Jérôme Guéchot

Diffusion-weighted magnetic resonance imaging for the assessment of fibrosis in chronic hepatitis C†

Liver biopsy is the gold standard for assessing fibrosis but has several limitations. We evaluated a noninvasive method, so‐called diffusion‐weighted magnetic resonance imaging (DWMRI), which measures the apparent diffusion coefficient (ADC) of water, for the diagnosis of liver fibrosis in patients with chronic hepatitis C virus (HCV). We analyzed 20 healthy volunteers and 54 patients with chronic HCV (METAVIR: F0, n = 1; F1, n = 30; F2, n = 8; F3, n = 5; and F4, n = 10) prospectively included. Patients with moderate‐to‐severe fibrosis (F2‐F3‐F4) had hepatic ADC values lower than those without or with mild fibrosis (F0‐F1; mean: 1.10 ± 0.11 versus 1.30 ± 0.12 × 10−3 mm2/s) and healthy volunteers (mean: 1.44 ± 0.02 × 10−3 mm2/s). In discriminating patients staged F3‐F4, the areas under the receiving operating characteristic curves (AUCs) were 0.92 (±0.04) for magnetic resonance imaging (MRI), 0.92 (±0.05) for elastography, 0.79 (±0.08) for FibroTest, 0.87 (±0.06) for the aspartate aminotransferase to platelets ratio index (APRI), 0.86 (±0.06) for the Forns index, and 0.87 (±0.06) for hyaluronate. In these patients, the sensitivity, specificity, positive predictive value, and negative predictive value were 87%, 87%, 72%, and 94%, respectively, with an ADC cutoff level of 1.21 × 10−3 mm2/s. In discriminating patients staged F2‐F3‐F4, the AUC values were 0.79 (±0.07) for MRI, 0.87 (±0.05) for elastography, 0.68 (±0.09) for FibroTest, 0.81 (±0.06) for APRI, 0.72 (±0.08) for the Forns index, and 0.77 (±0.06) for hyaluronate. Conclusion: This preliminary study suggests that DWMRI compares favorably with other noninvasive tests for the presence of significant liver fibrosis. (HEPATOLOGY 2007.)

Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study.

BACKGROUND & AIMS Blood tests and transient elastography (Fibroscan™) have been developed as alternatives to liver biopsy. This ANRS HCEP-23 study compared the diagnostic accuracy of nine blood tests and transient elastography (Fibroscan™) to assess liver fibrosis, vs. liver biopsy, in untreated patients with chronic hepatitis C (CHC). METHODS This was a multicentre prospective independent study in 19 French University hospitals of consecutive adult patients having simultaneous liver biopsy, biochemical blood tests (performed in a centralized laboratory) and Fibroscan™. Two experienced pathologists independently reviewed the liver biopsies (mean length=25±8.4 mm). Performance was assessed using ROC curves corrected by Obuchowskis method. RESULTS Fibroscan™ was not interpretable in 113 (22%) patients. In the 382 patients having both blood tests and interpretable Fibroscan™, Fibroscan™ performed similarly to the best blood tests for the diagnosis of significant fibrosis and cirrhosis. Obuchowskis measure showed Fibrometer® (0.86), Fibrotest® (0.84), Hepascore® (0.84), and interpretable Fibroscan™ (0.84) to be the most accurate tests. The combination of Fibrotest®, Fibrometer®, or Hepascore® with Fibroscan™ or Apri increases the percentage of well classified patients from 70-73% to 80-83% for significant fibrosis, but for cirrhosis a combination offers no improvement. For the 436 patients having all the blood tests, AUROCs ranged from 0.82 (Fibrometer®) to 0.75 (Hyaluronate) for significant fibrosis, and from 0.89 (Fibrometer® and Hepascore®) to 0.83 (FIB-4) for cirrhosis. CONCLUSIONS Contrarily to blood tests, performance of Fibroscan™ was reduced due to uninterpretable results. Fibrotest®, interpretable Fibroscan™, Fibrometer®, and Hepascore® perform best and similarly for diagnosis of significant fibrosis and cirrhosis.

Cytokine response to burn injury : relationship with protein metabolism

Plasma levels of interleukin 1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), interleukin 6 (IL-6), and markers of protein metabolism were determined in 12 burn patients throughout the healing period (day 2 to 21 post-injury) to determine the pattern of variations in plasma cytokine concentration. To establish the relationship between cytokine production and the nutritional status a wide range of severity standpoints (burn surface area ranging from 9% to 82%) was chosen. Interleukin 6 levels were increased in all patients throughout the study period; maximum concentrations (615 +/- 198 pg/mL) were reached on day 4 and correlated (p < 0.01) with the extent of burn injury. Tumor necrosis factor alpha levels were also elevated; they were significantly higher on day 7 in the patients who developed sepsis than in the other patients (67 +/- 21 pg/mL vs. 20 +/- 7 pg/mL; p < 0.05) but did not correlate with the extent of burn injury. Interleukin 1 beta was rarely detected. Cortisolemia on day 7 was inversely correlated with levels of TNF alpha but not with those of IL-6. Interleukin 6 levels correlated positively with protein turnover (phenylalaninemia) and catabolism (3-methylhistidine/creatinine ratio) and negatively with levels of fibronectin and transthyretin. Our data indicate that the systemic cytokine response to burn injury is mainly represented by IL-6. These data also support the hypothesis that IL-6 is a key mediator of the variations in protein metabolism following burn injury.

Serum hyaluronan as a marker of liver fibrosis in chronic viral hepatitis C: effect of α-interferon therapy.

BACKGROUND/AIMS It has been suggested that increases in serum hyaluronan levels might be a marker of fibrosis in chronic viral hepatitis C. Patients receiving alpha-interferon therapy are an excellent model to determine the relationship between serum hyaluronan and liver fibrosis, since results suggest that alpha-interferon could reduce liver fibrosis. METHODS We studied the relationship between serum hyaluronan and histopathological indices of liver fibrosis, inflammation and necrosis, before and after alpha-interferon therapy (3 MU, three times weekly for 6 months), and the effect of treatment on serum hyaluronan and on histological liver fibrosis, in 52 patients. Hyaluronan levels were measured using a radiometric assay and the liver histopathological indices were scored according to the Knodell system. RESULTS The serum hyaluronan level correlated with the extent of liver fibrosis both before and after alpha-interferon therapy (p < 0.0001), but not with the histopathological indices of liver inflammation or necrosis. Parallel changes in serum hyaluronan and liver fibrosis occurred: serum hyaluronan levels fell significantly in patients in whom fibrosis improved (p < 0.01, n = 11), increased significantly in patients in whom fibrosis worsened (p < 0.05, n = 10), and did not change significantly in patients in whom fibrosis was unmodified (n = 31). Furthermore, fibrosis improved only when the antiviral effect of alpha-interferon was reflected by persistent normalization of serum alanine aminotransferase, although there was no correlation between serum hyaluronan levels and alanine aminotransferase activities. CONCLUSION Serum hyaluronan thus appears to be a non-invasive index of liver fibrosis.

Prognostic value of serum hyaluronan in patients with compensated HCV cirrhosis

BACKGROUND/AIM Serum hyaluronan (HA) levels increase according to the degree of liver fibrosis in patients with chronic viral hepatitis C. Patients with liver disease and markedly high serum HA levels have cirrhosis with typical signs of hepatic sinusoidal capillarization, a factor of aggravation of cirrhosis The aim of this study was to evaluate the prognostic value of serum HA for severe complications in asymptomatic patients with HCV cirrhosis. METHODS Six hundred and sixty-eight patients with anti-HCV antibodies and increased serum alanine aminotransferase were referred to our hospital for evaluation, including liver biopsy. At entry, serum HA levels were measured in 91 patients (64 men, 27 women, 56 +/-11 years old) out of 103 who had asymptomatic, biopsy-proven cirrhosis According to the criteria of Child-Pugh, 82 were classified A and 9 B. The follow-up period was 6 to 82 months (median: 38 months), and 51 of these patients received alpha-interferon therapy during the first year. Severe complications were defined as death or liver transplantation, ascites, bleeding from esophageal varices, encephalopathy, or hepatocellular carcinoma. RESULTS Serum HA levels at entry were higher in the cirrhotic patients in whom severe complications occurred during the follow-up period (520+/-426 microg/l vs 197+/-146 microg/l, p<0.0001). The patients with serum hyaluronan levels >350 microg/l displayed higher probabilities of occurrence of severe complications (p<0.0001). Other factors associated with the occurrence of complications or death were: serum bilirubin >18mol/l (p = 0.03), platelet count <112x10(9)/l (p= 0.02), prothrombin time <63% (p<0.0001), serum albumin <36 g/l (p=0.002), alkaline phosphatase >81 IU/l (p=0.01), and no interferon treatment (p= 0.0003). Multivariate analysis identified five independent factors predictive of severe clinical complications, namely: hyaluronan (p=0.006), prothrombin time (p=0.04), bilirubin (p=0.04), albumin (p=0.04), and no therapy (p=0.03). CONCLUSION Serum HA level is predictive for occurrence of severe complications in HCV cirrhosis, and can be used as a prognostic marker, in addition to the parameters of the Child-Pugh score, particularly in patients with compensated cirrhosis.

Action of ornithine alpha-ketoglutarate, ornithine hydrochloride, and calcium alpha-ketoglutarate on plasma amino acid and hormonal patterns in healthy subjects.

Ornithine alpha-ketoglutarate (OKG) has been useful as an adjuvant of enteral and parenteral nutrition. However, its metabolism and mechanism of action remain unclear although it is known that alpha-ketoglutarate (alpha KG) and ornithine (ORN) follow, in part, common metabolic pathways. Six fasting healthy male subjects underwent three separate oral load tests: (i) they received 10 g of OKG (i.e., 3.6 g of alpha KG and 6.4 g of ORN); (ii) 6.4 g of ORN as ornithine hydrochloride, and (iii) 3.6 g of alpha KG as calcium alpha-ketoglutarate. Blood was drawn 15 times over a five-hour period for measurements of plasma amino acids, alpha KG, insulin, and glucagon. After OKG and ORN administration, plasma ORN peaked at 60-75 min (494 +/- 91 and 541 +/- 85 mumol/L). The increase in plasma alpha KG was very small. OKG, alpha KG, and ORN all increased glutamate concentrations at 60 min (mean: +43%, +68%, +68%, respectively, p less than 0.05 compared to basal values). However, only OKG increased proline and arginine levels at 60 min (mean: +35%, p less than 0.01 and mean: +41%, p less than 0.05). Furthermore, glutamate, proline, and arginine concentrations correlated linearly with ornithine levels at 60 min. Finally, OKG increased insulinemia and glucagonemia (mean: +24% at 15 min, p less than 0.05 and +30% at 60 min, p less than 0.01, respectively). These data provide evidence that the combination of ORN and alpha KG modifies amino acid metabolism in a way which is not observed when they are administered separately. In addition, the OKG-mediated increase in insulin levels probably does not appear to result from a direct action of ORN on pancreatic secretion.

Performance of 11 biomarkers for liver fibrosis assessment in HIV/HBV co-infected patients.

BACKGROUND/AIMS The aim of this study was to compare the performance of 11 biochemical scores to estimate liver fibrosis in HIV/HBV co-infection. METHODS Performance was evaluated using the Receiver Operating Characteristics (ROC) curve method. The Kappa index was used to study overall agreement with liver biopsy results. Interpretative algorithms were established by optimizing sensitivity and specificity and the percentage of correctly classified patients. RESULTS One hundred and eight patients (F0-F1, n = 47; F2, n = 28; F3, n = 17; F4, n = 16) were considered for the evaluation of serum biomarker performance. The AUROCs of the Fibrotest, Hepascore, Fibrometer, and Zengs scores ranged from 0.74 to 0.77 for significant fibrosis (> or = F2), from 0.79 to 0.84 for advanced fibrosis (> or = F3) and from 0.87 to 0.92 for cirrhosis (F4). Thresholds defined for each stage of fibrosis were close to those previously published for the Fibrotest and Hepascore. Strict concordance with biopsies correctly classified 50% of the patients. CONCLUSIONS Fibrotest, Fibrometer, Hepascore, and Zengs score were the most accurate non-invasive biochemical scores for liver fibrosis assessment in HIV/HBV co-infection. Global performance of biomarkers was not significantly improved by a decision tree combining the results of two biochemical scores.

Effect of liver transplantation on sex-hormone disorders in male patients with alcohol-induced or post-viral hepatitis advanced liver disease

The effects of liver transplantation on the pituitary-gonadal axis and sex-hormone metabolism were evaluated by studying hormonal status (androgens, oestrogens, and gonadotropins) and sex-hormone-binding globulin levels in men with advanced liver disease of both alcoholic and viral origins. Comparison of the results prior to and 6 months after liver transplantation showed that successful liver transplantation in men induced significant differences in sex-hormone levels and in pituitary-gonadal function in both alcoholic and post-hepatitis patients. Plasma testosterone and dihydrotestosterone levels increased, oestrogen (oestrone and oestradiol) and androstenedione levels fell while gonadotropin (FSH and LH) levels increased. There was also a fall in plasma prolactin levels. Sex-hormone binding globulin plasma levels were elevated prior to transplantation and decreased thereafter. These data show that male patients with advanced liver disease have biological hypogonadism and feminization, irrespective of the aetiology, and that these abnormalities rapidly improve after successful liver transplantation. Therefore in men with advanced liver disease the biochemical signs of sex hormone disturbance are reversible and may be largely related to the liver disease.

Liver adenoma and focal nodular hyperplasia in a man with high endogenous sex steroids.

The authors report the case of a 29-yr-old man presenting with both hepatocellular adenoma and focal nodular hyperplasia. The patient had never been treated with androgens or estrogens. Investigations revealed the existence of high plasma levels of androgens and estrogens. In addition, the patient presented features compatible with the syndrome of partial androgen resistance. We propose that the hepatic lesions could be secondary to an abnormally high secretion of sex steroids. We suggest that in the absence of known intake of either estrogens or androgens, the existence of hepatocellular adenoma or focal nodular hyperplasia, or both, should indicate a search for abnormal secretion of sex steroids.

VALUES OF SPERM THIOBARBITURIC ACID- REACTIVE SUBSTANCE IN FERTILE MEN

BACKGROUND The objective of this study was to establish for the first time reference levels of sperm malondialdehyde, a stable lipid peroxidation product, in a cohort of fertile men. METHODS Sperm malondialdehyde, a thiobarbituric acid-reactive substance, was assayed using the 2-thiobarbituric acid method. RESULTS Sperm malondialdehyde levels, expressed in nM/10(8) spermatozoa, were normally distributed in our cohort of fertile men and averaged 0.0287 +/- 0.0162 (mean +/- S.D.). CONCLUSIONS Given the impact of lipid peroxidation on spermatozoa and thereby on male fertility, the assay of sperm membrane thiobarbituric acid-reactive substance is clearly of interest. Malondialdehyde levels found in our study form a basis for normal values of sperm thiobarbituric acid-reactive substance observed in the semen of fertile men.