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.

Noninvasive Assessment of Fibrosis Regression after Direct-acting Antiviral Treatment in Hepatitis C Virus Patients.

BACKGROUND: New direct acting antiviral agent (DAA) therapies are associated with a high sustained virological response rate (SVR) in hepatitis C virus (HCV) patients. The understanding of the impact of SVR on fibrosis stage is limited. OBJECTIVES: To determine the effect of treatment with the DAAs on long-term liver fibrosis stages, as determined by shear-wave elastography (SWE) or FibroTest. METHODS: Fibrosis stage was determined at baseline and at 6-month intervals after end of treatment (EOT), using two-dimensional SWE or FibroTest©; APRI and FIB-4 scores. RESULTS: The study comprised 133 SVR12 patients. After a median follow-up of 15 months (range 6-33), liver fibrosis stage decreased by at least 1 stage in 75/133 patients (56%). Cirrhosis reversal was observed in 24/82 (29%). Repeated median liver stiffness SWE values in cirrhotic patients were 15.1 kPa at baseline (range 10.5-100), 13.4 kPa (range 5.5-51) at 6 months, and 11.4 kPa (range 6.1-35.8) at 12 months after EOT, P = 0.01. During the second year after EOT, no statistically significant differences in liver fibrosis stage in 12, 18, and 24 months were found. Splenomegaly was the only significant negative predictor of liver fibrosis regression during all time points of repetitive noninvasive assessment. CONCLUSIONS: Following successful DAA treatment, the majority of our HCV patients with advanced fibrosis demonstrated significant improvement, as assessed by non-invasive methods. Advanced fibrosis stage was a negative predictor of fibrosis regression. Longer follow-up periods are required to further establish the impact of DAAs treatment in HCV patients with advanced fibrosis.

Ombitasvir/paritaprevir/ritonavir & dasabuvir ± ribavirin following protease inhibitors failure - a prospective multi-centre trial.

BACKGROUND: Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of 65-75% but was associated with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs. METHODS: An investigator-initiated, open-label, multi-centre clinical trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 weeks according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance associated variants. RESULTS: Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m2). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan® score F3-4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P < 0.001). Seven patients (17.9%) experienced serious adverse events (3 Psychiatric admissions, 1 pneumonia, 1 ankle fracture, 2 palpitations), and 12 patients (30.8%) experienced self-reported adverse events, mostly weakness. CONCLUSION: 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment. TRIAL REGISTRATION: NCT02646111 (submitted to ClinicalTrials.gov, December 28, 2015).

Role of Doppler Ultrasound Combined With Clinical Features in the Diagnosis of Transjugular Intrahepatic Portosystemic Shunt Dysfunction in the Era of Covered Stents.

OBJECTIVES: Our goal was to discuss the role of Doppler ultrasound (US), combined with clinical features, in the diagnosis of transjugular intrahepatic portosystemic shunt (TIPS) dysfunction in the era of covered stents. In light of the lack of research regarding the accuracy of Doppler US in TIPS dysfunction evaluations when using covered stents and a recent major meta-analysis, which primarily reviewed studies with bare metal stents but few with covered stents, we aimed to provide our single-center case study for further investigation. METHODS: All patients from 2010 to 2019 who underwent angiography for a covered stent preceded by a Doppler US examination in our institution were retrospectively reviewed. RESULTS: All of the Doppler US and angiographic examination results showed complete agreement, and 11 of 12 were positive for TIPS dysfunction. CONCLUSIONS: Combining the presence of positive clinical signs for TIPS dysfunction with Doppler US may increase its accuracy. Considering our results, there may be a need to reinvestigate Doppler US as a noninvasive, inexpensive, and available tool for the diagnosis of TIPS dysfunction in the era of covered stents, despite recent publications depicting Doppler US as inadequate for evaluating a TIPS.

The Role of Liver Segment-to-Spleen Volume Ratio in the Staging of Hepatic Fibrosis in Patients with Hepatitis C Virus Infection.

BACKGROUND: Accurate assessment of liver fibrosis is crucial for the management of patients with hepatitis C virus (HCV) infection. OBJECTIVES: To evaluate the performance of liver segment-to-spleen volume ratio in predicting the severity of liver fibrosis. METHODS: Sixty-four consecutive HCV patients were enrolled in this retrospective study. All patients underwent contrast-enhanced computed tomography (CT) and were divided into three groups based on their hepatic fibrosis stage evaluated by shear-wave elastography (SWE): non-advanced (F0-F1, n=29), advanced (F2, n=19) and severe fibrosis (F3-F4, n=16). Using semi-automated liver segmentation software, we calculated the following liver segments and spleen volumes for each participant: total liver volume (TLV), caudate lobe (CV), left lateral segment (LLV), left medial segment (LMV), right lobe (RV) and spleen (SV), a well as their ratios: CV/SV, RV/SV, LLV/SV, LMV/SV and TLV/SV. RESULTS: RV/SV was found to discriminate between patients with non-advanced and advanced fibrosis (P = 0.001), whereas SV, CV, RV, TLV/SV, LMV/SV and RV/SV discriminated between patients with advanced and severe fibrosis (P < 0.05). RV/SV ≤ 3.6 and RV ≤ 2.9 were identified as the best cutoff values to differentiate non-advanced from advanced fibrosis and advanced from severe fibrosis with sensitivities of 72.2% and 92.7%, specificities of 72.7% and 77.8%, and with an area under the receiver operating characteristic (ROC) curve of 0.797 and 0.847, respectively (P ≤ 0.002). CONCLUSIONS: RV/SV may be used for the assessment and monitoring of liver fibrosis in HCV patients prior to the administration of antiviral therapy, considering SWE as the reference method.

[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.

Direct antiviral agents for chronic hepatitis C virus infection improve health-related quality of life significantly in the long term.

INTRODUCTION: Direct antiviral agents (DAAs) are new drugs for the treatment of chronic hepatitis C virus (HCV) infection. These drugs are very effective and well tolerated. HCV can cause liver disease as well as extrahepatic manifestations, including a profound negative impact on health-related quality of life (HRQL). AIM OF THE STUDY: To evaluate HRQL in the long term (> 6 months after finishing treatment) after successful treatment with DAAs. To the best of our knowledge, this is the first study that evaluates quality of life in the long term after DAA treatment. MATERIAL AND METHODS: This is an observational study which included 100 patients treated with DAAs for chronic HCV infection between January 2015 and August 2018. Patients were assigned randomly. The average time after finishing treatment was 29.96 months. The Liver Disease Symptom Index (LDSI) 2.0 Questionnaire was used to evaluate quality of life before and after treatment. RESULTS: Seven of 9 parameters of the LDSI 2.0 Questionnaire showed significant improvement in the long term after successful treatment with DAAs. Two parameters (arthralgia and jaundice) did not improve significantly. Quality of life improved in both males and females similarly. Improvement did not correlate with the severity of liver fibrosis. CONCLUSIONS: Treatment with DAAs improves HRQL significantly in the long term.

Real-World Outcomes in Historically Underserved Patients with Chronic Hepatitis C Infection Treated with Glecaprevir/Pibrentasvir.

INTRODUCTION: Glecaprevir/pibrentasvir is approved for treating chronic hepatitis C virus (HCV) genotypes (GT) 1-6. We evaluated real-world effectiveness, safety, and patient-reported outcomes of glecaprevir/pibrentasvir in underserved patient populations, focusing on persons who use drugs infected with HCV. METHODS: Data were pooled from nine countries (13 November 2017-31 January 2020). Patients had HCV GT1-6, with or without compensated cirrhosis, with or without prior HCV treatment and received glecaprevir/pibrentasvir consistent with local label at their physician's discretion. Patients with prior direct-acting antiviral exposure were excluded from efficacy and quality-of-life analyses. The percentage of patients achieving sustained virologic response at post-treatment week 12 (SVR12) was assessed. Mean changes from baseline to SVR12 visit in 36-Item Short-Form Health Survey mental and physical component summary scores were reported. Safety was assessed in patients receiving at least one dose of glecaprevir/pibrentasvir. RESULTS: Of 2036 patients, 1701 (83.5%) received 8-week glecaprevir/pibrentasvir. In 1684 patients with sufficient follow-up, SVR12 rates were 98.0% (1651/1684) overall, 98.1% (1432/1459) in 8-week treated patients, 97.0% (519/535) in persons who use drugs, and greater than 95% across subgroups. Mean changes from baseline in mental and physical component summary scores were 3.7 and 2.4, respectively. One glecaprevir/pibrentasvir-related serious adverse event was reported; six glecaprevir/pibrentasvir-related adverse events led to discontinuation. CONCLUSIONS: Glecaprevir/pibrentasvir was highly effective, well tolerated, and improved quality of life in HCV-infected persons who use drugs and other underserved patients. TRIAL REGISTRATION: These multinational post-marketing observational studies are registered with ClinicalTrials.gov, number NCT03303599.

Alterations in the Gut Microbiome in the Progression of Cirrhosis to Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. While cirrhosis is the main risk factor for HCC, the factors influencing progression from cirrhosis to HCC remain largely unknown. Gut microbiota plays a key role in liver diseases; however, its association with HCC remains elusive. This study aimed to elucidate microbial differences between patients with HCC-associated cirrhosis (HCC-cirrhosis) and cirrhotic patients without HCC and healthy volunteers and to explore the associations between diet, lifestyle, and the microbiome of these patients. Fecal samples and food frequency questionnaires were collected from 95 individuals (30 HCC-cirrhosis patients, 38 cirrhotic patients without HCC, and 27 age- and body mass index [BMI]-matched healthy volunteers). 16S rRNA gene sequencing was performed. Bacterial richness in cirrhosis and HCC-cirrhosis patients was significantly lower than in healthy controls. The HCC-cirrhosis group was successfully classified with an area under the curve (AUC) value of 0.9 based on the dysbiotic fecal microbial signature. The HCC-cirrhosis group had a significant overrepresentation of Clostridium and CF231 and reduced Alphaproteobacteria abundance compared to cirrhotic patients without HCC. Patients with HCC-cirrhosis who were overweight displayed significantly decreased bacterial richness and altered microbiota composition compared to their normal-weight counterparts. There was a significant correlation in the HCC-cirrhosis group between intake of artificial sweeteners and the presence of Akkermansia muciniphila A unique microbial signature was observed in patients with HCC-cirrhosis, irrespective of cirrhosis stage, diet, or treatment. BMI, dietary sugar, and artificial sweeteners were significantly associated with alterations in the microbiome of HCC-cirrhosis patients. However, the increased abundance of Clostridium and CF231 observed in HCC-cirrhosis patients was not influenced by environmental factors, implying that this change was due to development of HCC.IMPORTANCE Development of hepatocellular carcinoma in patients with cirrhosis is associated with alterations in intestinal microbiota, including an escalation of dysbiosis and reduced bacterial richness. This study demonstrates that reduced bacterial richness and dysbiosis escalate with the progression of cirrhosis from compensated to decompensated cirrhosis and to HCC-associated cirrhosis (HCC-cirrhosis). Moreover, we report for the first time the effect of environmental factors on HCC-cirrhosis. Excess weight was associated with increased dysbiosis in patients with HCC compared to their normal-weight counterparts. Moreover, fatty liver, consumption of artificial sweeteners, and high-sugar foods were associated with altered microbial composition, including altered levels of Akkermansia muciniphila in HCC-cirrhosis. We have successfully determined that levels of Alphaproteobacteria and the two genera CF231 and Clostridium are significantly altered in cirrhotic patients who develop hepatocellular carcinoma, independently of cirrhosis severity and dietary habits.

Long-term Follow-up of Severe Eosinophilic Hepatitis: A Rare Presentation of Hypereosinophilic Syndrome.

Idiopathic hypereosinophilic syndrome (HES) is a rare, heterogeneous disorder characterized by a strikingly high eosinophil count (>1,500 cells/µL), over a long period of time (>6 months), with end organ damage. We present a 60-year-old patient with idiopathic HES with isolated liver involvement, a rare systemic disease and a rare solid organ involvement. The patient had a thorough investigational work up until HES was established, including liver biopsy. He needed intensive immunosuppressive treatment at first with steroids, then with azathioprine in conjunction with a low dose of steroids. After 16 years of follow-up, the patient showed no evidence of liver dysfunction. To the best of our knowledge, this is the longest follow-up for a patient with HES-associated chronic hepatitis. Our observation suggests that, with appropriate treatment, liver involvement in HES may be well controlled without deterioration to advanced liver failure.

Feasibility study of ultrasonic fatty liver biopsy: texture vs. attenuation and backscatter.

The objective of this study was to compare textural to attenuation/backscatter indices of fatty liver correlated to histology to suggest the better approach for an objective noninvasive ultrasonic "biopsy". Forty-four patients with severe steatosis by histopathology were selected for this study. Ten patients had "pure" fatty liver and 34 had in addition fibrosis and/or inflammation. Ultrasonic images were acquired before needle insertion. The ROI used for biopsy was marked on the ultrasonic image and characterized by three attenuation/backscatter and 18 textural related indices. Statistical analysis was performed using logistic regression. Twenty-one healthy subjects served as control. The attenuation/backscatter indices were superior to textural indices in differentiating between the categories studied. Pure fatty livers could be reliably identified (AUC = 1, SE = 0). Among the 18 textural indices, "co-occurrences sum entropy" and "co-occurrences entropy" presented the best results. Attenuation/backscatter based indices appear to have better potential than the textural based indices.

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.

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.

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.