A. Baptista

Histological grading and staging of chronic hepatitis

‘Armed Forces instifute of Pathology, Washington, USA, 2University of Lisbon. Lisbon, Portugal, -‘Hofstetten, Switzerland, 4Servizio di Anatomia e Istologia Patologica. Spedali Civili, Brescia, Italy, 5Department of Medicine, University of Leuven, Leaven, Belgium, 61nstitute for Pathology, University of Basel, Basel, Switzerland, 7Department of Pathology, University of Graz. Graz, Austria, 8Department of Pathology, University of Leuven, Leuven, Belgium. 9 Weiden, Germany, ‘ODepartment of Pathology, Western Infirmary, University of Glasgow, Glasgow, UK, “Department of Pathology, ~osp~talfor Sick Children, University of Toronto, Toronto, Canada, ~‘~nstitute of Liver Studies, King’s College Hospital, London, UK, 13Frederiksberg, Denmark, Is Watt, Switzerland, “Vienna, Austria

Hepatocyte apoptosis, expression of death receptors, and activation of NF-κB in the liver of nonalcoholic and alcoholic steatohepatitis patients

OBJECTIVES:The increasing incidence of nonalcoholic (NASH) and alcoholic steatohepatitis (ASH), associated with lack of effective treatment, has prompted intensive studies on disease pathogenesis. Apoptosis is recognized as common in liver injury and may also contribute to tissue inflammation, fibrogenesis, and development of cirrhosis. In this study, we identified mechanisms of apoptosis induction in human steatohepatitis, and evaluated potential associations between apoptosis, liver pathology, and clinical presentation in NASH and ASH.METHODS:Hepatocyte apoptosis was evaluated by the TUNEL assay in 20 patients with NASH (all ambulatory), 40 with ASH (20 ambulatory, 20 hospitalized), and 20 controls. Liver biopsies were also graded for inflammation and fibrosis. Immunohistochemistry was performed for death receptors (Fas and TNF-R1), activated caspase-3, NF-κB p65, antiapoptotic Bcl-2 protein, and uncoupling protein 2 (UCP-2).RESULTS:TUNEL-positive hepatocytes were markedly increased in NASH (p < 0.05) and ASH (p < 0.01). Similar results were obtained for activated caspase-3, confirming the occurrence of apoptosis. The Fas receptor was upregulated in ASH, especially in hospitalized patients (p < 0.01), whereas TNF-R1 was expressed both in NASH and ASH (p < 0.01). In addition, patients with ASH showed a remarkable expression of active NF-κB, as compared to NASH and controls (p < 0.01). Degrees of inflammation and fibrosis correlated with NF-κB p65 expression, which in turn coincided with apoptosis albeit Bcl-2 and UCP-2 expression.CONCLUSIONS:Liver injury in NASH and ASH is associated with increased hepatocyte apoptosis mediated by death receptors. Further, apoptosis correlates with active NF-κB expression, and disease severity. This potential mechanistic link might provide multiple interesting targets for therapeutic intervention.

Non-alcoholic fatty liver: another feature of the metabolicsyndrome?

Abstract Background and aims: Hepatic steatosis and nonalcoholic steatohepatitis (NASH) have been associated with obesity, non insulin-dependent diabetes mellitus and hyperlipidemia. The present study was designed in order to evaluate whether patients with steatosis/NASH presented common features with the metabolic syndrome. Methods: In 30 patients with nonalcoholic fatty liver the prevalence of hypertension and diabetes; the glucose/insulin profile, lipid profile, and serum leptin were evaluated and correlated with body composition and energy expenditure, assessed by bioimpedance spectroscopy and indirect calorimetry, respectively. Results were compared with a group of eight controls. Results: Obesity was present in 80% of patients, hypertension in 50% and non insulin dependent diabetes in 33%. Glucose metabolism was altered in 69%, with elevated insulin in 14 patients. Serum leptin, higher in women, was increased in patients: 33.9 ± 38.9 vs 9.6 ± 6.9 ng/ml, P Conclusions: There is a strong association between nonalcoholic fatty liver and features of the metabolicsyndrome, suggesting a simultaneous insulin resistance and decreased sensitivity to leptin.

Tamoxifen-associated steatohepatitis - report of three cases

The authors describe three cases of tamoxifen-associated steatohepatitis, which resulted from a daily dosage of 20 mg used as the adjuvant treatment of breast carcinoma. Liver tests became normal after discontinuation of tamoxifen.

Nonalcoholic steatohepatitis: A long-term follow-up study. Comparison with alcoholic hepatitis in ambulatory and hospitalized patients

A previous publication analyzed the clinicopathological characteristics of 105 patients with steatohepatitis: 32 nonalcoholic, 21 ambulatory alcoholics, and 52 hospitalized alcoholics; we now report an up to 12-year follow-up (mean 5.9 ± 4.7). Between 1988 and 1993, all patients with a histological diagnosis of steatohepatitis were included; necrosis, inflammation, Mallory bodies, and fibrosis were graded. Complete follow-up data were obtained in 78%. Survival curves were similar between nonalcoholic and ambulatory alcoholics; they were, however, better in nonalcoholic than hospitalized alcoholics (P < 0.0001), and in ambulatory relative to hospitalized (P = 0.0001) alcoholics. Nonalcoholics had a better prognosis than the combined alcoholic groups (P = 0.001). Patients with moderate to severe Mallory bodies and severe fibrosis had a significantly worse survival (P < 0.01), whereas severity of hepatocellular damage and neutrophil or mononuclear infiltration had no significant impact. In conclusion, alcoholic patients as a whole had a worse prognosis, yet the ambulatory subgroup had a prognosis similar to nonalcoholic patients.

Histopathology of portal hypertension: a practical guideline

T Roskams, A Baptista, L Bianchi, A Burt, F Callea, H Denk, J De Groote, V Desmet, S Hubscher, K Ishak, R MacSween, B Portmann, H Poulson, P Scheuer, L Terracciano & H Thaler Department of Pathology, K.U. Leuven, Leuven, Belgium, Hospital de Santa Maria, Lisboa, Portugal, University of Basel, Basel, Switzerland, University of Newcastle, Newcastle, UK, Spedali Civili of Brescia, Brescia, Italy, University of Graz, Graz, Austria, Department of Hepatology, K.U. Leuven, Leuven, Belgium, Department of Pathology, University of Birmingham, Birmingham, UK, Armed Forces Institute of Pathology, Washington, DC, USA, Department of Pathology, Western Infirmary, University of Glasgow, Glasgow and Institute of Liver Studies, Kings College Hospital, London, UK, Frederics Berg, Denmark, Department of Pathology, Royal Free Hospital, London, UK, and Wien, Austria

Jaundice associated with naproxen.

Hepatic injury in association with naproxen therapy is described and documented by liver biopsy in one patient. Histological findings were consistent with a drug-induced hepatitis, and cessation of therapy led to reversal of the clinical and biochemical changes. Circumstantial evidence is in favour of a hypersensitivity response to the drug rather than direct hepatotoxicity. Increased awareness of clinicians of this probably rare side effect of naproxen may help prompt identification of similar cases.

CLASTOGENIC FACTORS AS BIOMARKERS OF OXIDATIVE STRESS IN CHRONIC HEPATITIS C.

Background/Aims: Clastogenic factors (CFs) are composed of lipid peroxidation products, cytokines and other oxidants with chromosome-damaging properties. They are regularly observed after radiation exposure and in chronic inflammatory diseases, where they are supposed to be risk factors for carcinogenesis. It appeared of interest to investigate their presence in the plasma of patients with chronic hepatitis C. Methods: CFs are detected by chromosomal breakage studies. They were compared to malondialdehyde (MDA), total plasma thiols (t-SH), alanine aminotransferase (ALT), viral load and histological data. Results: CFs were increased in 19 of 20 patients, 16 had increased MDA levels and 15 had decreased t-SH levels. Mean values were significantly different from the 20 controls (p < 0.001). After the first 3 months of interferon treatment, all three markers showed significant improvement, but were not completely normalized. There was a positive correlation between CFs and necroinflammatory activity (p < 0.03), while MDA was correlated with fibrosis (p < 0.03). Viral load was correlated with necrosis and inflammation (p < 0.05). Conclusion: The presence of CFs in chronic hepatitis C confirms the occurrence of oxidative stress in this disease and could be useful in clinical trials for testing antioxidants. The CF test is a sensitive assay for the detection of oxidative stress and correlates with necroinflammatory activity.

The diagnostic significance of periportal hepatic necrosis and inflammation

In this review the several types of cell damage and cell death which may be found in liver biopsy specimens are defined. We describe the different processes which occur at the portal/parenchymal or septal/parenchymal interface, viz. periportal spillover, periportal hepatitis, classic or lymphocytic piecemeal necrosis and biliary piecemeal necrosis. The diagnostic implications of these lesions in relation to the clinicopathological diagnosis and prognosis in various liver diseases are discussed.

Fatal hepatitis associated with ranitidine.

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