Generalized peripheral lymphadenopathy in a patient treated for chronic HCV infection.

BACKGROUND: A 62-year-old white woman was admitted to hospital with a 2-month history of progressive, painless, left supraclavicular and axillary lymph node enlargement. The patient's history was significant for chronic HCV infection, for which she had just completed a 48-week course of treatment with pegylated interferon alpha (180 microg once weekly) plus ribavirin (1,000 mg daily). She attained an end-of-treatment response and subsequent qualitative measurement of HCV RNA confirmed a sustained virological response. The onset of progressive painless lymph node enlargement had been noted by the patient during the last 2 weeks of her treatment for HCV. INVESTIGATIONS: Physical examination, otorhinolaryngological examination, laboratory investigations (including complete blood counts, liver function tests and serological tests), mammography, thyroid and abdominal ultrasound, CT scans, abdominal MRI, upper gastrointestinal endoscopy, colonoscopy, supraclavicular lymph node biopsy, (67)Ga scintigraphy and bronchoalveolar lavage. DIAGNOSIS: Granulomatous lymphadenitis of uncertain etiology with sarcoid-type and tuberculoid-type granulomas. MANAGEMENT: Standard antituberculosis treatment with isoniazid, rifampicin, pyrazinamide and ethambutol for 2 months, followed by isoniazid and rifampicin for 7 months.

Bile acid levels are increased in the liver of patients with steatohepatitis.

BACKGROUND/AIMS: The pathogenesis of steatohepatitis remains largely unknown; however, bile acids may play a role as potential mediators of liver damage. The aim of this study was to characterize bile acid profiles in liver tissue of patients with steatohepatitis. METHODS: Bile acid composition was determined by gas-liquid chromatography in liver tissue from patients with nonalcoholic steatohepatitis (NASH; n=15), patients with alcoholic steatohepatitis (ASH; n=14), and controls (n=8). Liver biopsies were graded for steatosis, inflammation, and fibrosis. RESULTS: Bile acids were moderately increased in liver tissue of steatohepatitis patients compared with controls (P<0.05). Deoxycholic, chenodeoxycholic, and cholic acids were elevated by 92, 64, and 43%, respectively, in patients with steatohepatitis (P<0.05). Cholic acid was the prevailing bile acid in NASH patients and in controls. More hydrophobic bile acid species were elevated in ASH patients compared with controls (P<0.05). Significant correlations were found in NASH patients between hepatic chenodeoxycholic acid and fibrosis, and between cholic acid and trihydroxy/dihydroxy bile acids and inflammation (P<0.05). In patients with ASH, cholic acid and trihydroxy/dihydroxy bile acids were correlated with steatosis (P<0.01). CONCLUSION: This study shows a distinct pattern of bile acids in the liver of patients with steatohepatitis. Further, the association between bile acids and histological liver injury suggests an association of specific bile acids and disease progression, possibly through bile acid-induced liver injury.

Elevated nitric oxide and 3',5' cyclic guanosine monophosphate levels in patients with alcoholic cirrhosis.

AIM: To evaluate whether serum levels of nitric oxide (NO*) and plasma levels of cyclic guanosine monophosphate (cGMP) and total glutathione (GSH) are altered in patients with alcoholic cirrhosis and to examine their correlation with the severity of liver disease. METHODS: Twenty-six patients with alcoholic liver cirrhosis were studied. Serum levels of NO* and plasma levels of cGMP and GSH were measured in 7 patients with compensated alcoholic cirrhosis (Child-Pugh A) and 19 patients with advanced cirrhosis (Child-Pugh B and C). The model for end-stage liver disease (MELD) score was evaluated. Sixteen healthy volunteers served as controls. Liver enzymes and creatinine levels were also tested. RESULTS: NO* and cGMP levels were higher in patients with Child-Pugh B and C cirrhosis than in Child-Pugh A cirrhosis or controls (NO*: 21.70 +/- 8.07 vs 11.70 +/- 2.74; 21.70 +/- 8.07 vs 7.26 +/- 2.47 micromol/L, respectively; P < 0.001) and (cGMP: 20.12 +/- 6.62 vs 10.14 +/- 2.78; 20.12 +/- 6.62 vs 4.95 +/- 1.21 pmol/L, respectively; P < 0.001). Total glutathione levels were lower in patients with Child-Pugh B and C cirrhosis than in patients with Child-Pugh A cirrhosis or controls (16.04 +/- 6.06 vs 23.01 +/- 4.38 or 16.04 +/- 6.06 vs 66.57 +/- 26.23 micromol/L, respectively; P < 0.001). There was a significant correlation between NO* and cGMP levels in all patients with alcoholic cirrhosis. A significant negative correlation between reduced glutathione/glutathione disulfide and the MELD score was found in all cirrhotic patients. CONCLUSION: Our results suggest a role for oxidative stress in alcoholic liver cirrhosis, which is more significant in decompensated patients with higher levels of NO* and cGMP and lower GSH levels than in compensated and control patients. Altered mediator levels in decompensated patients may influence the hemodynamic changes in and progression of liver disease.

Rising costs and hospital admissions for hepatocellular carcinoma in Portugal (1993-2005).

AIM: To determine, for hepatocellular carcinoma (HCC), the patient demographic profile and costs of their admissions to the hospitals of the Portuguese National Health System from 1993 to 2005. METHODS: The National Registry (ICD-9CM, Inter-national Classification of Diseases, 155.0) provided data from the 97 Hospitals in Portugal. RESULTS: We studied 7932 admissions that progressively rose from 292 in 1993 to 834 in 2005, having a male predominance of 78% (6130/7932). The global rate of hospital admissions for HCC rose from 3.1/10(5) in 1993 to 8.3/10(5) in 2005. The average length of stay decreased from 17.5 +/- 17.9 d in 1993 to 9.3 +/- 10.4 d in 2005, P < 0.001. The average hospital mortality for HCC remained high over these years, 22.3% in 1993 and 26.7% in 2005. Nationally, hospital costs (in Euros - EUR) rose in all variables studied: overall costs from 533,000 Euros in 1993, to 462,9000 Euros in 2005, cost per day of stay from 105 Euros in 1993, to 597 Euros in 2005, average cost of each admission from 1828 Euros in 1993, to 5550 Euros in 2005. In 2005, 1.8% (15/834) of hospital admissions for HCC were related to liver transplant, and responsible for a cost of about 1.5 million Euros, corresponding to one third of the overall costs for HCC admissions in that same year. CONCLUSION: From 1993 to 2005 hospital admissions in Portugal for HCC tripled. Overall costs for these admissions increased 9 times, with all variables related to cost analysis rising accordingly. Liver transplant, indicated in a small group of patients, showed a disproportionate increase in costs.

Are genetic polymorphisms of tumour necrosis factor alpha, interleukin-10, CD14 endotoxin receptor or manganese superoxide dismutase associated with alcoholic liver disease?

BACKGROUND: Four polymorphisms have been described associated with either increased risk for alcoholic liver disease (ALD) or more serious histological lesions: tumour necrosis factor alpha (TNF-alpha) G(-238)A, interleukin-10 (IL-10) C(-627)A, promoter of CD14 endotoxin receptor gene C(-159)T and manganese superoxide dismutase (MnSOD) C(-1183)T/valine --> alanine. METHODS: We sought confirmatory evidence, through individual and simultaneous analysis of the four aforementioned polymorphisms, in 176 heavy drinkers: ALD (n = 100) if histology-compatible or clinical evidence of hepatic decompensation; and no evidence of liver disease (NLD) (n = 76) if normal liver tests on two occasions or normal liver histology (steatosis alone). RESULTS: Patients with ALD were older (53+/-10 vs. 48+/-10 years, P<0.05), with a similar sex distribution. TNF-alpha G(-238)A showed no difference in heterozygous GA-genotype prevalence (ALD, 9.0%/NLD, 7.9%). IL-10 C(-627)A showed no difference between groups, either homozygote AA (8.0% vs. 10.5%) or heterozygote CA (34.0% vs. 39.5%). CD14 promoter C(-159)T showed no difference between groups in T-allele frequency, either homozygote TT (27% vs. 21%) or heterozygote CT (49% vs. 50%). Alanine MnSOD allele carriers showed no difference between groups in either the heterozygote (55.0% vs. 49.3%) or homozygote (22% vs. 25%). No difference was observed in the probability of having simultaneously two, three or four of the implicated polymorphisms: respectively, 43%, 33% and 0% in ALD, and 43%, 24% and 5% in NLD (not significant). CONCLUSIONS: No association was found between the previously implicated polymorphisms of TNF-alpha, IL-10, CD14 and MnSOD, either individually or simultaneously, and the presence of established ALD.

Lymphocyte T helper-specific reactivity in sustained responders to interferon and ribavirin with negativation (seroreversion) of anti-hepatitis C virus.

BACKGROUND: Seroreversion, negativation of anti-hepatitis C virus previously positive, is sometimes found in some chronic hepatitis C-sustained responders (SRs) to antiviral therapy. AIMS: To determine the probability of seroreversion in SR treatment with Interferon and Ribavirin, and lymphocyte T helper (CD4+) reactivity to HCV antigens. METHODS: Thirty SR were followed on average for 54.8 months. Anti-HCV was tested by third generation test. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood and cultured to evaluate CD4+ proliferation in response to 2 microg/ml of eight HCV recombinant antigens from core, NS3, NS4, NS5 regions. RESULTS: Seroreversion was verified in 23% of patients (7/30), appearing at 47.5+/-24.0 months. The probability of anti-HCV loss in this group was 25% at 56 months after ending therapy. In 57% (4/7), anti-HCV returned to positive. These 7 SR patients with seroreversion also showed weaker CD4+ reactivity in 5% of tests (3/56) than the remaining 23 anti-HCV-positive SRs who showed stronger reactivity in 18% of tests (33/184), P=0.036. CONCLUSIONS: One-quarter of the SR showed seroreversion of anti-HCV and weaker CD4+ specific HCV proliferation than those who remained anti-HCV positive. The data suggest that complete viral eradication is a possible and achievable clinical objective.

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.

Oxidative stress in chronic hepatitis C: the effect of interferon therapy and correlation with pathological features.

AIMS: To evaluate the oxidative stress parameters before, during and after interferon treatment. PATIENTS/METHODS: Twenty patients were treated with interferon a2b 5 MU, three times a week, subcutaneously, for 12 months. Liver biopsy was performed six months before treatment and at the six month follow-up. Chromosomal breakage studies were evaluated by the adjusted clastogenic score (ACS, normal value [nv] 1.1 +/- 2.4%). Plasma malondialdehyde (MDA) was measured according to the Yagi method (nv 6.6 +/- 1.4 nmol/mL) and total thiols using the Ellman's reagent (DTNB) (nv 9.8 +/- 1.3 micromol/g protein). A serum marker of fibrogenesis, the amino-terminal propeptide of Procollagen type III (PIIIP), was quantified by radioimmunoassay (nv 0.37 +/- 0.18 U/L). RESULTS: Compared with reference samples, the plasma of patients before treatment showed an increase of ACS (9.2 +/- 3.2%, P<0.001); higher MDA values (12.6 +/- 2.7 nmol/mL, P<0.001) and total plasma sulfhydryl groups (t-SH) were decreased (6.3 +/- 1.1 micromol/g protein, P<0.001). During treatment and at the follow-up, a decrease in ACS was noticed in all patients (P<0.001), but without normalization; a decrease in MDA was seen, with progressive normalization until the end of the follow up only in sustained responders (P<0.003), while an increase of t-SH was seen, with progressive normalization until the end of follow up in all patients (P<0.005). A positive correlation of ACS with grading of inflammation was found (r=0.52, P<0.03) but not with fibrosis staging. In contrast, plasma MDA correlates with fibrosis staging (r=0.51, P<0.03) and with PIIIP (r=0.57, P<0.03) but without grading of inflammation. CONCLUSIONS: The present study confirmed the presence of oxidative stress in chronic hepatitis C patients. Interferon promotes a long term inhibition of oxidative stress with concomitant improvement of activity and fibrosis. In the management of chronic hepatitis C, adjuvant therapy with antioxidants could be useful.

Quality of life after cholecystectomy and after successful lithotripsy for gallbladder stones: a matched-pairs comparison.

BACKGROUND: There are few data on the quality of life of patients after successful extra-corporeal shock-wave lithotripsy of gallbladder stones and how it compares with the quality of life of patients who underwent cholecystectomy. DESIGN: Prospective case-control study. PATIENTS AND METHODS: Eighteen consecutive patients who had been rendered stone free in 1992 in our unit and who have not shown recurrence until now were selected. For comparison, 18 individually matched (sex, age, body mass index and number of gallbladder stones) controls were selected among the patients who underwent unsuccessful extra-corporeal shock-wave lithotripsy at the same time, eventually undergoing cholecystectomy. Between January and April 2000, all 36 patients answered a validated questionnaire on quality of life focusing on digestive complaints: the Gastro Intestinal Quality of Life Index (GIQLI). RESULTS: The overall GIQLI scores for both groups were good: a median of 128 points (out of a maximum of 144 points) for the extra-corporeal shock-wave lithotripsy group versus a median of 124 points for the cholecystectomy group. The slight advantage of the extra-corporeal shock-wave lithotripsy group was not significant (P = 0.33, paired sign-test). However, the extra-corporeal shock-wave lithotripsy group scored significantly better in the eight questions regarding dyspeptic complaints (P = 0.01, paired sign-test), mainly in the items regarding nausea and need for dietary restriction. There were no significant differences in the questions regarding symptoms of gastro-oesophageal reflux disease, bowel complaints or general well-being. CONCLUSIONS: The quality of life after either cholecystectomy or extra-corporeal shock-wave lithotripsy is good overall, but cholecystectomy might be associated with a higher rate of dyspeptic complaints than a gallbladder preserving treatment like extra-corporeal shock-wave lithotripsy.