hepatitis B recurrence, 33 hepatitis B virus (HBV)-related cirrhotic patients were treated with lamivudine before liver transplantation and with lamivudine together with low-dose HBIG (46 500 IU the first month followed by 5,000 lU/monthly) after surgery. While on lamivudine, serum HBV DNA level decreased significantly in all patients and in 11 (33%) the Child-Pugh score improved. Twenty-six patients were transplanted. Among the 25 who survived for longer than 12 months, only one (4%) experienced a hepatitis B recurrence over an average follow-up of 31 months, a rate significantly lower (P = 0.0002) than the 50% recurrence rate among a historical control group of 12 patients. However, low-level HBV replication was detected sporadically throughout the follow-up in 64% of patients. Over the medium-term, combined prophylaxis with lamivudine and HBIG significantly decreases the risk of hepatitis B recurrence after liver transplantation. Though low-level HBV infection recurred in two thirds of patients, the pathogenic expression of HBV was prevented.
We determined the prevalence of hepatitis C virus markers and the clinical course in patients tra... more We determined the prevalence of hepatitis C virus markers and the clinical course in patients transplanted for terminal type C or non-A, non-B cirrhosis. Hepatitis C virus infection recurred in 16 of 17 patients (94%) with type C cirrhosis (seropositive for hepatitis C virus prior to ...
Background/Aims: Interferon (IFN) with ribavirin combination therapy (CT) was proposed for the tr... more Background/Aims: Interferon (IFN) with ribavirin combination therapy (CT) was proposed for the treatment of hepatitis C recurring in liver transplants. We assessed the efficacy of two protocols of CT in transplanted patients with recurrent severe hepatitis C virus (HCV) hepatitis.
detected in a-smooth muscle actin-positive myofibroblasts lining fibrotic septa in human cirrhoti... more detected in a-smooth muscle actin-positive myofibroblasts lining fibrotic septa in human cirrhotic livers. Conclusions: Intracellular generation of ROS, through activation of specific signaling pathways, is a critical event for directional migration of HSC/MFs and MSCs. Ó
The histopathology of hepatitis delta virus disease was studied in carriers of HBsAg with chronic... more The histopathology of hepatitis delta virus disease was studied in carriers of HBsAg with chronic hepatitis delta antigen-positive hepatitis and in serial biopsies of patients with acute hepatitis delta virus hepatitis that progressed to chronicity. There was no histologic feature distinctive of hepatitis delta virus from other types of viral hepatitis. Biopsy specimens of patients with chronic disease exhibited portal and periportal inflammation with piecemeal necrosis, conforming to a picture of aggressive hepatitis often accompanied by cirrhosis. Characteristic was a marked intralobular infiltration by mononuclear cells and a degenerative eosinophilic change of the hepatocytic cytoplasms conducive to the formation of acidophilic bodies. Liver specimens from patients with hepatitis delta virus hepatitis exhibited aspects of focal, confluent and bridging necrosis. The disease progressed to chronicity irrespective of the original histological features. The expression of intrahepatic hepatitis delta antigen was reduced in the phase of the acute hepatitis but increased in parallel with the development of chronic active liver disease. In late-stage cirrhosis, expression of hepatitis delta antigen was usually low.
The course of chronic hepatitis B was studied in 30 patients who had antibody to hepatitis e anti... more The course of chronic hepatitis B was studied in 30 patients who had antibody to hepatitis e antigen and hepatitis B virus DNA in the serum and hepatitis B core antigen in the liver. Over a 2-year period, no patient experienced a sustained spontaneous remission of disease, and follow-up liver histology revealed worsening of the disease in four patients. After 2 years of observation, 24 patients were allocated randomly to one of two groups: 12 patients served as untreated controls and 12 received recombinant human alpha-interferon-2a in a dose of 9 million units intramuscularly three times weekly for 16 weeks. Patients who remained viremic after 16 weeks received 3 million units three times weekly for an additional 8 weeks. Abnormal amino-transferases and serum hepatitis B virus DNA persisted without appreciable changes in all untreated patients. Hepatitis B virus DNA rapidly became undetectable and serum aminotransferases fell to normal in eight treated patients. After the end of treatment, hepatitis B virus DNA became detectable once again in seven patients, in six of whom a peak of aminotransferases (range: 256 to 850 units per liter) ensued; subsequently, hepatitis B virus DNA disappeared, and serum aminotransferases again fell to normal in two of the seven. Overall, hepatitis B virus DNA was no longer detectable in serum and liver histology improved in three treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Therapy of chronic hepatitis delta with standard interferon therapy has met with limited efficacy... more Therapy of chronic hepatitis delta with standard interferon therapy has met with limited efficacy. This study was designed to examine the efficacy and safety of peginterferon with or without ribavirin. Thirty-eight serum hepatitis B surface antigen-and HDV RNA-positive patients with alanine aminotransferase (ALT) more than 1.5 times the upper normal limit received peginterferon alpha-2b (1.5 g/kg) alone as monotherapy (n ؍ 16) or in combination with ribavirin (n ؍ 22), for 48 weeks. Thereafter, all the patients were maintained on peginterferon for 24 weeks and followed for 24 weeks off therapy. The primary end point studied was the virological and biochemical response at the end of follow-up. HDV RNA was determined by single or nested polymerase chain reaction assays. Twenty-seven patients (71%), 11 receiving monotherapy and 16 receiving the combination treatment, completed the follow-up. At the end of treatment, a virological response was observed in 3 of the patients treated with peginterferon (19%) and in 2 of the patients treated with combination therapy (9%), and a biochemical response was observed in 6 (37.5%) and 9 patients (41%), respectively. In nonresponders, ALT diminished from a mean of 174 ؎ 53 to 86 ؎ 41 IU/L. At the end of follow-up, serum HDV RNA was negative in 8 patients (21%), and a biochemical response was detected in 10 patients (26%). Treatment was discontinued in 25% of the patients, and dosing was modified in 58%. In conclusion, a prolonged course of peginterferon alpha-2b resulted in clearance of serum HDV RNA and ALT normalization in a fifth of patients with chronic hepatitis D, while ribavirin had no effect on the viral clearance rate. Overall tolerance of therapy was poor. (HEPATOLOGY 2006;44:713-720.) See Editorial on Page 536 Abbreviations: HDV, hepatitis delta virus; ALT, alanine aminotransferase; HBV, hepatitis B virus; IFN, interferon; RBV, ribavirin; PEG-IFN, pegylated interferon; anti-HD, antibody to hepatitis delta antigen; HBsAg, hepatitis B surface antigen; anti-HBe, antibody to hepatitis B e antigen. From the
This study aims to determine the presence of the components of the metabolic syndrome in primary ... more This study aims to determine the presence of the components of the metabolic syndrome in primary nonalcoholic steatohepatitis (NASH) and to assess the role of liver disease in the genesis of peripheral hyperinsulinemia. Nineteen patients (18 men and 1 woman; mean age, ؎ SD, 38 ؎ 10 years; body mass index [BMI], 26 ؎ 2 kg/m 2 ) with histologic evidence of NASH were enrolled; 19 age-and sex-matched normal subjects were investigated as controls. Plasma glucose, insulin, and C-peptide levels were measured during an oral glucose tolerance test, and a frequently sampled intravenous glucose tolerance test (FSIGT), analyzed by minimal modeling technique, was performed. Compared with controls, the NASH group had lower insulin sensitivity (3.84 ؎ 2.44 vs. 7.48 ؎ 3.01 10 -4 ؋ min -1 /U/mL; P ؍ .0003) and higher total insulin secretion (21 ؎ 13 vs. 10 ؎ 3 nmol/L in 240 minutes; P ؍ .001). Hepatic insulin extraction was similar in both groups (69.8% ؎ 16.1% vs. 70.2% ؎ 18.3%; P ؍ .854). According to the results of the oral glucose tolerance test, no patient was classified as diabetic, 5 were classified as glucose intolerant, and 1 was classified as having impaired fasting glycemia. Nine patients (47%) had at least the 2 minimum criteria required to define the metabolic syndrome according to the European Group for the Study of Insulin Resistance (EGIR). In conclusion, hyperinsulinemia and insulin resistance occur frequently in patients with NASH; these conditions do not stem from a reduced hepatic insulin extraction but from an enhanced pancreatic insulin secretion compensatory to reduced insulin sensitivity. The derangement of insulin regulation, often associated with the metabolic syndrome, may play a causal role in the pathogenesis of NASH. (HEPATOLOGY 2002;35:367-372.) See Editorial on Page 497 Abbreviations: NASH, nonalcoholic steatohepatitis; EGIR, European Group for the Study of Insulin Resistance; BMI, body mass index; FSIGT, frequently sampled intravenous glucose tolerance test; SI, insulin sensitivity index. From the
European Journal of Gastroenterology & Hepatology, 2004
Hepatocellular carcinomata are relatively rare in the western hemisphere, but they are much more ... more Hepatocellular carcinomata are relatively rare in the western hemisphere, but they are much more common in South-East Asia and sub-Saharan Africa due to high endogenous levels of hepatitis B and C. Ectopic liver tissue usually is found incidentally (frequently at cholecystectomy), but it may also be found due to neoplastic changes or compressive effects. Ectopic liver tissue has an increased neoplastic potential over orthotopic liver, which we postulate is due to compromised vascular supply and biliary drainage. These lesions may be susceptible to surgical resection, although long-term follow-up data are poor. Ectopic or accessory liver tissue is a rare condition. Most commonly, it is found incidentally, but it may also be found as a result of neoplasia or compressive effects. These lesions appear to have an increased potential for the development of hepatocellular carcinoma in the absence of malignancy in the mother liver. Due to their anatomical features, these carcinomata appear to be susceptible to curative resection, although long-term follow-up data are poor. These carcinomata have been reported more frequently from South-East Asia than from Western countries; however, the common risk factors for hepatocellular carcinoma, such as infection with hepatitis B or C and cirrhosis, appear to be less implicated than in carcinomata of the orthotopic liver. In ectopic or accessory liver tissue, development of hepatocellular carcinoma may be the result of compromised vascular supply or biliary drainage.
Patients with the clinical syndrome of visceral larva migrans as a result of Toxocara species, ha... more Patients with the clinical syndrome of visceral larva migrans as a result of Toxocara species, have typical lesions in the liver consisting of granulomas that contain numerous eosinophils and often Charcot-Leyden crystals. This syndrome is rarely taken into account in patients with cholestatic syndrome, especially when hypereosinophilic reaction is absent. We report the case of a 47-year-old immunocompetent woman who presented with abdominal pain, in whom multiple focal liver lesions were discovered. She had come in contact with dogs. Diagnosis of toxocariasi was done. A good clinical response has been obtained by treating with thiabendazole. We present the findings of various imaging studies of the patient. This report shows that visceral larva migrans may be the cause of a chronic liver disease and should be suspected also in patients without fever and hypereosinophilia with cryptogenic cholestatic and focal liver lesions.
Uploads
Papers by Ezio David