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Biomedical subjects

M Beaugrand

Publications and source records attributed to M Beaugrand.

At least 19 recordsLinked to original sources
PubMed2006

Preclinical and post-treatment changes in the HCC-associated serum proteome.

SELDI-based proteomic profiling of body fluids is currently in widespread use for cancer biomarker discovery. We have successfully used this technology for the diagnosis of hepatocellular carcinoma (HCC) in hepatitis C patients and now report its application to serial serum samples from 37 hepatitis C patients before development of HCC, with HCC and following radiofrequency ablation of the tumour. As with alpha-fetoprotein, an accepted biomarker for HCC, we hypothesised that HCC-associated proteomic features would 'return to normal' following successful treatment and the primary aim of our study was to test this hypothesis. Several SELDI peaks that changed significantly during HCC development were detected but they did not reverse following treatment. These data may be interpreted to suggest that the characteristic SELDI profile is not linearly related to tumour burden but may result from the progression of underlying liver disease or from the emergence of precancerous lesions. beta2-Microglobulin, a protein previously reported to be markedly elevated in patients with HCV related HCC, was also the most significantly HCC associated proteomic feature (m/z 11720) in this study.

Aged↗
PubMed2006

Changes in the serum proteome associated with the development of hepatocellular carcinoma in hepatitis C-related cirrhosis.

Early diagnosis of hepatocellular carcinoma (HCC) is the key to the delivery of effective therapies. The conventional serological diagnostic test, estimation of serum alpha-fetoprotein (AFP) lacks both sensitivity and specificity as a screening tool and improved tests are needed to complement ultrasound scanning, the major modality for surveillance of groups at high risk of HCC. We have analysed the serum proteome of 182 patients with hepatitis C-induced liver cirrhosis (77 with HCC) by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI). The patients were split into a training set (84 non-HCC, 60 HCC) and a 'blind' test set (21 non-HCC, 17 HCC). Neural networks developed on the training set were able to classify the blind test set with 94% sensitivity (95% CI 73-99%) and 86% specificity (95% CI 65-95%). Two of the SELDI peaks (23/23.5 kDa) were elevated by an average of 50% in the serum of HCC patients (P<0.001) and were identified as kappa and lambda immunoglobulin light chains. This approach may permit identification of several individual proteins, which, in combination, may offer a novel way to diagnose HCC.

Amino Acid Sequence↗
PubMed2006

Interferon gamma-secreting HCV-specific CD8+ T cells in the liver of patients with chronic C hepatitis: relation to liver fibrosis--ANRS HC EP07 study.

Little is known about the role of specific hepatitis C virus (HCV) CD8+ T cells in liver damage, especially for the progression of fibrosis, during the highly variable course of chronic C hepatitis. The aim of this study was to investigate the presence of HCV-specific CD8+ T cells in the liver of patients with chronic C hepatitis and to examine their clinical significance by relating the response to liver fibrosis and progression rate, serum viral load, serum aminotransferase levels, inflammatory activity and in situ characteristics of the intrahepatic infiltrate. Fifteen patients were prospectively included in the study. Intrahepatic lymphocytes were tested for interferon gamma (IFNg) production in response to HCV class I-restricted epitopic peptides using enzyme-linked immunospot analysis. Liver biopsy samples were evaluated for fibrosis, fibrosis progression rate, activity, and in situ number of CD8+ cytotoxic lymphocytes and apoptotic cells. An IFNg-specific CD8+ T-cell response was detected in the liver samples of 47% of patients which was significantly related to a lower stage of fibrosis (P = 0.02) and a lower progression rate of fibrosis (P = 0.01). It was neither related to the number of cytotoxic lymphocytes infiltrating the liver nor to hepatocyte apoptosis. In conclusion, our results indicate that the presence of HCV-specific IFNg-secreting T cells in the liver of patients with chronic C hepatitis is associated with low liver fibrosis and fibrosis progression rate, suggesting that these IFNg-secreting T cells might limit the progression of liver damage.

Adult↗
PubMed2005

Evolution of previous sarcoidosis under type 1 interferons given for severe associated disease.

Sarcoidosis is a granulomatous disorder with a well-known T helper (Th) type 1 cell commitment and a key pathogenic role of interferon (IFN)-gamma. However, little is known about the influence of type 1 IFNs, such as IFN-alpha and IFN-beta, on the course of previous sarcoidosis. The aim of this study was to determine whether type 1 IFNs can safely be used in patients with sarcoidosis for severe associated disease. The present study examined a series of four patients with sarcoidosis, treated by IFN-alpha or IFN-beta for viral hepatitis (three cases) or multiple sclerosis (one case). IFN was initiated soon after apparent recovery (three cases) or during a worsening phase of sarcoidosis (one case). Hydroxychloroquine was added in the case with active disease. Patients received interferon for 6-24 months and had close monitoring during and after IFN therapy. Interestingly, no recurrence or exacerbation of sarcoidosis had occurred at 4 yrs of follow up. Two patients were cured from viral hepatitis, whilst treatment for another failed. No neurological progression was observed in the remaining patient. This series suggests that, despite the T helper type 1 phenotype of sarcoid granulomatous reaction, type 1 interferons do not exacerbate sarcoidosis in remission and this makes their use possible if indicated. However, their effect in persistent forms of the disease needs further evaluation.

Adult↗
PubMed2003

Review article: intra-arterial treatments in patients with hepatocellular carcinoma.

In Western countries, most of the patients with hepatocellular carcinoma (HCC) are not eligible for curative treatments. Intra-arterial treatments have a palliative effect that could lead to extensive tumour necrosis and therefore have been widely used. Arterial embolization, Lipiodol-targeted chemoembolization and intra-arterial injection of radioactive iodine mixed with Lipiodol provided promising results in terms of tumoral growth, but were also responsible for severe side-effects, particularly in patients with cirrhosis. Their influence on survival has been assessed by randomized trials with contradictory results. In patients with advanced cases, embolization alone has limited or no influence on survival, and chemoembolization provided a beneficial effect mostly in patients with viral liver diseases, without liver failure, and with an adequate portal flux. The effects of radioactive iodine either in the treatment of advanced cases or the prevention of recurrences after a curative treatment must be investigated further.

Carcinoma, Hepatocellular↗
PubMed2003

Reinforced interferon alpha-2b and ribavirin is more effective than standard combination therapy in the retreatment of chronic hepatitis C previously nonresponsive to interferon: a randomized trial.

Interferon-alpha (IFN) monotherapy results in sustained virological clearance in a minority of patients with chronic hepatitis C. The aim of this study was to assess the effect of a reinforced regimen combining ribavirin and high-dose IFN for 48 weeks compared with a nonreinforced regimen combining a standard IFN regimen and ribavirin for 24 weeks in nonresponders with chronic hepatitis C. A total of 231 patients with chronic hepatitis C and previous nonresponse to IFN monotherapy were randomized. The reinforced group (n = 114) received IFN-2b 6 million units (MU) thrice weekly (TIW) and ribavirin for 48 weeks, and the nonreinforced group (n = 117) received IFN-2b 3 MU TIW and ribavirin for 24 weeks. The main outcome measure was a sustained virological response, defined as negative serum hepatitis C virus (HCV)-RNA 24 weeks following the end of treatment. This endpoint was determined in 98 patients of the reinforced group and 105 patients of the nonreinforced group. At the end of follow-up, a sustained virological response was observed in 29 of the 98 patients (29.6%) in the reinforced group vs 16 of the 105 patients (15.2%) in the nonreinforced group (P = 0.014). In multivariate analysis, factors associated with a sustained virological response were treated with a reinforced regimen [odds ratio (OR) 2.9; P = 0.06] and genotype 2 or 3 (OR 8.8; P < 0.0002). A total of 160 patients had paired biopsies before and after treatment. Histological activity improvement was observed in 32 of 80 patients (40%) and fibrosis worsening in 26 of 80 patients (33%) in the reinforced group vs 13 of 80 (16%) and 19 of 80 (24%) in the nonreinforced group (P = 0.30 and 0.20, respectively). Hence in nonresponders, a high-dose 48-week regimen of IFN and ribavirin combination was more effective than a regimen with interferon at lower dose and ribavirin for 24 weeks only.

Adolescent↗
PubMed2003

Lack of association between HFE gene mutations and hepatocellular carcinoma in patients with cirrhosis.

BACKGROUND: Liver cirrhosis may lead to hepatocellular carcinoma (HCC), regardless of its cause. Genetic and/or environmental factors may modulate the risk of HCC. Mutations in the HFE gene are responsible for genetic haemochromatosis, a condition known to be associated with liver cirrhosis, HCC, or both. It has recently been suggested that the C282Y HFE gene mutation may be more frequent in patients with HCC that have developed in the non-cirrhotic liver than in the general population. Whether or not HFE gene mutations are associated with an increased risk of HCC in patients with cirrhosis is unknown. AIM: To assess the prevalence of HFE gene mutations in cirrhotic patients with and without HCC. PATIENTS AND METHODS: A total of 133 consecutive cirrhotic patients with HCC were prospectively studied for the presence of C282Y and H63D mutations. The control group consisted of 100 cirrhotic patients without HCC. We used restriction enzyme digestion of polymerase chain reaction amplified genomic DNA for determination of HFE genotypes. Iron loading was assessed on non- tumoral liver biopsy samples from 89 patients with HCC and 73 patients without HCC. RESULTS: The prevalence of C282Y heterozygotes was similar in patients with and without HCC (5% v 4%, respectively; p=0.65) and did not differ from that expected in the general population. None of the HCC patients was found to be homozygous for C282Y or H63D, nor compound heterozygous. The prevalence of H63D heterozygotes was similar in patients with and without HCC (31% v 38%, respectively; p=0.25). No relation was detected between HFE genotypes and hepatic iron loading in patients with or without HCC. CONCLUSION: C282Y and H63D mutations do not appear to be associated with an increased risk of HCC in patients with cirrhosis.

Carcinoma, Hepatocellular↗
PubMed2001

Clinical and biological relevance of hepatocyte apoptosis in alcoholic hepatitis.

BACKGROUND/AIMS: Although human and experimental studies have shown that apoptosis plays a role in hepatocyte death in alcoholic liver disease, its clinical and biological significance has not been investigated in alcoholic hepatitis (AH). The aim of this study was to quantify hepatocyte apoptosis in AH and to attempt to relate it to the clinical and biological severity of the disease. METHODS: The hepatocyte apoptotic index was determined using a double in situ transferase-mediated dUTP nick end (TUNEL) and CD15 (neutrophils) labelling on 35 liver biopsies from patients with AH lesions of different severities. The specificity of TUNEL labelling for apoptosis was monitored both by morphology and fractin (a caspase actin cleavage site) immunostaining. RESULTS: The hepatocyte apoptotic index ranged from 0.3 to 28% and was related to the severity of alcoholic hepatitis as measured by the Maddrey score (P < 0.05; Mann-Whitney test) while ballooning (which reflects hepatocytes potentially undergoing necrosis) and neutrophil indexes were not. CONCLUSIONS: This suggests that hepatocyte apoptosis could be a therapeutic target to treat or to prevent alcoholic hepatitis in cirrhotic patients. Co-localization of apoptotic hepatocytes with neutrophils and the strong quantitative correlation would suggest an apoptosis dependent transmigration of neutrophils.

Actins↗
PubMed2001

Worsening of hepatic dysfunction as a consequence of repeated hydroxyethylstarch infusions.

BACKGROUND/AIMS: Due to its apparent safety and low cost, hydroxyethylstarch (HES) is increasingly used as a volume expander. The aim of this retrospective study was to highlight the risk of hepatic dysfunction after iterative HES infusions. METHODS: Between April 1996 and April 1998, nine patients were referred for worsening of their clinical condition after repeated HES infusions. Six patients had previous chronic liver disease, cirrhosis in four cases. All patients underwent a liver biopsy. RESULTS: All post-HES liver biopsies showed diffuse microvacuolization of Kupffer cells, which was associated with focal hepatocyte vacuolization in seven cases. The vacuoles contained periodic acid Schiff positive material at their margins and were lysosomal by electron microscopy. The clinical symptoms of hepatic disease, although difficult to interpret in cirrhotic patients, worsened after HES infusions. Portal hypertension was noted in three non-cirrhotic patients. Serum alkaline phosphatase and gammaglutamyl transferase activities were increased when compared with previous values. Eight patients died, six of them within 1-4 weeks of hepatic failure or septic shock. In the only living patient, symptoms improved after HES withdrawal. CONCLUSIONS: Repeated administration of HES could favour severe portal hypertension, liver failure and sepsis, particularly in the setting of chronic liver disease. The basis of these adverse effects is the lysosomal storage of HES in Kupffer cells and hepatocytes.

Aged↗
PubMed2001

Homozygosity for alanine in the mitochondrial targeting sequence of superoxide dismutase and risk for severe alcoholic liver disease.

BACKGROUND & AIMS: For similar ethanol consumption, some subjects only develop macrovacuolar steatosis whereas others develop severe liver lesions. A genetic dimorphism encodes for either alanine or valine in the mitochondrial targeting sequence of manganese superoxide dismutase and could modulate its mitochondrial import. METHODS: The DNA of 71 white patients with alcoholic liver disease and 79 white blood donors was amplified and genotyped. RESULTS: The frequency of the alanine-encoding allele and the percentage of alanine homozygotes were higher in all patients than in controls and increased with the severity of liver lesions. The percentage of alanine homozygotes was 19% in controls, 17% in alcoholic patients with macrovacuolar steatosis, 43% in patients with microvesicular steatosis, 58% in patients with alcoholic hepatitis, and 69% in patients with cirrhosis. Alcohol consumption in alcoholics was similar whatever the genotype. Alanine homozygosity did not change the risk of developing macrovacuolar steatosis in alcoholics, but increased by 3-fold that of microvesicular steatosis, and 6- and 10-fold that of alcoholic hepatitis and cirrhosis. CONCLUSIONS: Homozygosity for alanine in the mitochondrial targeting sequence of manganese superoxide does not modify alcohol consumption and the risk of macrovacuolar steatosis in alcoholics but is a major risk factor for severe alcoholic liver disease.

Adult↗
PubMed2001

[Sarcoidosis and the liver].

During systemic sarcoidosis, the liver is involved in about 66% of cases, usually clinically silent. The laboratory abnormalities include hypergammaglobulinemia and moderate increases in serum alkaline phosphatase activity; Imaging findings are extremely rare. As in the other organs, liver sarcoidosis is characterized histopathologically by epithelioid, typically noncaseating granulomas generally scattered widely, but many tend to be portal or periportal. In rare instances, liver sarcoidosis is complicated by portal hypertension or chronic cholestasis. Corticosteroids are the main treatment, indicated in case of symptomatic liver involvement and/or in case of extensive liver fibrosis. When portal hypertension is developed, specific treatment of esophageal varices is required.

Adult↗
PubMed2001

[Looking for large-cell dysplasia in liver needle biopsies how and why?].

Liver large cell dysplasia (LCD) is identifiable only at the microscopic level as foci of large hepatocytes with pleomorphic hyperchromatic nuclei and prominent nucleoli. LCD is mainly observed in cirrhotic livers, on surgical specimens, within macroregenerative nodules or low grade dysplastic nodules but also on liver needle biopsies. For needle biopsies, the prevalence of LCD ranges between 15% and 20%. in case of associated hepatocellular carcinoma, the prevalence is around 40%. LCD is more frequent in hepatitis B virus-induced liver cirrhosis than in cirrhosis related to other causes. Two prospective studies showed that LCD is a predictive factor for the occurrence of hepatocellular carcinoma in cirrhotic patients. Nevertheless LCD is probably not a precancerous lesion; dysplastic hepatocytes are biologically senescent polyploid cells unable to carry out normal cell division. Diagnosis of LCD on liver needle biopsy is indicative for the presence of large and numerous foci of LCD within the whole parenchya and allows consequently to select cirrhosis associated with advanced liver cell secescence, i.e. cirrhosis in which multistep genetic alterations of liver cell carcinogenesis could have happened with the greatest probability. Therefore pathologists have to identify and indicate the presence of LCD in the reports of liver needle biopsies

Biopsy, Needle↗
PubMed2000

Latent autoimmune thyroiditis in untreated patients with HCV chronic hepatitis: a case-control study.

In order to establish a relationship between Hepatitis C virus (HCV) chronic infection and autoimmune thyroiditis, 97 untreated patients with biopsy-proven HCV chronic hepatitis and 97 controls were studied. An ultrasound examination of the thyroid and an assay of serum thyroid-stimulating hormone (TSH), thyroid hormones and anti-thyroid antibodies were performed in all cases. The overall prevalence of thyroid abnormalities was higher in patients than in controls (17 vs. 4%, P<0.01) and the prevalence of anti-thyroid antibodies was significantly different between the two groups (P<0. 02). HCV patients with (n=13) compared to HCV patients without anti-thyroid antibodies (n=84) were older, predominantly female, and more frequently had increased serum TSH levels or a hypoechogenic pattern of the thyroid gland, while Knodell's score and prevalence of cirrhosis were similar. Latent autoimmune thyroiditis is more frequent in untreated HCV patients than in controls. This finding raises questions about the mechanism of autoimmunity induced by HCV and provides an explanation for the high rate of overt autoimmune thyroiditis during interferon treatment in these patients.

Adult↗
PubMed2000

Serum laminin and type IV collagen are accurate markers of histologically severe alcoholic hepatitis in patients with cirrhosis.

BACKGROUND/AIMS: Severe alcoholic hepatitis occurs mainly in patients with cirrhosis, and has a high death rate. Corticosteroid therapy has been particularly advocated as reducing mortality in patients with severe histologic lesions. However, identification of these patients is difficult, requiring transvenous liver biopsy. Extracellular matrix serum markers have been proposed as non-invasive diagnostic tools in alcoholic liver disease. The aim of this study was to determine the accuracy of 5 extracellular matrix serum markers, i.e. laminin (Lam), N-terminal peptide of type III procollagen (PIIINP), type I (CI), type III (CIII) and type IV (CIV) collagens in identifying patients with severe histologic alcoholic hepatitis from among those with cirrhosis and suspected alcoholic hepatitis. METHODS: We studied 80 consecutive patients with alcoholic cirrhosis and clinical suspicion of alcoholic hepatitis referred for transvenous liver biopsy. Clinical severity of alcoholic hepatitis was assessed according to Maddrey's score. Histological severity was scored using the sum of the 3 following items: polynuclear infiltration (0-3); hepatocytes alterations (0-3); Mallory bodies (0-2). According to this score, patients were divided into 3 groups: mild (1-3), moderate (4-6), and severe (7-8) alcoholic hepatitis. Serum levels of the 5 extracellular matrix serum markers were measured at the time of biopsy using radioimmunoassays. Diagnostic value for histologically severe alcoholic hepatitis of the 5 extracellular matrix serum markers was assessed using receiver operating characteristic curves. RESULTS: Histological alcoholic hepatitis was present in 67 patients (mean alcoholic hepatitis score: 3.4+/-2.3). Maddrey's score was 66% sensitive and 69% specific for the diagnosis of severe histologic alcoholic hepatitis. The serum Lam and CIV concentrations were the most accurate in identifying correctly patients with severe histologic alcoholic hepatitis. At a cut-off of 4.1 UI/ml, Lam was 90% sensitive and 77% specific, whereas at a cut-off of 150 ng/ml, CIV was 89% sensitive and 77% specific. Combination of markers did not result in improved diagnostic value. CONCLUSION: In patients with cirrhosis, determination of serum Lam or CIV could represent a simple and accurate non-invasive method for identification of patients with histologically severe alcoholic hepatitis eligible for corticosteroid treatment.

Adult↗
PubMed2000

Liver iron is predictive of death in alcoholic cirrhosis: a multivariate study of 229 consecutive patients with alcoholic and/or hepatitis C virus cirrhosis: a prospective follow up study.

BACKGROUND/AIMS: A study was undertaken of liver biopsy samples from 229 consecutive patients with alcoholic or hepatitis C virus related cirrhosis who were prospectively followed until January 1996 to evaluate the influence of liver iron content on survival and the occurrence of hepatocellular carcinoma. METHODS: Hepatic iron content was measured with a validated semiquantitative score, and its predictive value for survival and the occurrence of hepatocellular carcinoma was assessed. RESULTS: 130 patients had detectable iron at enrollment. During follow up (57 (28) months), 95 patients died and 39 patients developed hepatocellular carcinoma. No significant relation was found between hepatic iron and the occurrence of hepatocellular carcinoma. Conversely, the presence of iron was predictive of death in alcoholic patients (p = 0.007) by the log rank test but not in patients with hepatitis C virus related (p = 0.71) or mixed (p = 0.98) cirrhosis. The predictive value of hepatic iron content in patients with alcoholic cirrhosis was confirmed by the Cox model using either a binary coding (p = 0.009; relative risk = 2.27; 95% confidence interval 1.2 to 4.19) or the continuous values (p = 0.002). CONCLUSIONS: These results suggest that hepatic iron enhances liver lesions caused by alcohol but not those caused by hepatitis C virus.

Carcinoma, Hepatocellular↗