Signal transduction in hepatic stellate cells.
Pinzani M. Marra F. Carloni V.
Istituto di Medicina Interna, Universita di Firenze, Italy.
Hepatic stellate cells (HSC) are presently regarded as one of the key cell types involved in the progression of liver fibrosis and in the related pathophysiological and clinical complications. Following acute or chronic liver tissue damage, HSC undergo a process of activation towards a phenotype characterised by increased proliferation, motility, contractility and synthesis of extracellular matrix (ECM) components. Several factors have been shown to play a key role in the promotion of the full-blown picture of activated HSC. These include extensive changes in the composition and organisation of the ECM, the secretion of several growth factors, cytokines, chemokines, products of oxidative stress and other soluble factors. It is evident that each cellular response to extracellular stimuli must be framed in a scenario where different forces modulate one another and result in a prevalent biological effect. Along these lines, the identification and characterisation of intracellular signalling pathways activated by different stimuli in HSC represent a mandatory step. In this review article we have made an attempt to summarise recent acquisitions to our knowledge of the involvement of different intracellular signalling pathways in key aspects of HSC biology.
Angiogenesis in hepatocellular carcinoma as evaluated by CD34 immunohistochemistry.
Kimura H. Nakajima T. Kagawa K. Deguchi T. Kakusui M. Katagishi T. Okanoue T. Kashima K. Ashihara T.
Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Japan.
To clarify the relationship between angiogenesis and hepatocarcinogenesis on progression of hepatocellular carcinoma (HCC), we quantitatively evaluated angiogenesis by CD34 immunohistochemistry in liver cirrhosis (LC), adenomatous hyperplasia (AH), and HCC, and proliferative activity estimated by Ki-67 immunohistochemistry. Angiogenesis was evaluated by CD34 immunohistochemistry using monoclonal antibody HPCA-2, and tumor proliferative activity was evaluated using monoclonal antibody MIB-1. We used an image analysis system to assess the microvessel density as the area percentage of the endothelial area. Angiogenesis was generally observed in HCC and there was no significant difference among all clinical stages and histological grades of HCC. On the other hand, the staining of CD34 was partly observed in sinusoids of AH, although no positive staining was seen in any sinusoids of LC. The proliferative activity was significantly correlated with the clinical stage and histological grade of HCC. Our results indicate that the quantitation of angiogenesis does not provide significant prognostic information in HCC, but that it may have diagnostic value in distinguishing HCC from non-HCC. Meanwhile, AH, which is not morphologically diagnosed as cancer, shows positive staining for CD34, suggesting that some portion of AH contains cancerous characteristics.
Autonomic nervous system activity during infusion of L-arginine in patients with liver cirrhosis.
Saijyo T. Nomura M. Nakaya Y. Saito K. Ito S.
Second Department of Internal Medicine, School of Medicine, University of Tokushima, Japan.
Patients with liver cirrhosis exhibit a hyperdynamic circulatory state as evidenced by tachycardia and an increase in cardiac output accompanied by an elevation of sympathetic tone. This condition is due to the excessive release of nitric oxide (NO), an endogenous vasodilator, which is in turn related to the abnormal induction of NO synthase. The present study investigated whether the intravenous infusion of L-arginine, the precursor of NO, may cause a similar hyperdynamic circulatory state. A new method, the analysis of power spectrum heart rate variability, was used to evaluate autonomic nervous activity. Twenty patients with liver cirrhosis underwent continuous Holter monitoring of the ECG during the intravenous administration of L-arginine (10 g) (Fisher's solution) infused over 60 min. Power spectral analysis was computed from 512 beats of the Holter ECG data. Low frequency (LF; 0.04-0.15 Hz) and high frequency (HF; 0.15-0.40 Hz) spectral powers and the ratio of LF to HF (LF/HF) were calculated every 10 min before and after the infusion of L-arginine. The LF power, which reflects sympathetic tone modified by vagal tone, and the LF/HF, an indicator of sympathetic tone, were both significantly increased during the infusion (p
Hepatitis C virus genotypes: epidemiological and clinical associations. Benelux Study Group on Treatment of Chronic Hepatitis C.
Kleter B. Brouwer JT. Nevens F. van Doorn LJ. Elewaut A. Versieck J. Michielsen PP. Hautekeete ML. Chamuleau RA. Brenard R. Bourgeois N. Adler M. Quint WG. Bronkhorst CM. Heijtink RA. Hop WJ. Fevery J. Schalm SW.
Dept. of Virology, Erasmus University, Rotterdam, The Netherlands.
In a cohort of 292 chronic hepatitis C patients living in the Benelux countries the relationship between viral genotype and geographical origin, route of transmission, clinical characteristics and severity of liver disease was analyzed. HCV-RNA isolates could be classified by the Line Probe Assay (LiPA) as 1a, 1b, 2, 3, 4 or 5 in 286 (98%) cases. Patients of European origin were predominantly infected with HCV subtype 1b (164/254, 65%, CI 58-70%), as were patients of Asian origin (7/13, 54%). Patients originating from Surinam (South America) had predominantly type 2 (9/10, 90%), whereas Africans were mainly infected with type 4 (7/9, 77%). Blood transfusion was the mode of transmission in 142 (50%) patients, intravenous drug abuse (IVDA) in 40 (14%), occupational needle accident or tattoo in 11 (4%); no obvious source of infection was found in 93 (33%). In patients infected by blood transfusion, subtype 1b was predominant (70%, CI 61-77%), whereas subtypes la and 3 were predominant in those infected by IVDA (25% and 45%, respectively, p
Hepatitis C associated with Guillain-Barre syndrome.
Lacaille F. Zylberberg H. Hagege H. Roualdes B. Meyrignac C. Chousterman M. Girot R.
Department of Paediatrics, Hopital des Enfants Malades, Paris, France.
Hepatitis C is frequently associated with immune-mediated diseases, such as cryoglobulinemia. Guillain-Barre syndrome is an acute demyelinating neuropathy of probable immune pathogenesis. We describe two patients with Guillain-Barre syndrome, and associated chronic hepatitis C, the second one previously treated with interferon. The link between both conditions may be hepatitis C being the trigger of this immune polyneuropathy. Guillain-Barre syndrome should be added to the list of conditions associated with hepatitis C.
Fulminant hepatic failure associated with dicoumarol therapy.
Castedal M. Aldenborg F. Olsson R.
Department of Medicine, Sahlgrenska University Hospital, Goteborg, Sweden.
Coumarins have been associated with non-predictable hepatic injury. In the case of dicoumarol, there is no hard evidence in the literature of a causal connection with liver damage. We report the case of a 73-year-old woman who developed a fatal liver disease of a mixed hepatocellular-cholestatic type after 3 months of treatment with dicoumarol. A thorough diagnostic work-up did not reveal any other possible cause of the liver disease.
The first decade of the transjugular intrahepatic portosystemic shunt (TIPS): state of the art.
Rossle M. Siegerstetter V. Huber M. Ochs A.
School of Medicine, Department of Gastroenterology and Hepatology, Freiburg, Germany.
The transjugular intrahepatic portosystemic shunt (TIPS) is an interventional treatment resulting in decompression of the portal system by creation of a side-to-side portosystemic anastomosis. Since its introduction 10 years ago, more than 500 publications have appeared demonstrating rapid acceptance and increasing clinical use. This review summarizes the present knowledge of technical aspects and complications, follow-up of patients, and indications. With respect to the technique, the TIPS procedure is probably one of the most difficult interventions and, therefore, technical success and complications clearly depend on the skills of the operator. Thus, the number and kind of complications reported in this review do not necessarily relate to the procedural complications of an experienced center. The follow-up of the TIPS patient has to assess shunt patency, liver function and hepatic encephalopathy. Shunt patency can best be monitored by duplex-sonography. Routine radiological revision seems not to be helpful and does not improve results, i.e., rebleeding and survival. Short term patency may be improved by anticoagulation, while such a treatment does not influence long-term patency. With respect to the indications of TIPS, much is known about treatment of variceal bleeding. The nine randomized studies that are available to date show that survival is comparable between patients receiving TIPS or endoscopic treatment. The second group of patients is the group with refractory ascites and related complications, such as hepatorenal syndrome and hepatic hydrothorax. It has been demonstrated that TIPS improves these complications, but randomized studies are still lacking. In addition, TIPS has been applied successfully to patients with Budd-Chiari syndrome, portal vein thrombosis, before liver transplantation, and for the treatment of ectopic portal hypertensive bleeding.
The Fas system is not significantly involved in apoptosis in human hepatocellular carcinoma.
Kubo K. Matsuzaki Y. Okazaki M. Kato A. Kobayashi N. Okita K.
First Department of Internal Medicine, Yamaguchi University, School of Medicine, Ube, Japan.
We investigated the role of apoptosis in relation to proliferative activity in hepatocellular carcinoma (HCC) using in situ DNA nick end labeling (ISNEL) and immunostaining for the Ki-67 antigen in 35 patients with HCC. We also performed immunostaining for Fas and Fas ligand (Fas L) to determine the relationship between the Fas system and apoptosis. The ratio of the ISNEL labeling index (LI) to the Ki-67 LI was significantly lower in HCC than in surrounding nontumorous liver tissue (p
Absence of human herpesvirus 8 DNA sequences in vascular tumors of the liver.
Ishak KG. Bijwaard KE. Makhlouf HR. Taubenberger JK. Lichy JH. Goodman ZD.
Department of Hepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
Kaposi's sarcoma-associated herpes virus (KSHV), also designated human herpesvirus 8 (HHV8), has been detected consistently in Kaposi's sarcoma, body cavity lymphoma and multicentric Castleman's disease, both in human immunodeficiency virus (HIV)-positive and -negative patients. Identification of KSHV/HHV8 DNA sequences in various benign and malignant vascular tumors in HIV-negative patients was reported in one study, but was not confirmed in several other studies. The vascular lesions, other than Kaposi's sarcoma, in which sequences could not be detected have included malignant vascular tumors of serous membranes, infantile capillary hemangiomas, and several benign and malignant vascular tumors of the spleen. We studied 30 primary benign and malignant vascular tumors of the liver; KSHV/HHV8 DNA sequences could not be detected in any. We conclude that this virus plays no role in the etiology of vascular tumors of the liver.
Hepatoblastoma: DNA nuclear content, proliferative indices, and pathology.
Rugge M. Sonego F. Pollice L. Perilongo G. Guido M. Basso G. Ninfo V. Pennelli N. Gambini C. Guglielmi M. Fabiano A. Leandro G. Keeling JW.
Istituto di Anatomia Patologica, Cattedra di Istochimica & Immunoistochimica Patologica, Universita di Padova, Veneto, Italy.
Hepatoblastoma (HB) is the most frequent malignant liver tumor in infancy, and both its biological features and its prognostic behavior are still under investigation. DNA content and proliferative activity of the tumor have been considered as biological parameters related to the tumor's aggressiveness. The present study attempts to investigate the possible association between histologic subtype, DNA content, and proliferative indices in HB. DNA content and the proportion of cells in the S-phase were assessed by flow cytometry in 34 cases of HB (14 prior to chemotherapy, 20 after chemotherapy), using formalin-fixed, paraffin-embedded archival samples. The proliferative cell nuclear antigen (PCNA) labeling index was also evaluated by immunohistochemistry, and both the flow cytometry (FC) and the immunohistochemical data were correlated with tumor pathology. A significant association was found between histological type, DNA content and the percentage of cells in the S-phase, with aneuploidy and the highest proportions of S-phase cells significantly associated with embryonal tumors. The PCNA labeling index was found to be significantly higher in embryonal than in fetal phenotype. The biological heterogeneity of HB is Confirmed by the different nuclear content of the fetal (diploid) and embryonal (aneuploid) epithelial components of the tumor, also ruling out the likelihood of fetal (diploid) clones deriving from the embryonal (aneuploid) neoplastic cells. Since the highly proliferative neoplastic clones (i.e., embryonal) are thought to be more sensitive to antimitotic drugs, further studies are indicated to determine the relationship between ploidy, proliferative indices and chemoresponsiveness.
Nucleoside analogue therapy in fibrosing cholestatic hepatitis--a case report in an HBsAg positive renal transplant recipient.
Brind AM. Bennett MK. Bassendine MF.
Centre for Liver Research, School of Clinical Medical Sciences, Newcastle upon Tyne, UK.
A 45-year-old HBsAg carrier (HBeAb positive with normal liver function tests) underwent renal transplantation for mesangioproliferative glomerulonephritis. Sixteen months later he developed jaundice. Investigations showed he remained HBeAb positive, but HBV-DNA levels were 99 pg/ml, indicating active replication of a HBV pre-core mutant. He was commenced on lamivudine therapy with a subsequent rapid fall in HBV-DNA levels to 2.8 pg/ml, but liver function tests continued to deteriorate and he developed hepatorenal failure. Liver biopsy showed fibrosing cholestatic hepatitis. He underwent liver transplantation, which was complicated by lactic acidosis. Lamivudine was withdrawn and HBV prophylaxis with HB immunoglobulin was commenced. Unfortunately he died 38 days post-transplant of surgical complications with no evidence of HBV recurrence. We discuss the use of nucleoside analogues in fibrosing cholestatic hepatitis and review the literature.