Serum Hyaluronan Research Articles

Assessment of liver fibrosis by a noninvasive method of transient elastography and biochemical markers

To assess the correlation between the fibrotic area (FA) as calculated by a digital image analysis (DIA), and to compare the diagnostic accuracy of FibroScan to the other existing Liver fibrosis (LF) markers using the receiver operating curve analysis. We recruited 30 patients who underwent a liver resection for three different etiologies including normal liver, hepatitis B, and hepatitis C. Liver stiffness was measured by using a FibroScan. The FA was then calculated by DIA to evaluate LF in order to avoid any sampling bias. The FA negatively correlated with Prothrom-bin time (PT), platelet count, lecithin-cholesterol acyltransferase (LCAT), and pre-albumin (ALB). On the other hand, the findings of FibroScan correlated with similar markers. The FA positively correlated with FibroScan, serum hyaluronate level, and type IV collagen level, and aspartate transaminase to platelet ratio index (APRI). The area under the receiver operating curve for FibroScan was higher than that for the other markers, even though the statistical significance was minimal. Our findings suggest that FibroScan can initially be used to assess LF as an alternative to a liver biopsy (LB) and serum diagnosis, because it is a safe method with comparable diagnostic accuracy regarding the existing LF markers.

Antioxidants vitamin E and C attenuate hepatic fibrosis in biliary-obstructed rats

To investigate whether antioxidants vitamin E and C can retard development of hepatic fibrosis in the biliary-obstructed rats. Fifty Wistar albino rats were randomly assigned to 5 groups (10 rats in each). Bile duct was ligated in 40 rats and they were treated as follows: group vitC, vitamin C 10 mg/kg sc daily; group vitE, vitamin E 15 mg/kg sc daily; group vitEC, both of the vitamins; bile duct-ligated (BDL, control) group, physiological saline sc. The fifth group was assigned to sham operation. At the end of fourth week, the rats were decapitated, and hepatic tissue biochemical collagen content and collagen surface area were measured. Hepatic tissue specimens were histopathologically evaluated according to Scheuer system. Serum hyaluronate levels were measured by ELISA method. Despite being higher than sham group, hepatic collagen level was significantly decreased in each of the vitC, vitE and vitEC groups (32.7 +/- 1.2, 33.8 +/- 2.9, 36.7 +/- 0.5 mug collagen/mg protein, respectively) compared to BDL (48.3 +/- 0.6 mg collagen/g protein) (P < 0.001 for each vitamin group). Each isolated vitamin C, isolated vitamin E and combined vitamin E/C supplementation prevented the increase in hepatic collagen surface density (7.0% +/- 1.1%, 6.2% +/- 1.7%, 12.3% +/- 2.0%, respectively) compared to BDL (17.4% +/- 5.6%) (P < 0.05 for each). The same beneficial effect of vitamin C, vitamin E and combined vitamin E/C treatment was also observed on the decrease of serum hyaluronate levels compared to BDL group (P < 0.001). The relative liver and spleen weights, serum transaminases, cholestatic enzymes, bilirubins and histopathological inflammation scores were not different between the antioxidant treatment groups and the control. However, fibrosis staging scores were obviously reduced only in the vitamin E/C combination group (vit EC: 2.4 +/- 0.8 vs BDL: 3.1 +/- 0.7; P < 0.05). Each antioxidant vitamin E, vitamin C and their combination retard hepatic fibrosis in biliary-obstructed rats. Oxidative stress may play a role in the pathogenesis of hepatic fibrosis in secondary biliary cirrhosis.

Raised chondroitin sulfate epitopes and hyaluronan in serum from rheumatoid arthritis and osteoarthritis patients

Serum hyaluronan (HA) and chondroitin sulfate (CS) epitopes WF6 and 3B3 (+) were determined to investigate disease association in patients with osteoarthritis (OA), rheumatoid arthritis (RA) and healthy controls. Specific assays for HA and CS epitopes WF6 and 3B3 (+) were established and applied to a cross-sectional study of serum samples from patients (96 OA, 57 RA and 50 healthy controls). Both CS epitopes were increased in serum of many OA and RA patients and average levels were significantly above in healthy controls. In contrast serum HA was increased in RA, but only in few OA patients. CS epitopes WF6 and 3B3 (+) are raised in serum of patients with both OA and RA and were thus distinct from serum HA. The results suggest that OA may be detected systemically as well as RA. The range of levels of CS epitopes detected in OA and RA was wide and correlation with any aspect of disease activity is yet to be determined.

Serologic and Histologic Findings in Patients with Capsular Contracture After Breast Augmentation with Smooth Silicone Gel Implants: Is Serum Hyaluronan a Potential Predictor?

In this study, breast implant capsular tissues and blood samples from 25 cases were studied to characterize the relationship between capsular findings and serum analysis. The serum fibrosis indexes hyaluronan and the aminoterminal propeptide of procollagen type III (PIIINP) are fairly well correlated in several other studies with the inflammation grade and fibrosis in patients with progressive fibrotic disorders such as liver cirrhosis. The study enrolled 25 female patients (average age, 40 +/- 12 years) with capsular contracture after bilateral cosmetic breast augmentation using smooth silicone gel implants (Mentor). The implants were placed in a submuscular position through an incision in the inframammary fold. The implant removals were prompted by development of capsular fibrosis (Baker grades 1-4). Samples of capsular tissue were obtained from all the patients for standard histologic and immunohistochemical analyses. Blood samples were drawn from all the patients immediately before surgery. Sera from 20 healthy female patients (average age, 34 +/- 9 years) who had undergone plastic surgery for reduction mammaplasty were used as controls. Histology. Capsular tissue was significantly thicker in patients with grades 3 and 4 contracture than in women with grade 2 contracture according the classification by Baker. There was a moderate (n = 15) or severe (n = 10) chronic inflammatory reaction in the capsules around the implants. Fibroblasts and macrophages represented the major cell population found in the fibrous capsules. In addition, activated CD4+ cells were detected. An inner layer with synovia-like metaplasia and multinucleated giant cells was found. Fibroblast-like cells formed the most common cell type in the capsules, along with macrophages, scattered polymorphonuclear leukocytes, lymphocytes, plasma cells, and mast cells. Serum analysis. There was a significantly higher level (p < 0.05) of hyaluronan serum concentration in patients with capsular contracture (26 +/- 14 microg/l) than in control subjects (12 +/- 6 microg/l). There was a positive correlation between the grade of capsular contracture (Baker 1-4) and the hyaluronan serum concentration (Baker 1-2: 15 +/- 3 microg/l; Baker 3-4: 35 +/- 12 microg/l) (r2 = 0.73; p < 0.05). : In this study, serum hyaluronan levels were significantly elevated in patients with constrictive fibrosis after breast augmentation, and there was a positive correlation with the stage of capsular contracture. Serum hyaluronan concentration may help in defining patients at risk for capsular fibrosis. If treatment with new drugs can be started as a preventive measure, it may be possible to reduce the rate of patients who require surgical intervention.

Serum hyaluronidase aberrations in metabolic and morphogenetic disorders

Hyaluronidases are endo-glycosidases that degrade both hyaluronan (hyaluronic acid) (HA) and chondroitin sulfates. Deficiency of hyaluronidase activity has been predicted to result in a phenotype similar to that observed in mucopolysaccharidosis (MPS). In the present study, we surveyed a variety of patients with phenotypes similar to those observed in MPS, but without significant mucopolysacchariduria to determine if some are based on aberrations in serum hyaluronidase (Hyal-1) activity. The study included patients with well-characterized dysmorphic disorders occurring on genetic basis, as well as those of unkown etiology. The purpose of the study was to establish how wide spread were abnormalities in levels of circulating Hyal-1 activity. A simple and sensitive semi-quantitative zymographic procedure was used for the determination of activity. Levels of both beta-N-acetylglucosaminidase and beta-glucuronidase whose activities contribute to the total breakdown of hyaluronan (HA) were also measured, as well as the concentration of circulating HA. Among 48 patients with bone or connective tissue abnormalities, low levels of Hyal-1 activity were found in six patients compared to levels in 100 healthy donors (2.0-3.2 units/microL vs 6(+/- 1 SE) units/microL). These six patients exhibited a wide spectrum of clinical abnormalities, in particular shortened extremities: they included three patients with unknown causes of clinical symptoms, one patient with Sanfilippo disease, one of the seven patients with achondroplasia, and one with hypophosphotemic rickets. Normal levels of serum Hyal-1 activities were found in patients with Morquio disease, GM1 gangliosidosis, I cell-disease, 6 of the 7 patients with achondroplasia, Marfan's-syndrome and Ehlers-Danlos syndrome. No patient totally lacked serum Hyal-1 activity. Serum HA concentration was elevated in patients with Sanfilippo A and I-cell disease. Determination of serum and leukocyte Hyal-1 and serum HA may be useful to evaluate patients with metabolic and morphogenetic disorders.

Serum hyaluronate as a non-invasive marker of hepatic fibrosis and inflammation in HBeAg-negative chronic hepatitis B.

BackgroundHBV infection is a serious global heath problem. It is crucial to monitor this disease more closely with a non-invasive marker in clinical trials. We aimed to evaluate the predictive value of serum hyaluronate for the presence of extensive liver fibrosis and inflammation.Methods28 healthy volunteers and 65 patients with HBeAg negative chronic hepatitis B were enrolled. Liver biopsies scored according to Ishak system. Association of serum hyaloronate with liver fibrosis and inflammation were assessed, and cut off points for serum hyaluronate levels were identified by receiver operating characteristics (ROC) curves and their values for prediction of fibrosis and inflammation were assessed.ResultsIn patients with CHB serum hyaluronate had the most significant correlation and predictive values for the liver fibrosis and inflammation comparing to the other variables. At the cut off point of 126.4 ngm/ml it could discriminate extensive fibrosis from milder ones with sensitivity of 90.9% and specificity of 98.1%. With the same value it could discriminate extensive inflammation from their milder counterparts with sensitivity of 63.6% and specificity of 92.6%.ConclusionSerum hyaluronate was the best predictor of extensive liver fibrosis and inflammation and it could discriminate subgroups of patients with chronic hepatitis B. It could be used as a non-invasive test to monitor these patients more closely with developing anti viral agents in clinical trials.

Variation of serum hyaluronan with activity in individuals with knee osteoarthritis

Serum hyaluronan (HA) was evaluated for diurnal variation in participants with osteoarthritis (OA) of the knee. Twenty participants with radiographic OA of at least one knee were admitted overnight to the General Clinical Research Center for serial serum sampling. Serum was obtained between 6:00 p.m. and 8:00 p.m. on Day 1 (T3) after a day of normal activity. During the night of bed rest, participants remained supine for a minimum of 5 h between the hours of 3:00 a.m. and 8:00 a.m. Blood was drawn prior to arising from bed (T0), and 1h (T1) and 4 h (T2) after arising and performing usual morning activities, including eating breakfast. During the morning, participants were encouraged to remain physically active and were not permitted to sit for more than 30 min at a time. Serum HA was measured by enzyme-linked immunosorbent assay. Results were analyzed using non-parametric Freidman's test with Dunn's post-hoc Multiple Comparison test. Serum levels of HA increased significantly from T0 to T1 (P < 0.01). There were no other significant changes in serum HA levels observed between any of the other time points. Although a rise in serum HA with activity and eating has been demonstrated previously in individuals with rheumatoid arthritis, this is the first study to demonstrate a similar rise in individuals with OA. These results suggest that serum sampling for HA in OA clinical trials should be performed more than 1h after arising in the morning and at least 1h after breaking an overnight fast.

Role of hyaluronan and hyaluronan synthase in endometrial cancer

The aim of this study was to determine if the immunohistochemical expression of hyaluronan synthase (HAS) and serum levels of hyaluronan correlate with the clinicopathological manifestations of endometrial carcinoma. Sera were obtained from 59 endometrial cancer patients and 22 post-menopausal healthy women. Concentration of hyaluronan in sera was measured by an inhibitory ELISA using a hyaluronan-binding protein. Tissues obtained from 59 endometrial cancer patients were immunostained by the avidin-biotin-peroxidase complex method using anti-HAS1, anti-HAS2, anti-HAS3 and anti-CD44 antibody. A section was defined as having positive expression when >50% of the tumor cells were intensely stained. The expression of HAS1 was related to the depth of myometrial invasion, histological grade and lymph-vascular space involvement, but the expression of HAS2 and HAS3 was unrelated to these parameters. CD44 expression occurred more frequently in the HAS2- or HAS3-positive groups than in the HAS2- or HAS3-negative groups, and the expression of HAS1 was unrelated to CD44 expression. Serum levels of hyaluronan were higher in the endometrial cancer group than in the healthy control group, and increased with depth of myometrial invasion, histological grade and lymph-vascular space involvement. Serum hyaluronan levels were higher in the HAS1-positive group than in the HAS1-negative group, but the expression of HAS2 and HAS3 was unrelated to serum hyaluronan levels. HAS1 expression and an increase in serum hyaluronan in endometrial cancer may be associated with disease progression through myometrial invasion and lymph-vascular space involvement.

The serum hyaluronan is a potential marker for epithelial ovarian cancer

5066 Background: We have previously shown, that the stromal expression of hyaluronic acid (HA), a glycosaminoglycan, is an independent prognostic factor of poor survival in epithelial ovarian cancer. It’s concentration was also significantly elevated in malignant epithelial ovarian tumors compared to other non-malignant lesions of the ovary analyzed by quantitative ELISA-like assay. In this pilot study, we assessed the value of HA concentration in sera as a biomarker for ovarian cancer. Methods: The blood samples were collected from 81 patients before surgery. The study included malignant (n=24), and semimalignant (n=8) epithelial ovarian tumors, benign lesions of the ovary (n=45), and normal ovary (n=3). The concentration of HA was determined by a sandwich type ELISA-like assay in triplicates. The coefficient of variation for repeated assays on the same samples was 12.65% and that for replicates within an assays 2.90%. Results: Median HA concentration in normal serum was 25.4 ng/ml (range, 15.3–50.1). HA concentrations in the serum of patients with benign lesions of the ovary, borderline and malignant tumors were 19.7 ng/ml (0.0–126.1), 22.1 ng/ml (0.0–76.0) and 63.7 ng/ml (7.0–8037.5), respectively. The concentration of HA in the serum of patients with malignant tumors was significantly higher than in other groups (p < 0.0005). The approximate area under the ROC curve (AUC) was 0.83 (p <0.0005, 95% CI 0.71–0.94). CA125 was a better diagnostic tool with AUC of 0.936, but the combination of HA and CA125 was able to predict ovarian cancer with specificity of 100% and sensitivity of 83% (AUC=0.96, p<0.0005, 95% CI 0.91–1.0). Conclusions: Serum HA may have potential as a tumor marker in epithelial ovarian cancer. It is possible to increase the diagnostic specificity and sensitivity of CA125 by measuring serum HA. No significant financial relationships to disclose.

Hyaluronan-CD44 Interaction with IQGAP1 Promotes Cdc42 and ERK Signaling, Leading to Actin Binding, Elk-1/Estrogen Receptor Transcriptional Activation, and Ovarian Cancer Progression

In this study, we have examined the interaction of hyaluronan (HA)-CD44 with IQGAP1 (one of the binding partners for the Rho GTPase Cdc42) in SK-OV-3.ipl human ovarian tumor cells. Immunological and biochemical analyses indicated that IQGAP1 (molecular mass of approximately 190 kDa) is expressed in SK-OV-3.ipl cells and that IQGAP1 interacts directly with Cdc42 in a GTP-dependent manner. Both IQGAP1 and Cdc42 were physically linked to CD44 in SK-OV-3.ipl cells following HA stimulation. Furthermore, the HA-CD44-induced Cdc42-IQGAP1 complex regulated cytoskeletal function via a close association with F-actin that led to ovarian tumor cell migration. In addition, the binding of HA to CD44 promoted the association of ERK2 with the IQGAP1 molecule, which stimulated both ERK2 phosphorylation and kinase activity. The activated ERK2 then increased the phosphorylation of both Elk-1 and estrogen receptor-alpha (ER alpha), resulting in Elk-1- and estrogen-responsive element-mediated transcriptional up-regulation. Down-regulation of IQGAP1 (by treating cells with IQGAP1-specific small interfering RNAs) not only blocked IQGAP1 association with CD44, Cdc42, F-actin, and ERK2 but also abrogated HA-CD44-induced cytoskeletal function, ERK2 signaling (e.g. ERK2 phosphorylation/activity, ERK2-mediated Elk-1/ER alpha phosphorylation, and Elk-1/ER alpha-specific transcriptional activation), and tumor cell migration. Taken together, these findings indicate that HA-CD44 interaction with IQGAP1 serves as a signal integrator by modulating Cdc42 cytoskeletal function, mediating Elk-1-specific transcriptional activation, and coordinating "cross-talk" between a membrane receptor (CD44) and a nuclear hormone receptor (ER alpha) signaling pathway during ovarian cancer progression.

Sequential injection-ELISA based system for online determination of hyaluronan

Sequential injection-bead-based immunoassay system has been developed. The main purpose is to make immunoassay process more automated by manipulating the precise delivery of micro-volumes of reagents and the precise timing of incubation and washing steps with a computer program that controls the bi-directional syringe pump. The manifold was designed with the aims of reducing back pressure from beads that act as solid surfaces for immobilization of the target substance, reducing dispersion and dilution of the reagent during incubation, and maximizing signal while minimizing incubation time. This was done by introducing air segment to separate the reagent zone from the carrier stream and by using a suitable sensitive detector which, in this case, was an amperometer. In this study, hyaluronan (HA) was used as a target analyte because of its clinical significance as a potential biomarker for liver, bone and cancer diseases. Amount of hyaluronan was determined using competitive enzyme linked immuno sorbent assay (ELISA) based technique where immobilized HA and HA in solution compete to bind with a fixed amount of biotinylated HA-binding proteins (b-HABPs). Upon separation of the two phases, anti-biotin conjugated with enzyme and a suitable substrate were introduced to follow the binding reaction of the immobilized HA and b-HABPs whose degree of binding is indirectly proportional to the amount of HA in solution. A calibration curve was constructed from a series of concentrations of HA standards. Lowest detectable concentration was found to be 1 ng/mL with the dynamic working range of 1–5000 ng/mL and R.S.D. of intra-assay ( n = 7) and inter-assay ( n = 3) of various HA concentrations were 4–10% and 9–12%, respectively. Used beads could be reused by washing with 2 M guanidine. Total analysis time for this automatic assay was about 30 min as compared to the 5–8 h used in conventional batch well ELISA. The system could be applied to assay HA in human serum.

Serum hyaluronan levels and radiographic knee and hip osteoarthritis in African Americans and Caucasians in the Johnston County Osteoarthritis Project

Serum hyaluronan (HA) has been proposed as a potential biomarker of osteoarthritis (OA). We examined associations between serum HA and radiographic OA in an ethnically diverse, population-based sample. Participants were selected from the Johnston County Osteoarthritis Project, using stratified simple random sampling to achieve balance according to radiographic knee OA status, ethnic group, sex, and age group. Serum HA was measured by enzyme-linked immunosorbent assay. Radiographic OA variables included knee OA, knee OA laterality, knee OA severity, concomitant knee and hip OA, and total number of OA-affected knee and hip joints. Analysis of covariance was used to assess differences in mean serum levels of natural log-transformed HA (ln serum HA) between groups, adjusting for ethnicity, sex, age, body mass index (BMI), and self-reported comorbidities. Levels of ln serum HA were positively associated with all definitions of radiographic OA (P < 0.0001). Levels of ln serum HA were higher in Caucasians (P = 0.0094) and in men (P = 0.0038) and were moderately correlated with age (r = 0.35, P < 0.0001). The associations with radiographic OA, ethnicity, sex, and age remained statistically significant after adjustment (P < 0.0045). There were no interactions between ethnicity and the other covariates. These cross-sectional data support a role for serum HA as a biomarker of radiographic OA. The variations in levels of serum HA attributable to ethnicity, sex, and age were not explained by radiographic OA, BMI, or comorbidities. The lack of strong confounding between serum HA and comorbidities further supports a role for serum HA as a potential biomarker.

P70 Quantitation and relative chain length determination of hyaluronan (HA) and chondroitin sulfate (CS) in serum and synovial fluid

P70 Quantitation and relative chain length determination of hyaluronan (HA) and chondroitin sulfate (CS) in serum and synovial fluid

Variation of serum hyaluronan with activity in individuals with knee osteoarthritis

Variation of serum hyaluronan with activity in individuals with knee osteoarthritis

Serum markers detect the presence of liver fibrosis: A cohort study

Histologic examination of a liver biopsy specimen is regarded as the reference standard for detecting liver fibrosis. Biopsy can be painful and hazardous, and assessment is subjective and prone to sampling error. We developed a panel of sensitive automated immunoassays to detect matrix constituents and mediators of matrix remodeling in serum to evaluate their performance in the detection of liver fibrosis. In an international multicenter cohort study, serum levels of 9 surrogate markers of liver fibrosis were compared with fibrosis stage in liver biopsy specimens obtained from 1021 subjects with chronic liver disease. Discriminant analysis of a test set of samples was used to identify an algorithm combining age, hyaluronic acid, amino-terminal propeptide of type III collagen, and tissue inhibitor of matrix metalloproteinase 1 that was subsequently evaluated using a validation set of biopsy specimens and serum samples. The algorithm detected fibrosis (sensitivity, 90%) and accurately detected the absence of fibrosis (negative predictive value for significant fibrosis, 92%; area under the curve of a receiver operating characteristic plot, .804; standard error, .02; P < .0001; 95% confidence interval, .758-.851). Performance was excellent for alcoholic liver disease and nonalcoholic fatty liver disease. The algorithm performed equally well in comparison with each of the pathologists. In contrast, pathologists' agreement over histologic scores ranged from very good to moderate (kappa = .97-.46). Assessment of liver fibrosis with multiple serum markers used in combination is sensitive, specific, and reproducible, suggesting they may be used in conjunction with liver biopsy to assess a range of chronic liver diseases.

Serum Hyaluronate Level for Predicting Subclinical Liver Dysfunction after Hepatectomy

The serum hyaluronate (HA) level reflects sinusoidal endothelial cell function correlated with liver function. We have reviewed multiple liver function indicators from 37 patients who underwent hepatectomy for various liver diseases. The serum HA level was well correlated with the indocyanine green retention rate at 15 minutes (ICGR15), lectin-cholesterol (LCAT), hepatocyte growth factor (HGF), liver uptake ratio of technetium-99m galactosyl human serum albumin (99mTc-GSA) at 15 minutes (HH15), prealbumin, and hepatic uptake ratio of 99mTc-GSA at 15 minutes (LHL15). In addition, the model for end-stage liver disease (MELD) score at 7 days after operation was well correlated with serum HA, ICGR15, HH15, and LHL15. In patients who showed serum an HA level of = 100 ng/ml before hepatectomy, the MELD score had significantly deteriorated by 7 days after hepatectomy. Of the 20 patients who showed a serum HA level < 100 ng/ml before hepatectomy, 11 had high serum HA after hepatectomy. The bilirubin level 7 days after operation in this group was much higher than that for patients who maintained a serum HA level < 100 ng/ml after hepatectomy. In addition, the serum HGF level before hepatectomy in this group was significantly lower. We concluded that the serum HA level is a reliable indicator when evaluating liver function and predicting liver dysfunction after hepatectomy. Furthermore, patients with a significantly low HGF level who have a normal HA level are susceptible to liver dysfunction after hepatectomy.

Serum hyaluronan and hyaluronidase: very early markers of toxic liver injury

Background: Dimethylnitrosamine (DMN), a potent hepatotoxin, administered to rats, provides a convenient model for toxic liver injury. Indicators of early liver injury are important clinically, for surveillance, for screening new drugs that are potentially hepatotoxic and for identifying drugs that protect against liver injury. Both cirrhosis and wound healing culminate in deposition of fibrous connective tissue and scarring. Increased hyaluronan (HA) occurs in the earliest stage of wound healing. Hyaluronidase, the enzyme that degrades hyaluronan, is also elevated whenever rapid turnover of hyaluronan occurs. We test the hypothesis that elevated levels of circulating hyaluronan and hyaluronidase could provide indicators of very early liver damage. Methods: Dimethylnitrosamine was administered to adult male albino rats by intraperitoneal injections for 7 consecutive days. Results: Increased serum hyaluronan levels observed on day 2 reached a maximum on day 4. Hyaluronidase was elevated on the first day and reached a maximum on day 2 that was 30-times control levels. Hyaluronan-specific staining in liver sections was maximal on day 7, occurring predominantly in portal triads and in sinusoidal spaces. Individual hepatocytes were slightly enlarged and contained intracellular hyaluronan, which was not evident in control sections. Though circulating hyaluronan levels had decreased after day 4, continued hyaluronan staining persisted in liver sections through day 21. Conventional indicators of liver injury, such as serum aminotransferase enzymes, did not reach a peak until day 7. Conventional gross and histopathological changes, including severe centrilobular congestion and hemorrhagic necrosis, were observed only after day 7. Both hyaluronan and hyaluronidase are indicators of very early liver damage in the dimethylnitrosamine-treated rat, occurring well before conventional indicators appear, or before overt histopathologic changes of liver damage can be seen. However, levels are increased only transiently, indicating that serial assays are necessary. Conclusions: Measures of circulating hyaluronidase activity may be used to assess liver damage.

Serum hyaluronan as a marker reflecting the severity of cirrhosis and portal hypertension in postoperative biliary atresia

The majority of patients with biliary atresia (BA) develop progressive liver disease and serious complications of portal hypertension, including esophageal varices and ascites, despite successful Kasai operation. The aim of this study was to evaluate whether serum hyaluronan (HA) reflects the severity of cirrhosis and its complications in patients with postoperative BA. Fifty-four postoperative BA patients aged 1 to 19 years were recruited into this study. Serum HA was determined by ELISA-based assay, and serum HA levels were compared among groups of patients according to Child's classification as well as the presence of esophageal varices and ascites. Mean serum HA concentration was significantly increased in patients with Child C (534.35 +/- 573.02 ng/ml) in comparison to patients with Child B (97.67 +/- 104.22 ng/ml, p = 0.002) and Child A (36.27 +/- 71.41 ng/ml, p < 0.001). Mean serum HA concentration was also significantly higher in patients who had ascites or esophageal varices than in those who did not suffer from these complications. Furthermore, patients who had variceal hemorrhage had significantly higher mean serum HA levels than those without bleeding. Thus, serum HA levels may reflect the severity of cirrhosis and its complications, and may be useful in monitoring the clinical outcomes of patients with postoperative BA.

Prediction of liver fibrosis in patients with features of the metabolic syndrome regardless of alcohol consumption.

The aim of this study was to determine noninvasive predictive factors of significant liver fibrosis in patients with increased serum aminotransferases associated with features of metabolic syndrome (abdominal obesity, systemic hypertension, fasting hyperglycemia, and dyslipidemia). One hundred seventy-three patients were prospectively examined, regardless of alcohol consumption. Biometric, metabolic, and hepatic biochemical variables were tested for association with fibrosis assessed on liver biopsy according to the Metavir score system. Significant fibrosis, defined as Metavir scores F2, F3, or F4, was observed in 42 of 173 patients (24%). A logistic regression model and receiver operating characteristic curve were used to construct a simple index predictive of significant fibrosis. None of the patients with serum hyaluronate levels of 35 microg/L or less had significant fibrosis. In patients with serum hyaluronate levels >35 microg/L, no case of fibrosis stage F3 or F4 was found when serum carbohydrate-deficient transferrin/transferrin ratio was less than 0.9. In conclusion, in patients with increased serum aminotransferases associated with features of metabolic syndrome, a simple algorithm, including serum hyaluronate and serum carbohydrate-deficient transferrin/transferrin ratio, allows the exclusion of clinically relevant hepatic fibrosis, regardless of current or past alcohol consumption.

Diagnostic et quantification de la fibrose hépatique par IRM de diffusion : résultats préliminaires

Purpose Diagnosis and quantification of hepatic fibrosis are especially important in patients with chronic liver disease. Liver biopsy remains the gold standard for diagnosis of cirrhosis but has several limitations. The purpose of this study was to determine the usefulness of diffusion-weighted MR imaging, for the diagnosis of cirrhosis and quantification of hepatic fibrosis, and to define the best sequence parameters for this evaluation. Methods and Materials Diffusion-weighted imaging using a 1.5 T MR unit was performed in 14 healthy volunteers and 13 cirrhotic patients. Sets of 8 images with different b values (200, 400, 600, and 800 sec/mm 2) and different TR (3500 and 5000 ms) were acquired with breath-holding. Apparent diffusion coefficients (ADCs) were calculated. Correlation between Child-Pugh scores, serum hyaluronate concentrations and ADCs were performed. Results ADCs were significantly lower in cirrhotic patients (2,055 10 -3) compared to controls (2,915 10 -3) (p<0.05) when the b value was 200s/mm 2 and the TR was 5000ms. Significant correlations were observed between Child-Pugh scores and ADCs (p<0.05), and between serum hyaluronate concentrations and ADCs (p<0.05), when the b value was 400sec/mm 2 and the TR was 5000ms. Conclusion Our preliminary study showed that the measurement of ADCs has good potential for diagnosis and quantification of hepatic fibrosis, especially when using b values of 200sec/mm 2 and 400sec/mm 2.