Point Shear Wave Elastography for Assessing Liver Stiffness in Chronic Liver Diseases of Different Etiologies Compared to Biopsy.

BACKGROUND: Point shear-wave elastography (pSWE) is a new method to assess the degree of liver fibrosis. It has been shown to be effective in detecting stiffness in viral hepatitis. OBJECTIVES: To determine the feasibility of pSWE for assessing liver stiffness and fibrosis in liver diseases of different etiologies. METHODS: This prospective single-center study included a population of adult patients with chronic liver diseases from different etiologies, who were scheduled for liver biopsy, and a control group of healthy adults who prospectively underwent pSWE. Ten consecutive pSWE measurements of the liver were performed using a Philips iU22 ultrasound system. Stiffness degree was compared to liver biopsy results. Fibrosis degree was staged according to METAVIR scoring system. RESULTS: The study group was comprised of 202 patients who underwent liver biopsy and pSWE test and a control group consisting of 14 healthy adults who underwent pSWE for validation. In the study group, the median stiffness was 5.35 ± 3.37 kilopascal (kPa). The median stiffness for F0-1, F2, F3, and F4 as determined by liver biopsy results were 4.9 kPa, 5.4 kPa, 5.7 kPa, and 8 kPa, respectively. The median stiffness in the control group was 3.7 ± 0.6 kPa. Subgroup analyses were conducted for viral hepatitis vs. non-viral hepatitis and steatohepatitis vs. non-steatohepatitis groups. CONCLUSIONS: pSWE is a reproducible method for assessing liver stiffness and is in a linear relationship with fibrosis degree as seen in pathology. Compared with patients with non-significant fibrosis, healthy controls showed significantly lower values.

Histomorphometric Findings May Help Predicting Response in Patients with Chronic Liver Disease.

BACKGROUND: Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Several viral and host factors related to viral response have been reported in the era of treatment with pegylated (PEG)-interferon and ribavirin. OBJECTIVES: To quantify histological findings from patients with chronic HCV using computerized morphometry and to investigate whether the results can predict response to medical treatment with peg-interferon and ribavirin. METHODS: We followed 58 patients with chronic HCV infection with METAVIR score F1 and F2 in our liver unit who were grouped according to treatment response sustained viral response (SVR) and non-SVR. Liver needle biopsies from these patients were evaluated and histological variables, such as inflammatory cells, collagen fibers and liver architecture, were quantified using computerized morphometrics. The pathologist who performed the histomorphometric analysis was blinded to previous patient clinical and histological information. RESULTS: Histomorphometric variables including the density of collagen fibers were collected. The number of inflammatory cells in the portal space and textural variable were found to be statistically significant and could be used together in a formula to predict response to treatment, with a sensitivity of 93% and a 100% specificity. CONCLUSIONS: Histomorphometry may help to predict a patient's response to treatment at an early stage.

Non-invasive evaluation of a liver mass in a patient post splenectomy.

INTRODUCTION: Numerous conditions may cause liver lesions, solitary or multiple, benign or malignant. It can be crucial to establish the correct diagnosis. Splenosis is a rare condition that may result from the spillage of cells from the splenic pulp following abdominal trauma, accidental lesions to the spleen during operation or elective splenectomy. These splenic 'implants', which are often multiple, can be located anywhere in the peritoneal cavity, although they are most often found in the left upper quadrant of the abdomen. They may be confused with neoplasms or endometriosis, and may rarely be the cause of small bowel obstruction. CASE PRESENTATION: A 35-year-old man presented with a hepatic mass, and malignancy was suspected. After extensive investigation, it was diagnosed as splenosis using Tc-99m-labelled heat-denaturated red blood cells scintigraphy, without the need for liver biopsy. We consider this the most effective method for diagnosing splenosis. CONCLUSION: When splenosis is suspected, Tc-99m-labelled heat-denaturated red blood cells scintigraphy can be used to confirm the diagnosis, and may avoid invasive investigation.

Daclatasvir vs telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1.

AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin (pegIFN/RBV), in treatment-naive hepatitis C virus (HCV) genotype (GT) 1-infected patients. METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned (2:1) to daclatasvir vs telaprevir, stratified by IL28B rs12979860 host genotype (CC vs non-CC), cirrhosis status (compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype (GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus pegIFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus pegIFN/RBV; those without an extended rapid virologic response (eRVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of pegIFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus pegIFN/RBV followed by 12 (with eRVR) or 36 (no eRVR) wk of pegIFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12 (SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia (hemoglobin < 10 g/dL) and rash-related events, through week 12, were lower with daclatasvir + pegIFN/RBV than with telaprevir + pegIFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/mL, to investigate any link between NS5A polymorphisms associated with daclatasvir resistance and virologic outcome. RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups (6.0% and 8.2% in the GT1b and GT1a groups, respectively) than in the telaprevir groups (2.2% and 3.0%). Among GT1b-infected patients, daclatasvir plus pegIFN/RBV was noninferior to telaprevir plus pegIFN/RBV for SVR12 [85% (228/268) vs 81% (109/134); difference, 4.3% (95%CI: -3.3% to 11.9%)]. Anemia (hemoglobin < 10 g/dL) was significantly less frequent with daclatasvir than with telaprevir [difference, -29.1% (95%CI: -38.8% to -19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1a-infected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28B non-CC and cirrhosis - factors known to affect response to pegIFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients demonstrated that SVR12 was associated with IL28B host genotype (CC vs non-CC, P = 0.011) and cirrhosis status (absent vs present, P = 0.031). NS5A polymorphisms associated with daclatasvir resistance (at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4% (229/268) in the daclatasvir group, and by 85.1% (114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2% (90/134) and 69.7% (46/66), respectively. Discontinuations (of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria. CONCLUSION: Daclatasvir plus pegIFN/RBV demonstrated noninferiority to telaprevir plus pegIFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1b-infected patients, supporting the use of daclatasvir with other direct-acting antivirals.

Prognosis of primary sclerosing cholangitis in israel is independent of coexisting inflammatory bowel Disease.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a rare chronic progressive cholestatic disorder. We assessed its characteristics and natural history in Israel and compared its outcome with respect to coexisting inflammatory bowel disease (IBD). METHODS: Data on characteristics, course and outcome were retrospectively retrieved on patients diagnosed with PSC from five large Israeli medical centers between 1988 and 2012. Patients with isolated PSC were compared with those with coexisting IBD to identify predictors of outcome. RESULTS: Of 141 patients (56% males) with confirmed PSC, 98 (69.5%) had coexisting IBD. The average age at presentation was 38.8 ± 15.4 years and duration of follow-up was 7.93 ± 6.26 years. The crude estimated point prevalence was 4 cases per 105 persons. Demographics and clinical characteristics were similar among all patients except for symptoms at diagnosis (which were more prevalent among PSC­IBD patients) and utilization of multiple diagnostic modalities (which was more prevalent among isolated-PSC patients). More than one-third of the entire cohort had cirrhosis. A total of 15 patients (10.6%) died and 19 patients (13.5%) developed malignancy during follow-up. Nine patients (6.3%) underwent liver transplantation. Mean survival for the entire cohort was 26.3 ± 1.4 years and mean transplant-free survival was 23.5 ± 1.6 years. Cox proportional hazard regression for transplantation or death revealed two independent risk factors: cirrhosis and malignancy [hazard ratio 4.25 (p = 0.004) and 2.58 (p = 0.046), respectively]. CONCLUSIONS: Survival rate of PSC patients in Israel is longer than reported rates worldwide and is independent of coexisting IBD.

Cellularized biosynthetic microhydrogel polymers for intravascular liver tissue regeneration therapy.

INTRODUCTION: The liver is the natural microenvironment for hepatocytes transplantation but unfortunately engraftment efficiency is low. Cell-laden microhydrogels made of fibrinogen attached to poly(ethylene glycol) (PEG)-diacrylate side chains, were used as a cell carrier, for intravascular transplantation. This approach may reduce shear stress and immediate immunological pressure after intravascular transplantation and provide biomatrix for environmental support. AIMS: In vitro assessment of HuH-7 viability and function after polymerization within PEGylated fibrinogen-hydrogel. In vivo assessment of intraportal transplantation of cell-laden microhydrogels with rat adult parenchymal cells. METHODS: (1) In vitro assessment of HuH-7 cell viability and function, after cell-laden hydrogel (hydrogel volume 30 µL) fabrication, by propidium iodide (PI)/fluorescein diacetate (FDA), and MTT assays, albumin concentration and CYP1A activity. (2) Fabrication of cell-laden microhydrogels and their intraportal transplantion. Engraftment efficiency in vivo was evaluated by real-time qPCR of Y chromosome (SRY gene) and histology. RESULTS: The viability of cells in hydrogels in culture was comparable to viability of not embedded cells during the first 48 h. However, the viability of cells in hydrogels was reduced after 72 h compared with not embedded cells. Activity of CYP1A in hydrogel was comparable to that of not embedded cells (4.33±1 pmole/µg DNA/4 h vs. 5.13±1 pmole/µg DNA/4 h, respectively). Albumin concentration increased at day 3 in hydrogels to 1.4±0.6 µg/10(4)/24 h and was greater to that of free cells, 0.3±0.1 µg/10(4)/24 h. Cell-laden microhydrogels at a size of 150-150-600 µm (6×10(6) cells/rat) showed better engraftment efficiency at 21 days post-transplantation, compared with isolated cell transplantation (54.6%±5% vs. 1.8%±1.2%, p<0.001). CONCLUSIONS: The in vitro HuH-7 viability and function after polymerization in PEGylated fibrinogen hydrogel was comparable to cells without the hydrogel. Long-term survival and engraftment efficiency of intravascular transplanted adult hepatocytes is much better in within cell-laden microhydrogels compared with isolated cells. The overall efficiency of the procedure needs to be improved.

ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV.

BACKGROUND: The interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and dasabuvir with or without ribavirin has shown efficacy in inducing a sustained virologic response in a phase 2 study involving patients with hepatitis C virus (HCV) genotype 1 infection. We conducted two phase 3 trials to examine the efficacy and safety of this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. METHODS: We randomly assigned 419 patients with HCV genotype 1b infection (PEARL-III study) and 305 patients with genotype 1a infection (PEARL-IV study) to 12 weeks of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight or to matching placebo for ribavirin. The primary efficacy end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) 12 weeks after the end of treatment. RESULTS: The study regimen resulted in high rates of sustained virologic response among patients with HCV genotype 1b infection (99.5% with ribavirin and 99.0% without ribavirin) and among those with genotype 1a infection (97.0% and 90.2%, respectively). Of patients with genotype 1b infection, 1 had virologic failure, and 2 did not have data available at post-treatment week 12. Among patients with genotype 1a infection, the rate of virologic failure was higher in the ribavirin-free group than in the ribavirin group (7.8% vs. 2.0%). In both studies, decreases in the hemoglobin level were significantly more common in patients receiving ribavirin. Two patients (0.3%) discontinued the study drugs owing to adverse events. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS: Twelve weeks of treatment with ABT-450/r-ombitasvir and dasabuvir without ribavirin was associated with high rates of sustained virologic response among previously untreated patients with HCV genotype 1 infection. Rates of virologic failure were higher without ribavirin than with ribavirin among patients with genotype 1a infection but not among those with genotype 1b infection. (Funded by AbbVie; PEARL-III and PEARL-IV ClinicalTrials.gov numbers, NCT01767116 and NCT01833533.).

The combination of MK-5172, peginterferon, and ribavirin is effective in treatment-naive patients with hepatitis C virus genotype 1 infection without cirrhosis.

BACKGROUND & AIMS: MK-5172 is an inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A protease; MK-5172 is taken once daily and has a higher potency and barrier to resistance than licensed protease inhibitors. We investigated the efficacy and tolerability of MK-5172 with peginterferon and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection without cirrhosis. METHODS: We performed a multicenter, double-blind, randomized, active-controlled, dose-ranging, response-guided therapy study. A total of 332 patients received MK-5172 (100, 200, 400, or 800 mg) once daily for 12 weeks in combination with PR. Patients in the MK-5172 groups received PR for an additional 12 or 36 weeks, based on response at week 4. Patients in the control group (n = 66) received a combination of boceprevir and PR, dosed in accordance with boceprevir's US product circular. RESULTS: At 24 weeks after the end of therapy, sustained virologic responses were achieved in 89%, 93%, 91%, and 86% of the patients in the groups given the combination of PR and MK-5172 (100, 200, 400, or 800 mg), respectively, vs 61% of controls. In the MK-5172 group receiving 100 mg, 91% of patients had undetectable levels of HCV RNA at week 4 and qualified for the short duration of therapy. The combination of MK-5172 and PR generally was well tolerated. Transient increases in transaminase levels were noted in the MK-5172 groups given 400 and 800 mg, at higher frequencies than in the MK-5172 groups given 100 or 200 mg, or control groups. CONCLUSIONS: Once-daily MK-5172 (100 mg) with PR for 24 or 48 weeks was highly effective and well tolerated among treatment-naive patients with HCV genotype 1 infection without cirrhosis. Studies are underway to evaluate interferon-free MK-5172-based regimens. ClinicalTrials.gov number: NCT01353911.

Spontaneous bacterial peritonitis with a very high leukocyte count in ascitic fluid caused by Haemophilus influenzae.

We report on a case of spontaneous bacterial peritonitis (SBP) due to Haemophilus influenzae (H. influenzae) in an elderly patient with alcoholic cirrhosis. The patient presented with a 5 day history of fever, cough, and fatigue. Abdominal paracentesis revealed a very high neutrophil count (134,800 cells/µL). Secondary peritonitis and abdominal abscess were ruled out. Peritoneal fluid culture displayed the growth of H. influenzae. The patient was treated with ceftriaxone and showed signs of improvement. Eventually, the patient died due to septic shock caused by other organisms. H. influenzae is a very rare cause of SBP. This case report demonstrates that (1) H. influenzae should be considered a potential cause of SBP, and (2) a very high leukocyte count in ascitic fluid can be found in patients with SBP.

Metformin-induced mixed hepatocellular and cholestatic hepatic injury: case report and literature review.

INTRODUCTION: Metformin is a first-line drug choice for the treatment of type 2 diabetes mellitus (DM-2). Metformin-induced hepatotoxicity has rarely been reported. We report on a case of metformin-induced mixed hepatocellular and cholestatic liver injury in an elderly patient with DM-2 as well as review and summarize case reports of metformin hepatotoxicity available in English on the PubMed database. CASE: After receiving metformin 850 mg/day for 2 weeks, a 78-year-old male presented with a 10-day history of abdominal pain, vomiting, diarrhea, and jaundice. Laboratory analysis showed severe hepatocellular and cholestatic hepatic injury. Other causes for acute liver injury were ruled out. Discontinuation of metformin treatment led to significant subjective improvement after 1 week, and all hepatic abnormalities resolved by 2 months. CONCLUSION: Metformin is an important drug for the treatment of DM-2, which is also used for treatment of patients with fatty liver. It can, however, induce hepatocellular and cholestatic hepatic injury; both physicians and patients should be aware of this potential side effect.

Budesonide versus prednisone with azathioprine for the treatment of autoimmune hepatitis in children and adolescents.

OBJECTIVE: To compare the effect of budesonide vs prednisone therapy both in combination with azathioprine in pediatric patients with autoimmune hepatitis (AIH). STUDY DESIGN: Forty-six patients with AIH (11 males and 35 females) aged 9-17 years were enrolled in a 6-month, prospective, double-blind, randomized, active-controlled, multicenter phase IIb study evaluating budesonide (n = 19; 3 mg twice or 3 times daily) vs prednisone (n = 27; 40 mg/day tapered to 10 mg/day), both with azathioprine (1-2 mg/kg/day), followed by a further 6 months of open-label budesonide therapy. The primary efficacy endpoint was complete biochemical remission (normal serum alanine aminotransferase and aspartate aminotransferase levels) without predefined steroid-specific side effects. RESULTS: We observed no statistically significant difference in the percentage of patients who met the primary endpoint between the budesonide (3 of 19; 16%) and prednisone groups (4 of 27; 15%) after 6 months, nor in the percentage of patients who experienced biochemical remission (budesonide, 6 of 19 [32%]; prednisone, 9 of 27 [33%]), lack of steroid-specific side effects (budesonide, 10 of 19 [53%]; prednisone, 10 of 27 [37%]). The mean weight gain was 1.2 ± 3.5 kg in the budesonide group and 5.1 ± 4.9 kg in the prednisone group (P = .006). A total of 42 patients received open-label budesonide treatment for another 6 months. After 12 months, 46% of these patients achieved complete remission. CONCLUSION: Oral budesonide with azathioprine can induce and maintain remission in pediatric patients with AIH and may be considered an alternative therapy to prednisone. The treatment causes fewer side effects and does not lead to weight gain; however, it may be less effective than prednisone in inducing remission.

Periodontal status in post-liver transplantation patients: 10 years of follow-up.

OBJECTIVE: To compare the current (t1) periodontal status of post-liver transplantation patients to their status 10 years earlier (t0). METHOD AND MATERIALS: Seventeen patients 45 to 71 years of age who were evaluated approximately 10 years previously were enrolled in the study. All subjects had undergone a liver transplantation 1 to 10 years prior to the initial examination (t0). Clinical and radiographic parameters were recorded for the Ramfjord Index teeth and compared between t0 and t1, including Plaque Index (PI), Gingival Index (GI), probing depth (PD), clinical attachment level (CAL), and gingival overgrowth (GO). Bone loss was measured on digitized images of panoramic radiographs. RESULTS: Mean PI, GI, CAL, and GO were slightly lower at t1 than at t0; however, these differences were not statistically significant (P > .05, Student t test for paired observations). The mean PD was reduced at t1 (2.43 ± 0.18 mm) compared with t0 (3.35 ± 0.22 mm), which was statistically significant (P = .001, Student t test for paired observations). To the contrary, the mean radiographic bone loss at t1 was higher than at t0 (5.61 vs 4.48 mm, respectively), which was also statistically significant (P = .017). Tooth loss was observed in some of these patients, ranging from 0 to 4 during the 10 years of follow-up, which amounted to an annual rate of 0.24 teeth per patient. CONCLUSION: Post-liver transplantation patients maintained stable clinical periodontal parameters during a 10-year period; however, some radiographic bone loss occurred during this time.

Heparanase accelerates the proliferation of both hepatocytes and endothelial cells early after partial hepatectomy.

BACKGROUND AND AIMS: Heparanase (HPSE) is an endo-ß-D-glucuronidase, which cleaves heparan sulfate in the extracellular matrix (ECM) and has pro-angiogenic and pro-proliferative properties. The aim of this investigation was to study the effect of HPSE on hepatocytes and endothelial cells (EC) during liver regeneration. METHODS: Following 70% hepatectomy (PHP), rats were injected daily with 1-50µg HPSE/rat. Liver samples were stained with H&E and anti-bromodeoxyuridine (BrdU) antibody. mRNAs of hepatocyte growth factor (HGF), stem cell factor, tumor necrosis factor (TNF)-α, interleukin(IL)-6, and cyclinD1 were tested by real-time qPCR. Matrix metalloproteinases (MMPs) were tested by gel zymography. RESULTS: Compared to the saline control, HPSE increased hepatocyte proliferation 24h, 48h and 72h after PHP, with the maximal effect found at 24h with 50µg HPSE (40.9±2.5% vs. 8.6±4.3%, p<0.01 for BrdU staining; 5.5±0.9% vs. 0.8±0.5%, p<0.05 for mitosis). Proliferation of the sinusoidal and the portal vein radical ECs was also increased (p<0.05). HPSE caused a twofold increase in cyclinD1 mRNA (p<0.05) and in pro-MMP-9 levels (p<0.05). HPSE at all doses also caused significant reductions of TNF-α mRNA (p<0.05) and IL-6 mRNA, and no change in HGF mRNA. CONCLUSIONS: HPSE enhances liver regeneration by inducing proliferation of hepatocytes and both sinusoidal and vascular ECs. Since the effect of HPSE on hepatocytes occurred earlier than that observed in ECs, this effect is not related to HPSE's effect on ECs. The mechanism of HPSE action is probably indirect and is mediated by HPSE-dependent ECM cleavage and the release of pre-existing enzymes.

[Outcome of treatment with peg-interferon and ribavirin in HIV-HCV co-infected patients: "real life" single center experience].

BACKGROUND AND AIM: Recently, with the emergence of highly effective antiretroviral treatment (ART), chronic liver disease has become the leading cause of morbidity and mortality in co-infected HIV-HCV (Human immunodeficiency virus-Hepatitis C virus) patients. The overall SVR rate in this population remains unsatisfactory. The aim of this study was to evaluate the response to therapy in HIV-HCV co-infected patients in a single center. PATIENTS AND METHODS: Consecutive HIV-HCV co-infected patients were evaluated in the liver clinic between 2003 -2010. Liver needle biopsy was conducted in 100% of the patients. The patients were treated by a multidisciplinary team consisting of immunologists, hepatologists, social workers and nurses and a close follow-up was conducted. The 48 weeks duration of peg-interferon and ribavirin combination was used for all genotypes according to recent guidelines. Weight-adjusted ribavirin doses were applied. Treatment was initiated after stabilization of HIV parameters and successful weaning from drug and alcohol addiction. RESULTS: A total of 86 out of 143 HIV- HCV co-infected patients, were evaluated; 39 completed treatment. Of those 31 (77%) achieved SVR. Out of 22 genotype 1 patients, 18 (82%) achieved SVR. Six patients had spontaneous viral clearance and 8 are still receiving treatment. In 17 non-one genotype patients, the SVR rate was 76.4% (13 of 17 patients); 6 patients were defined as relapsers and non-responders. Overall adherence to the treatment was high. CONCLUSION: Measures, such as the use of a multidisciplinary approach, high adherence of physicians to the guidelines, weight-based ribavirin dose, and selecting patients who are ready to start therapy, can significantly improve the SVR rate in this difficult-to-treat patient population.

Prophylactic analgesia before percutaneous liver biopsy: a clinical comparative study.

INTRODUCTION: Liver biopsy remains the gold standard for the diagnosis and staging of liver diseases. Despite being painful, analgesia before liver biopsy is usually avoided due to the notion that pain is minor and due to the concern of masking possible abdominal symptoms. Postbiopsy pain levels were previously mapped for the purpose of analgesia planning. AIM: To compare pain and anxiety levels between two prophylactic treatment regimens, a combination of sublingual tramadol Hcl with oral lorazepam and oral diazepam only. PATIENTS AND METHODS: One hundred and thirteen consecutive patients were selected to receive either prophylactic analgesia with sublingual tramadol Hcl (50 mg) flashtabs and oral lorazepam [(1 mg) analgesia group (AG), n=56] or oral diazepam (5 mg) alone [nonAG (NAG), n=57]. Pain and anxiety levels were assessed using Visual Analogue Scale (1-10) and State Anxiety Inventory, respectively, 30 min before, and 30 min and 6 h after the biopsy. RESULTS: The groups were comparable with respect to baseline characteristics. Thirty minutes after the procedure, pain levels were significantly lower in the AG (mean Visual Analogue Scale ± standard error of the mean, 1.8 ± 0. 3; median=1) compared with the NAG (3.1 ± 0.3, median=3; P<0.005). Patients in the NAG (13.8%), reported high pain intensities (>7) compared with the patients in the AG (3.6%; P=0.09). Six hours after the procedure, pain intensity remained significantly lower in the AG compared with the NAG (0.8 ± 0.1 vs. 1.5 ± 0.2; P<0.005). Anxiety levels were comparable. CONCLUSION: Prophylactic combination of short-acting tramadol and lorazepam is effective, safe, and can be used routinely before liver biopsy.

Gaucher's disease type I: a disease masked by the presence of abnormal laboratory tests common to primary liver disease.

Gaucher's disease (GD) may go undiagnosed for many years, leading to severe complications that are preventable or reversible by enzyme replacement therapy with imiglucerase. GD is associated with cytopenia, bone complications, hepatosplenomegaly, hypermetabolism, and hyperactivity of the immune system manifested by polyclonal hyper gamma-globulinemia and an increased incidence of monoclonal gammopathies. High ferritin and presence of autoimmune antibodies may present and because of these abnormalities, clinical similarities with primary liver diseases may occur. We report on two patients who suffered diagnostic delay that could potentially lead to life-threatening manifestations of GD. Potential complications include: avascular necrosis, severe bleeding, chronic bone pain, life-threatening sepsis, pathologic fractures, growth failure, and liver pathology. Physician awareness will increase the likelihood of prompt detection of GD and improve its management.

Sustained virologic response to treatment in 100% of patients recently infected, nosocomially, with HCV genotype 2.

OBJECTIVE: In 2003, a cluster of hepatitis C virus (HCV)-infected patients with a common history of a surgical procedure, performed during 2001 to 2003, was identified in a medical center. An epidemiologic investigation linked a physician, infected with HCV genotype 2, as the possible source of infection in 35 patients. The evaluation, therapy, and outcome of this unique cohort are presented. DESIGN: HCV-RNA was isolated from sera of all patients and the double-stranded phosphorylation homology domain region was sequenced. After a routine clinical investigation 33 patients were offered antiviral therapy. Two patients were not treatment candidates due to old age and comorbidity. RESULTS: Twenty-two (66%) were women. The mean age was 48.5+/-16.9 years. Alanine aminotransferase level was 117+/-135 IU/L. Thirty patients were treated with pegylated interferon alpha 2a, 1 with pegylated interferon alpha 2b, and 1 with standard interferon. All received ribavirin 800 mg daily. One patient refused to be treated and was lost for follow-up. Time from acquisition of disease to initiation of therapy was 14.8+/-4.9 month (5.5 to 26). Therapy duration was 24 weeks except for 1 patient who stopped therapy after 16 weeks. Sustained virologic response was achieved in all 32 treated patients. The sequence motif of the phosphorylation homology domain region, studied in all patients, predicted good response to interferon. CONCLUSIONS: Our excellent results can be explained by a constellation of favorable viral characteristics, a short-term disease and adherence to therapy.

Growth hormone-stimulated IGF-1 generation in cirrhosis reflects hepatocellular dysfunction.

BACKGROUND/AIMS: Previous studies reported decreased serum IGF-1 levels in cirrhosis. We aimed to correlate GH-stimulated IGF-1 responses with both MELD and Child-Pugh scores and determine the impact of portal hypertension and nutrition on IGF-1 responses. METHODS: Fifty-three patients (56+/-2 yrs) with cirrhosis were enrolled. Serum IGF-1 levels were measured by RIA before and 24h after a single injection of GH (0.06 mg/kg). RESULTS: Compared to controls, basal IGF-1 levels were significantly decreased in patients with cirrhosis (17.3+/-6.3 vs 13.6+/-5.1, P<0.001). Increments in IGF-1 levels were significantly lower in cirrhotic patients (controls: 133% vs 49% in MELD score <10, 38% in MELD score 11-18, and 13% in MELD score 19-24, p<0.001). 37% of patients had blunted IGF-1 responses. Increments in IGF-1 levels correlated with albumin (r=0.6), portal congestive index (r=0.4), and MAMC (r=0.25). By multivariate analysis, only CP (OR 5.7) and MELD scores (OR 4.5) accurately differentiated between blunted or non-blunted IGF-1 responses and not portal hypertension (OR 0.9) or malnutrition (OR 1.35). CONCLUSIONS: Cirrhosis is associated with low IGF-1 levels and an attenuated response to exogenous GH. These findings correlate better with the extent of hepatic dysfunction rather than the presence of portal hypertension or malnutrition.

Heparanase enhances early hepatocyte inclusion in the recipient liver after transplantation in partially hepatectomized rats.

Hepatocyte transplantation is an emerging approach for the treatment of liver diseases. However, broad clinical application of this method has been limited by restricted source of cells and low efficiency of cell integration within the recipient liver. Heparanase cleaves heparan sulfate proteoglycans in the extracellular matrix and basement membrane, activity that affects cellular invasion associated with cancer metastasis and inflammation. This activity has a multifunctional effect on cell-cell interaction, cell adhesion, and angiogenesis. All these factors are important for successful integration of transplanted hepatocytes. Male donor hepatocytes pretreated with heparanase or untreated were transplanted into recipient female rat spleen following partial hepatectomy. Engraftment efficacy was evaluated by PCR for Y chromosome, histology and PCNA, and heparanase immunohistochemistry. In addition, proliferative activity of hepatocytes in vitro was determined by bromodeoxyuridine immunostaining. The number of heparanase-treated cells detected in the recipient liver was significantly increased three- to fivefold within 24-48 h posttransplantation and twofold at 14 days compared with untreated cells. The transplanted hepatocytes treated with heparanase were clearly seen inside portal vein radicles as cell aggregates up to 72 h posttransplantation. The number of portal radicles filled with heparanase-treated hepatocytes was increased compared to control early after transplantation. Heparanase treatment enhanced hepatocyte and sinusoidal endothelial cell proliferation in the liver, and hepatocyte proliferation within the spleen tissue. Preliminary in vitro studies with isolated hepatocytes treated with heparanase showed increased proliferative activity within 24-48 h of cell culture. These results suggest that preincubation of hepatocytes with heparanase increases the presence of hepatocytes within the recipient liver early following cell transplantation and stimulates both hepatocyte and sinusoidal endothelial cell proliferation.