Complications of percutaneous liver biopsy with Klatskin needles: a 36-year single-centre experience.

BACKGROUND: Liver biopsy is the gold standard in evaluating liver diseases but is susceptible to complications. Safety data on aspiration needle biopsies remain limited. AIM: To evaluate the safety of percutaneous liver biopsy performed with Klatskin needle. METHODS: Clinical and biochemical data were retrospectively retrieved from sequential subjects who underwent liver biopsy with Klatskin needle from 1978 to 2015. Subjects with complications underwent thorough chart reviews for hospital course. RESULTS: Of 3357 biopsies performed, complications occurred in 135 (4%) biopsies with 33 (1%) resulting in major complications. Severe pain occurred in 78 (2.3%) subjects and bleeding occurred in 21 (0.6%) subjects. Biliary injury occurred in 8 (0.2%) biopsies. Three subjects died as a result of massive intraperitoneal bleeding. Compared to viral hepatitis, biopsies performed with certain diagnosis had significantly higher odds of major complications: NRH (OR: 17), DILI (OR: 20), GVHD (OR: 32) and HCC (OR: 34). Subjects with major complications had higher pre-biopsy median AP (153 vs. 78 U/L, P < 0.001), ALT (105 vs. 64 U/L, P < 0.05), AST (62 vs. 47 U/L, P < 0.02), along with marginally lower total bilirubin (1.0 vs. 0.7 mg/dL, P < 0.01) and albumin (3.7 vs. 4.0 g/dL, P < 0.001). By multivariate backward logistic regression, platelets ≤100 K/µL and aPTT >35 were independent risk factors of post-biopsy bleeding. CONCLUSION: Klatskin needle liver biopsies are safe with rare procedural morbidity. Our data suggests certain acutely ill subjects and those with systemic illnesses may be at higher risk of major complications. Clinicians should weigh the risks and benefits of liver biopsy in these patients with other alternative approaches.

Hepatic expression levels of interferons and interferon-stimulated genes in patients with chronic hepatitis C: A phenotype-genotype correlation study.

IFNL4 is linked to hepatitis C virus treatment response and type III interferons (IFNs). We studied the functional associations among hepatic expressions of IFNs and IFN-stimulated genes (ISGs), and treatment response to peginterferon and ribavirin. Type I IFNs (IFNA1, IFNB1), type II (IFNG), type III (IFNL1, IFNL2/3), IFNL4 and ISG hepatic expressions were measured by qPCR from in 65 chronic hepatitis C (CHC) patients whose IFNL4-associated rs368234815 and IFNL3-associated rs12989760 genotype were determined. There was a robust correlation of hepatic expression within type I and type III IFNs and between type III IFNs and IFNL4 but no correlation between other IFN types. Expression of ISGs correlated with type III IFNs and IFNL4 but not with type I IFNs. Levels of ISGs and IFNL2/3 mRNAs were lower in IFNL3 rs12979860 CC patients compared with non-CC patients, and in treatment responders, compared with nonresponders. IFNL4-ΔG genotype was associated with high ISG levels and nonresponse. Hepatic levels of ISGs in CHC are associated with IFNL2/3 and IFNL4 expression, suggesting that IFNLs, not other types of IFNs, drive ISG expression. Hepatic IFNL2/3 expression is functionally linked to IFNL4 and IFNL3 polymorphisms, potentially explaining the tight association among ISG expression and treatment response.

Long-term therapy of chronic delta hepatitis with peginterferon alfa.

BACKGROUND: Chronic delta hepatitis virus (HDV) infection rapidly progresses to cirrhosis. Treatment with peginterferon for up to 2 years is often without durable response. AIM: To examine the efficacy and safety of long-term peginterferon in achieving a durable response. METHODS: Treatment was initiated with 180 µg/week of peginterferon alfa-2a with titration to a maximal tolerable dose, for up to 5 years. Liver biopsies and hepatic venous pressure gradients (HVPG) were evaluated at baseline, 1, 3 and 5 years. The primary endpoint was histological improvement or loss of serum HDV and HBsAg at 3 years. RESULTS: Thirteen patients were treated for a median of 140 weeks (6-260) with an average peginterferon dose of 180 µg/week (90-270). At baseline, most had advanced disease (median Ishak fibrosis = 3) with portal hypertension (HVPG = 10.2 ± 6 mmHg). Five of 13 patients (39%) achieved the primary endpoint, with three seroconverting for HBsAg after 24, 37 and 202 weeks of treatment. Histological inflammation improved after 1 year, (median HAI: 10 vs. 7, P = 0.01) with persistence in 4/5 patients at 3 years (median HAI: 7.5). Greatest improvements occurred in the first year. Baseline bilirubin and HBsAg levels were significantly lower in virological responders than nonresponders. After 12 weeks, virological responders had a significant decline in HBsAg (1.5 log10 IU/mL, P = 0.05). CONCLUSION: Despite increased doses and duration of therapy, treatment of chronic HDV with peginterferon remains unsatisfactory. Quantitative measures of HBsAg may be an important biomarker of early response to peginterferon therapy in chronic delta hepatitis virus infection.

Long-term outcome of chronic hepatitis C after sustained virological response to interferon-based therapy.

BACKGROUND: Although the short-term benefits of a sustained virological response (SVR) to interferon-based therapies of chronic hepatitis C (CHC) are well known, the long-term consequences of SVR are less clear. AIM: To assess changes in markers of disease activity and fibrosis in patients followed up to 23 years post-SVR. METHODS: The first 103 SVR patients (from 1984 to 2003) at the National Institutes of Health Clinical Center were evaluated. Serum markers before treatment and at the last visit were compared. Evaluations after 2007 included transient elastography (TE). RESULTS: Of 103 patients, three subsequently relapsed 0.7, 6.3 and 6.5 years post therapy. The remaining 100 patients (56 men, mean age 56 years) maintained SVR at final follow-up. No patients developed hepatic decompensation, but one with pre-treatment cirrhosis died 12 years post SVR of hepatocellular carcinoma. In comparison to pre-treatment values, markers improved at follow-up, including mean ALT (152-27 U/L), AST (87-24 U/L), alkaline phosphatase (78-69 U/L), IgG (1463-1113 mg/dL), platelet count (209 000-239 000/µL) and AST to platelet count ratio index (APRI: 1.31-0.33). TE was performed in 69 patients and was normal (<7.0 kPA) in 60%, moderately elevated (7.1-13.8) in 31% and cirrhotic range (>13.8) in 9%. TE and platelet counts at follow-up correlated with fibrosis on pre-treatment liver biopsy (P < 0.001). CONCLUSIONS: In 97% of patients with CHC, SVR is durable without evidence of disease progression, although some degree of hepatic fibrosis may persist and patients with pre-treatment cirrhosis are at continuing low risk for hepatocellular carcinoma.

Randomised clinical trial: the benefit of combination therapy with adefovir and lamivudine for chronic hepatitis B.

BACKGROUND: Combination antiviral therapy holds the promise of increasing response rates while decreasing antiviral resistance, but has yet to be shown to be beneficial or necessary in chronic hepatitis B. AIM: To evaluate the benefit of combination therapy with adefovir and lamivudine versus adefovir alone in maintaining virological, biochemical and histological responses. METHODS: Patients with chronic hepatitis B with and without previous lamivudine therapy were randomised to receive adefovir alone (10 mg/daily) or adefovir and lamivudine (100 mg/daily) for up to 192 weeks. Study endpoints were (i) maintained virological (HBV DNA <500 copies/mL), biochemical and histological response, (ii) loss of HBeAg and (iii) loss of HBsAg. RESULTS: A total of 41 patients were enrolled, including 31 HBeAg -positive and 31 treatment-naïve subjects. 30 patients remained on assigned therapy at 192 weeks. The percentage of patients achieving a combined maintained response was higher in the combination than the monotherapy arm, both at week 48 (59% vs. 26%, P = 0.06) and 192 (68% vs. 31%, P = 0.03). At week 192, 76% of the combination vs. 36% of the monotherapy group had loss of HBeAg (P = 0.03). One patient receiving adefovir cleared HBsAg. Adefovir resistance developed in 6 of 19 (32%) monotherapy but none of 22 combination treated patients (P = 0.03). CONCLUSIONS: Extended combination therapy with lamivudine and adefovir is associated with a high rate of long-term virological and biochemical response. Adefovir monotherapy appears to be less effective mainly because of poor initial response and the ultimate development of antiviral resistance (www.Clinical. Trials.gov NCT00023309).

Low- and standard-dose peginterferon alfa-2a for chronic hepatitis C, genotype 2 or 3: efficacy, tolerability, viral kinetics and cytokine response.

BACKGROUND: Chronic infection with hepatitis C, genotype 2/3, responds better than other genotypes to peginterferon and ribavirin treatment. We hypothesized that a lower dose of peginterferon would be as effective, but less toxic than standard doses. AIM: To test the hypothesis that a lower dose of peginterferon would be as effective as, but less toxic than, standard doses. METHODS: A total of 30 patients were treated with low-dose peginterferon alfa-2a (90 microg/week) and 27 patients with standard doses (180 microg/week) for 24 weeks in combination with 800 mg/day of ribavirin. Patients who failed treatment were offered 48 weeks of standard-dose treatment. Viral and serum inducible protein 10 (IP-10) levels were measured and early viral kinetic parameters were calculated. RESULTS: Sustained virological response was achieved in 68% of the low-dose and 87% of the standard-dose patients (per protocol, P = 0.79 for non-inferiority). Re-treatment was successful in all patients who tolerated full dose and duration. The standard-dose group had greater first-phase declines of viral levels and faster time to negativity. The second-phase slope was not dose-dependent. IP-10 induction was significantly greater with the standard dose. Although fatigue and general feeling during treatment were worse for standard dose, haematological toxicity and depression did not differ between groups. CONCLUSION: A lower dose of peginterferon is associated with some symptomatic benefit, but the response is not equivalent to standard dosing.

Low weight predicts neutropenia and peginterferon alfa-2a dose reductions during treatment for chronic hepatitis C.

Treatment-induced neutropenia frequently complicates the treatment course of patients treated with pegylated interferon alfa and ribavirin for chronic hepatitis C. We investigated the effect of weight on the risk for dose reductions caused by neutropenia in patients treated with a weight-independent dose of peginterferon alfa-2a. We retrospectively analysed single centre data for 172 patients enrolled in a multi-centre, open-label trial of peginterferon alfa-2a and ribavirin for chronic hepatitis C. Low body weight was significantly associated with dose reductions due to neutropenia. Patients weighing less than 62 kg had a 35% risk for significant neutropenia as opposed to a 12% risk for heavier patients (P = 0.001), and this side-effect occurred earlier during treatment. Low weight was an independent risk factor by multivariate analysis (hazard ratio 0.956/kg). The risk for treatment-induced neutropenia was associated with body surface area more than with the body mass index. In conclusion, a low pre-treatment weight strongly predicts the need for peginterferon alfa-2a dose reductions. This apparently reflects overall body size more than body fat content. It is prudent to frequently monitor blood counts for smaller-sized patients, especially during the first weeks of treatment.

Predictive value of serum globulin levels for the extent of hepatic fibrosis in patients with chronic hepatitis B infection.

The mechanism underlying disease progression in hepatitis B virus (HBV) infection is unknown. Immunoglobulins stimulate the proliferative activity of rat hepatic stellate cells in vitro. A strong association was found between serum immunoglobulin levels and hepatic fibrosis in patients with hepatitis C virus infection. Our objective was to determine if the same index could also be used in patients with chronic HBV infection. The records of 100 patients with biochemical, serological, virological and histological evidence of chronic HBV infection were reviewed for background factors and serum globulin and immunoglobulin levels. Mean (+/-SD) patient age was 44.0 +/- 14.7 years; 80 (80%) were male. Of the factors found to be significant on univariate analysis, the only significant predictors of severe hepatic fibrosis (stage > or = 2) on multivariate analysis were serum globulin level [odds ratio (OR) 5.97, 95% confidence intervals (CI) 1.82-19.53, P = 0.0004], platelet count (OR 0.98, CI 0.97-0.99, P = 0.001), and immunoglobulin G (IgG) level (OR 1.003, CI 1.000-1.007, P < 0.042) but not IgA, alkaline phosphatase, albumin or international normalized ratio. For each increase of 0.33 mg/dL in serum globulin, there was a 0.5 point increase in the stage of hepatic fibrosis. There appears to be a strong association between levels of serum globulin and IgG and extent of hepatic fibrosis in patients with chronic HBV infection. They can serve as noninvasive markers of hepatic fibrosis and, if confirmed, have important implications for the management of patients with chronic HBV infection.

Relating cluster and population responses to natural sounds and tonal stimuli in cat primary auditory cortex.

Most information about neuronal properties in primary auditory cortex (AI) has been gathered using simple artificial sounds such as pure tones and broad-band noise. These sounds are very different from the natural sounds that are processed by the auditory system in real world situations. In an attempt to bridge this gap, simple tonal stimuli and a standard set of six natural sounds were used to create models relating the responses of neuronal clusters in AI of barbiturate-anesthetized cats to the two classes of stimuli. A significant correlation was often found between the response to the separate frequency components of the natural sounds and the response to the natural sound itself. At the population level, this correlation resulted in a rate profile that represented robustly the spectral profiles of the natural sounds. There was however a significant scatter in the responses to the natural sound around the predictions based on the responses to tonal stimuli. Going the other way, in order to understand better the non-linearities in the responses to natural sounds, responses of neuronal clusters were characterized using second order Volterra kernel analysis of their responses to natural sounds. This characterization predicted reasonably well the amplitude of the response to other natural sounds, but could not reproduce the responses to tonal stimuli. Thus, second order non-linear characterizations, at least those using the Volterra kernel model, do not interpolate well between responses to tones and to natural sounds in auditory cortex.

Responses of auditory-cortex neurons to structural features of natural sounds.

Sound-processing strategies that use the highly non-random structure of natural sounds may confer evolutionary advantage to many species. Auditory processing of natural sounds has been studied almost exclusively in the context of species-specific vocalizations, although these form only a small part of the acoustic biotope. To study the relationships between properties of natural soundscapes and neuronal processing mechanisms in the auditory system, we analysed sound from a range of different environments. Here we show that for many non-animal sounds and background mixtures of animal sounds, energy in different frequency bands is coherently modulated. Co-modulation of different frequency bands in background noise facilitates the detection of tones in noise by humans, a phenomenon known as co-modulation masking release (CMR). We show that co-modulation also improves the ability of auditory-cortex neurons to detect tones in noise, and we propose that this property of auditory neurons may underlie behavioural CMR. This correspondence may represent an adaptation of the auditory system for the use of an attribute of natural sounds to facilitate real-world processing tasks.