I know why the caged bird sings: Distress tolerant individuals show greater resting state connectivity between ventromedial prefrontal cortex and right amygdala as a function of higher vagal tone.

BACKGROUND: Intolerance to psychological distress is associated with various forms of psychopathology, ranging from addiction to mood disturbance. The capacity to withstand aversive affective states is often explained by individual differences in cardiovagal tone as well as resting state connectivity of the ventromedial prefrontal cortex (vmPFC), a region involved in the regulation of emotions and cardio-autonomic tone. However, it is unclear which brain regions involved in distress tolerance show greater resting state functional connectivity (rsFC) as a function of resting heart rate variability (HRV). METHODS: One-hundred and twenty-six adults, aged 20 to 83.5 years, were selected from a lifespan cohort at the Nathan Kline Institute-Rockland Sample. Participants' distress tolerance levels were assessed based upon performance on the Behavioral Indicator of Resiliency to Distress (BIRD) task. Artifact-free resting-state functional brain scans collected during separate sessions were used. While inside the scanner, a pulse oximeter was used to record beat-to-beat intervals to derive high-frequency heart rate variability (HF-HRV). The relationship between HF-HRV and vmPFC to whole brain functional connectivity was compared between distress tolerant (BIRD completers) and distress intolerant (BIRD non-completers). RESULTS: Groups did not differ in their history of psychiatric diagnosis. Higher resting HF-HRV was associated with longer total time spent on the BIRD task for the entire sample (r = 0.255, p = 0.004). After controlling for age, gender, body mass index, head motion, and gray matter volume. Distress tolerant individuals showed greater rsFC (p < 0.005 (uncorrected), k = 20) between the vmPFC and default-mode network (DMN) hubs including posterior cingulate cortex/precuneus, medial temporal lobes, and the parahippocampal cortex. As a function of higher resting HF-HRV greater vmPFC connectivity was observed with sub-threshold regions in the right amygdala and left anterior prefrontal cortex, with the former passing small volume correction, in distress tolerant versus distress intolerant individuals. CONCLUSION: In a lifespan sample of community-dwelling adults, distress tolerant individuals showed greater vmPFC connectivity with anterior and posterior hubs of the DMN compared to distress intolerant individuals. As a function of greater HF-HRV, distress tolerant individuals evidenced greater vmPFC with salience and executive control network hubs. These findings are consistent with deficits in neural resource allocation within a triple network resting amongst persons exhibiting behavioral intolerance to psychological distress.

Longitudinal assessment of hepatitis C fibrosis progression by collagen and smooth muscle actin morphometry in comparison to serum markers.

BACKGROUND: Assessment of fibrosis progression in chronic liver disease relies upon non-invasive tools and changes in semi-quantitative histopathology scores that may not be reliable. AIM: To assess the diagnostic performance of the FibroSURE (FS) index and collagen/alpha smooth muscle actin (α-SMA) morphometry in relation to longitudinal changes in fibrosis on paired biopsies. METHODS: The study cohort included 201 chronic hepatitis C (CHC) nonresponders enrolled in a prior phase II anti-fibrotic study. Serum FS and paired biopsies, with both collagen and α-SMA morphometry, were evaluated at baseline and week 52. RESULTS: Study patients were mostly male (67%) and Caucasian (77%), with Ishak stages 2 (n = 79), 3 (n = 88) and 4 (n = 30), excluded (n = 4 stage 1 or 5). Mean biopsy length was 22.9 mm. For baseline Ishak 2/3 vs. 4, there were no significant differences in AUROCs for collagen (0.71), SMA (0.66) or FS (0.70). At week 52, 62% of patients had no change in Ishak stage, but collagen/α-SMA increased by 34-51% (P < 0.0001), and FS decreased by 5% (P = 0.008). Among the 33% of patients with +/-1 Ishak stage change, FS changes were not significant, but α-SMA increased 29-72%, and collagen increased by 12-38% (P = 0.01 for +1 only). CONCLUSIONS: Longitudinal changes in collagen and α-SMA morphometry are apparent prior to change in histological stage or FibroSURE in CHC nonresponders with intermediate fibrosis. This likely reflects quantitative morphological differences that are not detected by routine histological staging or serum markers such as FibroSURE.

Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial.

BACKGROUND: Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear. AIM: To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment. METHODS: Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes. RESULTS: At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33-1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes. CONCLUSIONS: Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164).

Differential expression of miRNAs in the visceral adipose tissue of patients with non-alcoholic fatty liver disease.

BACKGROUND: Progression of non-alcoholic fatty liver disease (NAFLD) can be facilitated by soluble molecules secreted by visceral adipose tissue (VAT). MicroRNAs (miRNAs) are likely to regulate some of these molecular pathways involved in pathogenesis of NAFLD. AIM: To profile miRNA expression in the visceral adipose tissue of patients with NAFLD. METHODS: Visceral adipose tissue samples were collected from NAFLD patients and frozen. Patients with biopsy-proven NAFLD were divided into non-alcoholic steatohepatitis (NASH) (n = 12) and non-NASH (n = 12) cohorts controlled for clinical and demographic characteristics. Extracted total RNA was profiled using TaqMan Human MicroRNA arrays. Univariate Mann-Whitney comparisons and multivariate regression analysis were performed to compare miRNA profiles. RESULTS: A total of 113 miRNA differentially expressed between NASH patients and non-NASH patients (P < 0.05). Of these, seven remained significant after multiple test correction (hsa-miR-132, hsa-miR-150, hsa-miR-433, hsa-miR-28-3p, hsa-miR-511, hsa-miR-517a, hsa-miR-671). Predicted target genes for these miRNAs include insulin receptor pathway components (IGF1, IGFR13), cytokines (CCL3, IL6), ghrelin/obestatin gene, and inflammation-related genes (NFKB1, RELB, FAS). In addition, two miRNA species, hsa-miR-197 and hsa-miR-99, were significantly associated with pericellular fibrosis in NASH patients (P < 0.05). Levels of IL-6 in the serum negatively correlated with the expression levels of all seven miRNAs capable of down regulating IL-6 encoding gene. CONCLUSIONS: miRNA expression from VAT may contribute to the pathogenesis of NAFLD - a finding which may distinguish relatively simple steatosis from NASH. This could help identify potential targets for pharmacological treatment regimens and candidate biomarkers for NASH.

T-helper cells and liver fibrosis in hepatitis C virus-monoinfected patients.

Limited data suggest that low T-helper cell levels may be observed in hepatitis C virus (HCV) monoinfected patients with decompensated liver disease. We sought to determine the distribution and relationship of T-helper cells (CD4) to liver fibrosis in HCV-monoinfected patients before and during pegylated interferon (PegIFN) therapy. CD4 populations were prospectively determined using flow cytometry. All subjects had compensated liver disease. Baseline and subsequent CD4 counts at treatment weeks 12, 24, 36 and 48 and at two time points following treatment discontinuation (weeks 60 and 72) were evaluated. Ishak score was determined by a central pathologist. At baseline, data from 267 subjects were available. Mean age was 50 and 68% were male/Caucasian. HCV viral load was >800 000 IU/mL in 55%. Nearly half (48%) were Ishak 4-6 with all stages represented. Mean CD4 count was 1004 cells/mm(3) + or - 400, and 6% had counts <500. There was a trend towards lower CD4 counts among cirrhotic subjects (P = 0.07). A CD4 decrease was noted following PegIFN initiation. Mean CD4 decline was 38.9% and was statistically significant for all fibrosis stages compared with baseline levels, but not between fibrosis levels. CD4 counts <500 cells/mm(3) are seen in <10% of HCV-monoinfected subjects. A trend towards lower CD4 counts in subjects with advanced fibrosis was observed. However, at baseline and during/after PegIFN therapy, no significant differences were observed between groups. CD4 counts declined during PegIFN treatment, but returned to baseline after completion. The significance of these findings in terms of disease progression and treatment response requires further evaluation.

Is histological diagnosis of primary liver carcinomas with fibrous stroma reproducible among experts?

AIMS: In the era of targeted therapeutics, histological typing of hepatobiliary carcinomas has major clinical implications. Little is known about the reproducibility of the pathological diagnosis of primary liver carcinomas. Therefore, this study aimed to evaluate the worldwide variation in the pathological expert diagnoses of primary liver carcinomas with fibrous stroma in patients who did not have cirrhosis. METHODS: A single set of slides was selected from 25 tumours, and this set was reviewed independently by 12 pathologists who have worldwide expertise in liver tumours. Reproducibility of the diagnoses was evaluated by Light's kappa, and diagnoses were clustered by multidimensional scaling. Immunohistochemistry was performed after histological review. RESULTS: The interobserver reproducibility for diagnosis of hepatocellular carcinoma subtypes and cholangiocarcinomas was poor (kappa 0.23-0.52), even when the experts considered that the diagnosis required no additional stains or clinical information. Interestingly, multidimensional scaling revealed three main clusters of tumours: hepatocellular carcinoma with no other specifications (n = 13), fibrolamellar hepatocellular carcinoma (n = 3) and cholangiocarcinoma (n = 9). Using immunohistochemistry, these histological clusters correlated with expression of anti-hepatocyte and anti-cytokeratin 19 (p<0.001). CONCLUSIONS: The results demonstrate the poor reproducibility among experts of the pathological diagnosis of primary liver carcinomas with fibrous stroma in patients who did not have cirrhosis, and highlight that the systematic use of immunohistochemistry may improve the diagnostic accuracy.

Ciprofloxacin-induced acute cholestatic liver injury and associated renal failure. Case report and review.

Ciprofloxacin, a commonly prescribed fluoroquinolone antibiotic, has generally been well-tolerated; however, there are rare reports of associated hepatic failure or renal failure. We describe a case of a 65 year-old man with a history of ischemic cardiomyopathy who was treated with ciprofloxacin 500 mg twice daily for cellulitis. Six days into his treatment course, he developed acute cholestatic jaundice and acute anuric renal failure. Clinical, laboratory, and pathologic data suggest that the patient had developed reversible, severe ciprofloxacin-induced cholestatic liver injury and acute tubular necrosis requiring hemodialysis. Within two months of stopping the ciprofloxacin, the patient was off dialysis and back to his baseline creatinine in three months. Liver tests normalized by five months. This report illustrates a case of cholestatic liver injury and renal failure involving ciprofloxacin use. We review the literature regarding hepatic and renal injury as it relates to ciprofloxacin. To our knowledge, this represents the first case report of simultaneous acute cholestatic liver injury and renal failure secondary to ciprofloxacin.

Adipokines and cytokines in non-alcoholic fatty liver disease.

BACKGROUND: Several adipocytokines have been implicated in the pathogenesis non-alcoholic fatty liver disease (NAFLD). AIM: To assess adipocytokines in NAFLD patients and controls. METHODS: A total of 95 patients (26 non-alcoholic steatohepatitis (NASH), 19 simple steatosis (SS), 38 obese controls and 12 non-obese controls) were included. Fasting serum insulin, glucose, visfatin, resistin, adiponectin, tumour necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8) and IL-6 were determined. Univariate and multivariate analyses were used to compare groups and determine associations. RESULTS: Serum TNF-alpha and IL-8 were higher in NAFLD patients when compared with both obese and non-obese controls. Analysis involving all patients revealed a significant correlation between serum TNF-alpha and IL-8 (P < 6.319e-08), and between IL-6 and IL-8 (P < 5.271e-15). Homeostatic model assessment scores negatively correlated with adiponectin in NAFLD (P < 0.0032). Serum visfatin was higher in all three obese groups than in non-obese controls (P < 0.02, P < 0.002 and P < 0.008). Visfatin in NASH patients was lower than SS and obese controls. Although TNF-alpha was associated with NAFLD (P < 0.02), it was interdependent on visfatin. In comparison to SS, four factors were independently associated with NASH: age, alanine aminotransferase, IL-8 and adiponectin (P < 0.05). Multivariate analysis indicated that TNF-alpha was the only independent predictor of fibrosis in NASH (P < 0.0004). CONCLUSION: These findings support a complex interaction between adipocytokines and the pathogenesis of NAFLD.

Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B.

BACKGROUND: Activation of hepatic stellate cells is the earliest step in fibrogenesis. Alpha-smooth muscle actin (alpha-SMA), expressed by activated hepatic stellate cells, and C-terminal procollagen alpha1(III) propeptide (PIIICP) are early markers of fibrogenesis and should precede fibrosis. AIM: Determine if suppression of hepatitis B virus replication with lamivudine would decrease fibrogenesis as measured by immunohistochemical markers. METHODS: Paired liver biopsies from patients with hepatitis B before and after therapy with lamivudine (n=47) or placebo (n=33) were studied. alpha-SMA and PIIICP were detected in paraffin-embedded tissue by immunohistochemistry and quantified in a blinded manner by video imaging analysis. RESULTS: Liver biopsies from patients treated with lamivudine showed a significant decrease in alpha-SMA expression (1.06+/-0.23 vs. 0.58+/-0.11, pre vs. post, P<0.05). Placebo recipients had increased levels of alpha-SMA (0.82+/-0.14 vs. 1.32+/-0.21, P<0.05). PIIICP was similarly decreased after lamivudine. Among subjects whose Histologic Activity Index fibrosis score was unchanged or worsened, the mean change in alpha-SMA expression was significantly decreased in the lamivudine group compared with placebo. CONCLUSIONS: Lamivudine decreased markers of hepatic stellate cell activation and collagen synthesis. Immunohistochemical techniques are sensitive for assessing fibrogenesis and will be useful in trials of antiviral and antifibrotic agents.

Eosinophilic granuloma of the liver: a characteristic lesion with relationship to visceral larva migrans.

Children with the clinical syndrome of visceral larva migrans as a result of Toxocara species have typical lesions in the liver and other viscera, consisting of palisading granulomas that contain numerous eosinophils and often Charcot-Leyden crystals; recognizable parasites are uncommon. Similar eosinophilic granulomas that are found incidentally in adults often cause diagnostic problems. To define better the clinical, laboratory, and pathologic features of these lesions, we reviewed 43 cases of hepatic eosinophilic granuloma (excluding cases of Langerhans' cell histiocytosis) collected in the files of the AFIP over a period of 31 years. The eosinophilic granulomas were found in patients of all ages (range 12 months to 77 years); 30% were younger than 20 years. There were 26 male and 17 female patients. Most patients (26 of 43; 60%) were asymptomatic, and the lesions were discovered incidentally. Others had fever (20%) or abdominal pain (20%). The granulomas were typically multiple (61%), with central necrosis surrounded by a mixed inflammatory infiltrate with numerous eosinophils and variable numbers of neutrophils. lymphocytes, and a palisade of epithelioid histiocytes and/or giant cells. Charcot-Leyden crystals were present in 19 cases (44%). Remnants of parasites (eight Toxocara sp., two Capillaria sp.) were identified in the tissue in 10 patients. There was a positive serologic test for Toxocara sp. in five additional cases. Immunohistochemical staining using polyclonal antiserum against Toxocara canis larvae demonstrated positivity in macrophages in eight of 13 cases tested. We conclude that identification of an eosinophilic granuloma in the liver should suggest the diagnosis of visceral larva migrans and prompt a search for the causative organism with serial sectioning of the block and serologic tests for Toxocara and other causative parasites.

Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.

BACKGROUND: A sustained virological response (SVR) rate of 41% has been achieved with interferon alfa-2b plus ribavirin therapy of chronic hepatitis C. In this randomised trial, peginterferon alfa-2b plus ribavirin was compared with interferon alfa-2b plus ribavirin. METHODS: 1530 patients with chronic hepatitis C were assigned interferon alfa-2b (3 MU subcutaneously three times per week) plus ribavirin 1000-1200 mg/day orally, peginterferon alfa-2b 1.5 microg/kg each week plus 800 mg/day ribavirin, or peginterferon alfa-2b 1.5 microg/kg per week for 4 weeks then 0.5 microg/kg per week plus ribavirin 1000-1200 mg/day for 48 weeks. The primary endpoint was the SVR rate (undetectable hepatitis C virus [HCV] RNA in serum at 24-week follow-up). Analyses were based on patients who received at least one dose of study medication. FINDINGS: The SVR rate was significantly higher (p=0.01 for both comparisons) in the higher-dose peginterferon group (274/511 [54%]) than in the lower-dose peginterferon (244/514 [47%]) or interferon (235/505 [47%]) groups. Among patients with HCV genotype 1 infection, the corresponding SVR rates were 42% (145/348), 34% (118/349), and 33% (114/343). The rate for patients with genotype 2 and 3 infections was about 80% for all treatment groups. Secondary analyses identified bodyweight as an important predictor of SVR, prompting comparison of the interferon regimens after adjusting ribavirin for bodyweight (mg/kg). Side-effect profiles were similar between the treatment groups. INTERPRETATION: In patients with chronic hepatitis C, the most effective therapy is the combination of peginterferon alfa-2b 1.5 microg/kg per week plus ribavirin. The benefit is mostly achieved in patients with HCV genotype 1 infections.

A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C.

This international, randomized, active-controlled, parallel-group, double-blind dose-finding study compared peginterferon alfa-2b (PegIntron) to interferon alfa-2b for the initial treatment of compensated chronic hepatitis C. We randomly assigned 1,219 subjects to receive either the standard three-times-weekly (TIW) interferon alfa-2b dose (3 MIU) or the once-weekly (QW) peginterferon alfa-2b (0.5, 1.0, or 1.5 microg/kg). Subjects were treated for 48 weeks and then followed for an additional 24 weeks. All 3 peginterferon alfa-2b doses significantly (P < or =.042) improved virologic response rates (loss of detectable serum HCV RNA) after treatment and after follow-up, as compared with interferon alfa-2b. Unlike the end-of-treatment virologic response, the sustained virologic response rate was not dose-related above 1.0 microg/kg peginterferon alfa-2b because of a higher relapse rate among patients treated with 1.5 microg/kg peginterferon alfa-2b, particularly among patients infected with genotype 1. All 3 peginterferon alfa-2b doses decreased liver inflammation to a greater extent than did interferon alfa-2b, particularly in subjects with sustained responses. No new adverse events were reported, and the majority of adverse events and changes in laboratory values were mild or moderate. In conclusion, peginterferon alfa-2b maintained (0.5 microg/kg) or surpassed (1.0, 1.5 microg/kg) the clinical efficacy of interferon alfa-2b while preserving its safety profile. The higher rate of virologic response during treatment with 1.5 microg/kg peginterferon alfa-2b in patients infected with genotype 1 and high viral levels warrants further evaluation.

Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c.

BACKGROUND AIMS: In hepatitis C there is controversy over the linearity of the rate of progression and the significance of gender, mode of infection and viral factors. METHODS: 2313 untreated patients with a reliable estimated duration of infection and liver fibrosis were included. Fibrosis progression was calculated using the Kaplan-Meier method and the rate of fibrosis progression using the hazard function. Seven risk factors were assessed: age at biopsy, gender, alcohol consumption, mode of infection, activity grade, hepatitis C virus genotype and RNA level. RESULTS: The percentage of patients without cirrhosis was 91% after 20 years of infection (95% CI:90-92%) and 56% after 40 years (95% CI:48-64%). Three independent factors were associated (P < 0.001) with a faster progression rate: age at infection, alcohol consumption of 50 g or more per day, and male gender. The mode of infection, histologic activity, genotype and viral load were not independently associated with fibrosis. Fibrosis progression was mainly dependent on age and the duration of infection and can be divided into four successive periods with very slow, slow, intermediate and rapid progression rates. CONCLUSION: In patients infected with hepatitis C, the majority of fibrosis progression occurred in those aged fifty years or older.

Interferon alpha 2B and ribavirin in severe recurrent cholestatic hepatitis C.

Severe recurrent cholestatic hepatitis C after liver transplantation has a poor prognosis and no standard therapy is currently available. Four cases of severe recurrent cholestatic hepatitis C treated with a combination of interferon alpha 2b and ribavirin are described. All four patients were transplanted for hepatitis C-related cirrhosis. The mean age at transplantation was 45 years (range 41-51 years). Three of the patients were male and one was female. All four patients had hepatitis C virus viremia before and after liver transplantation. At 2 to 23 months after liver transplantation, all four patients developed jaundice, cholestatic elevation of liver enzymes, and histopathology consistent with severe recurrent cholestatic hepatitis C. Combination of interferon and ribavirin was given with prompt virological suppression. Despite this rapid viral suppression, all four patients developed progressive graft failure with three deaths.

Hepatic decompensation associated with lamivudine: a case report and review of lamivudine-induced hepatotoxicity.

We report a case of a 62-yr-old man with chronic hepatitis B virus (HBV)-related cirrhosis who developed hepatic decompensation after being started on lamivudine requiring liver transplantation. Decompensated liver disease while on lamivudine has been previously reported on two occasions, both HIV coinfected patients on a combination of nucleoside analogues. Our patient is alive and well nearly 2 yr after successful liver transplantation.

Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: A National Heart, Lung, and Blood Institute collaborative study.

Persons with non-A, non-B hepatitis (cases) identified in 5 transfusion studies in the early 1970s have been followed ever since and compared for outcome with matched, transfused, non-hepatitis controls from the same studies. Previously, we reported no difference in all-cause mortality but slightly increased liver-related mortality between these cohorts after 18 years follow-up. We now present mortality and morbidity data after approximately 25 years of follow-up, restricted to the 3 studies with archived original sera. All-cause mortality was 67% among 222 hepatitis C-related cases and 65% among 377 controls (P = NS). Liver-related mortality was 4.1% and 1.3%, respectively (P =.05). Of 129 living persons with previously diagnosed transfusion-associated hepatitis (TAH), 90 (70%) had proven TAH-C, and 39 (30%), non-A-G hepatitis. Follow-up of the 90 TAH-C cases revealed viremia with chronic hepatitis in 38%, viremia without chronic hepatitis in 39%, anti-HCV without viremia in 17%, and no residual HCV markers in 7%. Thirty-five percent of 20 TAH-C patients biopsied for biochemically defined chronic hepatitis displayed cirrhosis, representing 17% of all those originally HCV-infected. Clinically evident liver disease was observed in 86% with cirrhosis but in only 23% with chronic hepatitis alone. Thirty percent of non-A, non-B hepatitis cases were unrelated to hepatitis viruses A,B,C, and G, suggesting another unidentified agent. In conclusion, all-cause mortality approximately 25 years after acute TAH-C is high but is no different between cases and controls. Liver-related mortality attributable to chronic hepatitis C, though low (<3%), is significantly higher among the cases. Among living patients originally HCV-infected, 23% have spontaneously lost HCV RNA.

Hemochromatosis (HFE) gene sequence analysis of formalin-fixed, paraffin-embedded liver biopsy specimens.

BACKGROUND: Hereditary hemochromatosis (HH) is a common disease predominantly characterized by mutations of the HFE gene. METHODS AND RESULTS: We investigated the utility of HFE gene sequence analysis in the diagnosis of HH in 61 prospectively accrued formalin-fixed, paraffin-embedded liver biopsy specimens with clinical or histologic features suggestive of HH. Mutations in codons 63 or 282 of the HFE gene were identified by direct sequencing; in 21 of these samples, quantitative hepatic iron testing was also performed. Changes characteristic of HH were present in 16 (26%) of the cases, and 54% of the cases showed HFE gene mutations. The most common alteration was homozygous mutation of codon 282 (11 cases, 18%), followed by the combined 63 + 282 heterozygous mutation (3 cases, 5%). Two cases (3%) showed biallelic mutation of codon 63. The other 28 cases (46%) showed no sequence abnormalities. Weak iron staining did not exclude HH; intense staining did not reliably predict HH. CONCLUSION: When HH is clinically and/or histologically suspected, HFE gene sequencing of formalin-fixed, paraffin-embedded liver biopsy specimens is a rapid and cost-effective approach to genotypic diagnosis of HH.

Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C.

The extent of liver fibrosis is an important prognostic factor in patients infected with hepatitis C virus. Administration of a combination of interferon and ribavirin produces a superior viral clearance response rate than interferon alone. The effect of this combination regimen on hepatic fibrosis has not been established. To determine the impact of combination regimen or interferon alone on the progression of liver fibrosis we pooled individual data of 1,509 patients with pretreatment and post-treatment biopsies from 3 randomized trials. Fibrosis progression and regression rates between biopsies were calculated by the Kaplan-Meier method and by the fibrosis progression rate per year. The percentage of patients without significant fibrosis (stage 0 or 1) at 96 weeks was 68 +/- 4% (mean +/- SE) when treated by combination regimen for 48 weeks, 64 +/- 4% by interferon alone for 48 weeks, 42 +/- 7% by combination regimen for 24 weeks (lower than both 48-week regimens P <.001), and 24 +/- 9% interferon alone for 24 weeks (lower than the combination regimen for 24 weeks; P =.02). Three factors were independently associated with fibrosis reduction: sustained viral response, duration of treatment, and baseline fibrosis stage (all P <.001 in proportional hazards regression model). These results show that interferon and ribavirin combination therapy significantly reduces the rate of fibrosis progression in patients with hepatitis C. This effect was most prominent in patients who achieved a virologic response, those receiving 48 weeks of therapy, and in patients with significant fibrosis at baseline.

Clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres: a novel member of the perivascular epithelioid clear cell family of tumors with a predilection for children and young adults.

The perivascular epithelioid cell family of tumors (PEComas), defined by their co-expression of melanocytic and muscle markers, includes angiomyolipoma, lymphangioleiomyoma, and clear cell "sugar" tumors of the lung, pancreas, and uterus. We present seven cases of a unique and previously unrecognized tumor of children and young adults, which represents a new addition to the PEComa group of tumors. Culled from three institutions over a 50-year period, all cases occurred in or immediately adjacent to the ligamentum teres and falciform ligament. Six patients were female and one male; their ages ranged from 3 to 21 years (median, 11 yrs). Tumor sizes ranged from 5 to 20 cm (median, 8 cm). All cases consisted of clear to faintly eosinophilic spindled cells arranged in fascicular and nested patterns. The cells had small but distinct nucleoli and low mitotic activity. Immunohistochemically, all cases were positive with antibodies to gp100 protein (HMB-45) and negative for S-100 protein. In three of the seven cases studied immunohistochemically, the tumors expressed smooth muscle actin, melan-A, microphthalmia transcription factor (MiTF), and myosin, but not desmin. No expression of the TSC2 gene product, tuberin, was seen in three cases. One case studied cytogenetically disclosed a t(3;10). Follow-up data, available in six of seven cases (median duration, 18 mos), showed five patients to be free of disease and one to have a radiographically presumed lung metastasis. We think these tumors comprise a new entity for which we propose the term "clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres." The differential diagnosis of these tumors includes clear cell sarcoma of tendons and aponeuroses, leiomyosarcoma, and angiomyolipoma.