Concomitant Liver Research Articles

A novel preoperative risk score to optimize patient selection for performing concomitant liver resection with cytoreductive surgery/HIPEC.

37 Background: While parenchymal hepatic metastases were previously considered a contraindication to cytoreductive surgery(CRS) and heated intraperitoneal chemotherapy(HIPEC), liver resection(LR) is increasingly performed concomitantly with CRS/HIPEC. As this practice continues to expand, identification of preoperative factors associated with poor outcomes is paramount. Methods: Patients from the US HIPEC Collaborative(2000-2017) with invasive appendiceal or colorectal adenocarcinoma undergoing primary, curative intent CRS/HIPEC with CC0-1 resection were included. LR was defined as a formal parenchymal resection. Primary endpoints were postoperative complications and overall survival(OS). Results: 658 patients were included. Average age was 54 years and 45% were male; 83 (15%) underwent liver resection of colorectal (58%) or invasive appendiceal (42%) metastases. Liver resection patients had more complications (81 vs 60%; p = 0.001), greater number of complications (2.3 vs 1.5; p < 0.001), and required more reoperations (22 vs 11%; p = 0.007) and readmissions (39 vs 25%; p = 0.014) than non-liver resection patients. Liver resection patients had decreased OS (2-year OS 62% vs 79%, p < 0.001), which persisted on multivariable Cox regression when accounting for PCI and histology type. Preoperative factors associated with decreased OS on multivariable analysis in patients undergoing liver resection included age < 60 years (HR:3.61), colorectal histology (HR:3.84), and multiple liver tumors (HR:3.45) (all p < 0.05). When assigning one point for each factor, there was an incremental decrease in 2-yr survival as the risk score increased from 0 to 3 (0: 100%; 1: 91%; 2: 58%; 3: 0%; p < 0.001). Conclusions: As concurrent liver resection with CRS/HIPEC has become more common, we created a simple risk score to stratify patients considered for CRS/HIPEC with liver resection. These data aid in striking the balance between an increased perioperative complication profile with the potential for improvement in overall survival.

Тhe role of the internal use of mineral water in the complex treatment of patients with chronic viral hepatitis C with concomitant non-alcoholic fatty liver disease

Introduction: The use of modern drugs with direct antiviral effect allows achieving a stable virologic response (SVR) in patients with chronic hepatitis C (CHC). However, in most cases, after the elimination of HCV infection, the progression of fibrosis continues with the development of its terminal stages and adverse outcomes for patients. The presence of non-alcoholic fatty liver disease (NAFLD) in these patients significantly increases the rate of progression of fibrosis and its complications, even after reaching SVR. Therefore, the search and development of new non-drug treatment technologies for this category of patients is relevant. Aim: to study the effectiveness of mineral water intake (with a high content of bicarbonates, sodium, potassium, and silicon compounds) in the new mode of use in the complex treatment of patients with chronic hepatitis C with concomitant NAFLD. Methods: anamnestic, clinical, general clinical, biochemical (indicators of lipid metabolism, HOMA index), serological (markers of viral hepatitis C, HCV RNA PCR, qualitative and quantitative determination, genotyping), ultrasonographic studies of the digestive system and statistical methods. Results: Patients with chronic hepatitis C (genotype 1b in the phase of replication, minimal and moderate activity) with concomitant NAFLD, which had been divided into two groups, were examined. Patients of group I (control group) received a standard complex of treatment (diet therapy that corresponded to the Mediterranean diet, dosed exercise regimen, antiviral therapy - sofosbuvir (400 mg) and ledipasvir (90 mg) - 3 months). Patients of group II (the main group) additionally received an internal course intake of mineral water (MW) according to our methodology: 3 ml per kg of patient’s body weight 30-40-60 min before meals, depending on the acidity in the stomach, and the same dose after food intake, three times a day (course - 2 months, a break - 2 months, a second course - 2 months). Evaluation of the effectiveness of treatment was carried out after six months from the start of treatment. Conclusion: The results prove the feasibility and effectiveness of using MW in a doubled dosage regimen in the complex treatment of patients with chronic hepatitis C with chronic concomitant NAFLD, which was determined by improving lipid metabolism, reducing signs of insulin resistance, improving ultrasonographic signs and preventing the development of fibrotic changes in the liver.

Тhe role of the internal use of mineral water in the complex treatment of patients with chronic viral hepatitis C with concomitant non-alcoholic fatty liver disease

Тhe role of the internal use of mineral water in the complex treatment of patients with chronic viral hepatitis C with concomitant non-alcoholic fatty liver disease

Pelvic hydatidosis: An exceptional location

Background: Hydatid disease is a zoonosis, still endemic in some Spanish areas. The most frequent sites are the liver and lungs, although it can affect any location due to hematogenous spread. Extrahepatic-extrapulmonary lesions account for only 10%, pelvic location is exceptional. Material & Method: We present two patients with pelvic hydatidosis, with and without concomitant liver lesions. Results: Case 1: a 42-year-old male with pulmonary resection at 3 years of age and a right hepatectomy at 8y. Abdominal ultrasound shows an incidental finding of a pelvic cyst. CT/MRI: three pelvic cysts (8.2, 7.5 and 3.2 cm) in contact with the bladder, prostate and rectum. Radical surgery of two lesions and partial resection of the most caudal one were performed (Figure 1). Case 2: a 33-year-old female with epigastric pain. An ultrasound identified hepatic and pelvic hydatidosis. CT: cystic lesions with septa and wall calcifications in both hepatic lobes and a 10cm mass in the hypogastrium. A total resection of the pelvic lesion and partial resection of hepatic lesion that affected segments II, III, Iva, VII and VIII were performed. Discussion: Hydatidosis can affect the pelvis primarily, with/without hepatic or pulmonary lesions; or may appear secondarily to peritoneal dissemination after intraabdominal cystic rupture. Most cases are incidental findings. Symptoms may be caused by the mass effect, anaphylaxis or cystic rupture. Treatment depends on the cyst size, location and symptoms, but surgery is mandatory if there is any type of complication such bleeding or rupture. Total resection is the gold standard, whenever possible. If there is contact between cysts and vascular structures or major organs, a partial resection can be done.

Non-Invasive Assessment and Management of Liver Involvement in Adults With Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a systemic disorder affecting mainly the lung and the liver and is caused by mutations in SERPINA1, the AAT gene. A homozygous "Pi*Z" mutation (Pi*ZZ genotype) may cause liver fibrosis on its own independently of pulmonary AATD manifestation, while heterozygous Pi*Z carriage (Pi*MZ genotype) is considered a strong risk factor for development of liver cirrhosis in patients with concomitant liver disease such as alcoholic and non-alcoholic liver disease. In Pi*ZZ homozygotes, liver disease constitutes the second leading cause of death and is highly heterogeneous. About 35% of Pi*ZZ individuals display significant liver fibrosis on biopsy (i.e., fibrosis stage ≥ 2 on scale 0-4). Among non-invasive methods for liver fibrosis assessment, liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE) has been most widely evaluated. Based on these data, Pi*ZZ adults have 20x increased odds of developing advanced liver fibrosis (i.e., fibrosis stage ≥ 3) than adults without AAT mutation. Risk factors for accelerated fibrosis progression are male sex, age ≥ 50 years, alcohol misuse, obesity, diabetes mellitus, or metabolic syndrome. Unlike VCTE, other ultrasound- and magnetic resonance-based elastography methods have been assessed in small cohorts of Pi*ZZ individuals and remain to be comprehensively validated. Among blood-based fibrosis tests, AST-to-platelet ratio index (APRI) correlates moderately with histologic fibrosis stage and LSM. Given APRI's wide availability, it can be used for risk stratification as an adjunct to LSM or when LSM is not at hand. Despite recent efforts, AATD-related liver disease, especially for genotypes other than Pi*ZZ, remains greatly understudied. AATD individuals should be offered liver biochemistry, liver ultrasound, and non-invasive fibrosis assessment at the time of diagnosis to detect potential complications and for proper risk stratification. If signs of AATD-related liver disease occur (i.e., pathologic fibrosis test or repeatedly elevated liver enzymes), patients should be referred to a health care center specialized in AATD-related liver disease and be screened for potentially treatable comorbidities. To exclude the latter, they may need a liver biopsy. Moreover, every health care provider of an AATD individual should be aware of the potential liver manifestation, counsel their patient on modifiable hepatic risk factors, and offer them regular liver check-ups.

Opportunities for the use of natural and preformed physical factors in the complex treatment of patients with chronic viral hepatitis C with associated non-alcoholic fatty liver disease

One of the urgent problems of modern hepatology remains the treatment of patients with chronic viral hepatitis C, which is associated with an increase in the incidence and development of complications - cirrhosis of the liver and hepatocellular carcinoma. The presence of non-alcoholic fatty liver disease in patients accelerates the progression rate of HCV infection and reduces the effectiveness and tolerability of antiviral therapy. The above circumstances initiated us to the search for new non-drug technologies for the treatment of this category of patients. The work aimed to evaluate the effectiveness of the integrated use of standard antiviral therapy, drinking silicon low-mineralized sodium bicarbonate mineral water, and EHF-therapy in patients with chronic viral hepatitis C with concomitant non-alcoholic fatty liver disease. We used the following methods: anamnestic, general clinical, biochemical, serological, immunological, Ultrasonographic examination of the digestive organs. We examined 42 patients who were divided into two groups. The control group (22 people) received the basic treatment complex, which included dietary nutrition, standard antiviral therapy for 12 months, and an internal intake of mineral water during the first month of treatment. The main group (20 people), in addition to the basic complex of treatment, additionally received EHF-therapy procedures for three months. Evaluation of the effectiveness of treatment was carried out after 1 and 3 months from the start of treatment. The treatment was accompanied by the positive dynamics of most signs of the disease in both groups, with a predominance of EHF-therapy. In patients of main group, the disappearance of complications of antiviral therapy was established - the absence of cytopenic syndrome, normalization of immunological status, stimulation of interferonogenesis, restoration of equilibrium in the lipid peroxidation system and antioxidant system. These positive results made it possible to complete the course of therapy for all patients and obtain a virological response in 50% of patients.

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism.

Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated.

Indications and outcomes of combined heart-liver transplant: A systematic review and met-analysis.

Combined heart-liver transplantation (CHLT) has become a viable option for treating concomitant heart and liver failure. However, data are lacking with respect to long-term outcomes. An electronic search was performed to identify all studies on CHLT. Following application of inclusion and exclusion criteria, a total of seven studies consisting of 99 CHLT patients were included from the original 1864 articles. CHLT recipient mean age was 53.0 years (95% CI 48.0-58.0), 67.5% of which (95% CI 56.5-76.9) were male. 65.5% (95% CI 39.0-85.0) of patients developed heart failure due to amyloidosis whereas 21.6% (95% CI 12.3-35.2) developed heart failure due to congenital causes. The most common indication for liver transplant was amyloidosis [65.5% (95% CI 39.0-85.0)] followed by liver failure due to hepatitis C [13.8% (95% CI 2.1-54.4)]. The mean intensive care unit length of stay was 8 days (95% CI 5-11) with a mean length of stay of 24 days (95% CI 17-31). Cardiac allograft rejection within the first year was 24.7% (95% CI 9.5-50.7), including antibody mediated [5% (95% CI 1.7-15.2)] and T-cell mediated rejection [22.7% (95% CI 8.8-47.1)]. Overall survival was 87.5% (95% CI 78.6-93.0) at 1 year and 84.3% (95% CI 75.4-90.5) at 5 years. CHLT in select patients with coexisting end-stage heart and liver failure appears to offer high survival and low rejection rates.

The TACE’s role in the management of primary liver cancer

Objective: Identify the most effective and safe method of transcatheter hepatic artery chemoembolization (TACE) in patients with primary liver cancer. Methods: Overall, 139 patients, who underwent 558 TACE procedures were included in the study. Gender in the group of patients was distributed approximately equally and amounted to 72 men (52%) and 67 women (48%), the average age was 57.8 (9.9) years (range from 23 to 92 years). In most patients, the underlying disease for the development of hepatocellular carcinoma was cirrhosis of the liver in the outcome of hepatitis C or B. Characteristics of liver tumors were examined by magnetic resonance imaging or computed tomography and ultrasound. For verification of the diagnosis, a percutaneous liver biopsy was performed under ultrasound guidance, and the level of alpha-fetoprotein was also determined. All patients were considered unresectable due to cirrhosis and / or local spread of the tumor. Chemoembolization was performed by following scheme: one procedure in 2 months, not less than 3 procedures. Doxorubicin was used for chemotherapy. As a carrier of chemotherapy, Lipiodol (Guerbet, France) or saturable Hepaspheres (Merit Medical, USA) were used. Each patient received from 3 to 13 procedures. Results: Postembolization syndrome occurred in all cases, but was effectively treated. One patient died due to acute liver failure with the borderline stage of the disease according to the BCLC classification (EASL 2012) and the multinodular form of HCC. There were no serious complications in the treatment process. In two patients in the area of the puncture of the femoral artery, pseudoaneurysm was formed, which was eliminated by compression under ultrasound guidance. About 10% of patients developed subacute cholecystitis in the postoperative period and were associated with non-targeted chemoembolization in the cystic artery. In all patients, the symptoms of cholecystitis at the time of discharge were relieved conservatively. Survival median – 19 months. Dynamics of tumors was assessed by RECIST criteria. In the group of patients with hepatocellular carcinoma after first 3 TAСEs partial response and stabilization were observed in 83%, progression in 17%. In 18 cases (13%), histologically proved tumor necrosis after TAСE was achieved, without progression during follow-up. Three patients after reducing of tumor size was resected, 32 patients continue treatment. Conclusion: Transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma shows high efficacy, low mortality and the development of postoperative complications in patients with concomitant liver cirrhosis and locally advanced tumor lesion.

Hepatocellular carcinoma screening practices among patients with chronic hepatitis B by Canadian gastroenterologists and hepatologists: An online survey.

xpert guidelines recommend hepatocellular carcinoma (HCC) surveillance among patients with high-risk chronic hepatitis B (CHB); however, physician screening practices are often variable. An online survey of HCC screening practice was distributed to members of the Canadian Association for the Study of the Liver. Data were analyzed using appropriate statistical tests with p < .05 significance. Of 71 respondents, 86% (n = 61) were gastroenterologists or hepatologists, and 72% (n = 51) reported having been in clinical practice for more than 5 years. A significant number of survey respondents performed HCC screening without consideration of concomitant non-alcoholic fatty liver disease (50.7%); non-Asian, non-African ethnicity (46.4%); and family history of HCC (28.6%). Most (67.6%) performed screening with ultrasound (US) at the time of specialty clinic visits, 28.2% had an automatic recall system, and only 2.8% referred back to primary care physicians to organize screening. More than half (54.9%) included alpha-fetoprotein in screening. Obstacles to screening included lack of an automatic recall system (42.9%), patient non-compliance (30.0%), and limited US/MRI access (17.1%). HCC screening practices with hepatitis B patients vary widely among Canadian specialists, especially in unique populations with limited data to inform screening recommendations. Implementation of an automatic recall system could potentially increase HCC surveillance.

Clinical factors associated with treatment outcomes in EGFR mutant non-small cell lung cancer patients with brain metastases: a case-control observational study

BackgroundNon-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations often develop brain metastases. Treatment with EGFR-tyrosine kinase inhibitors (TKIs) has shown the effectiveness; however, knowledge of the clinical factors associated with outcomes in NSCLC patients with EGFR mutations remains limited.MethodsTreatment-naive patients diagnosed with advanced non-squamous NSCLC with brain metastases harboring EGFR mutations and treated with an EGFR-TKI as first-line therapy were enrolled with analysis of their medical records.ResultsA total of 134 advanced NSCLC patients with brain metastases harboring EGFR mutations received an EGFR-TKI (gefitinib: 62, erlotinib: 49, and afatinib: 23) as the first-line therapy. Sixty-nine had exon 19 deletions (51.5%), and 56 (41.8%) had L858R mutations. There was no statistically significant difference in progression-free survival (PFS) and overall survival (OS) among the EGFR-TKIs. Significantly shorter OS was noted in patients with multiple brain metastases (hazard ratio [HR]: 2.43, p = 0.007), uncommon EGFR mutations (HR: 3.75, p = 0.009), and liver metastases. Thirty-eight patients (29.1%) received brain radiotherapy for brain metastases before disease progression, and had a significantly longer time until intracranial progression. However, the brain radiotherapy had no statistically significant impact on PFS or OS.ConclusionsPatients with uncommon mutations, multiple brain metastases, and concomitant liver metastases tended to have shorter OS. Brain radiotherapy could delay the time to intracranial disease progression but had no impact on survival. The different first-line EGFR-TKIs achieved similar treatment responses in terms of PFS and OS in the EGFR-mutated NSCLC patients with brain metastases.

The mid-infrared spectroscopy: A novel non-invasive diagnostic tool for NASH diagnosis in severe obesity.

Background & AimsThere is an urgent medical need to develop non-invasive tests for non-alcoholic steatohepatitis (NASH). This study evaluates the diagnostic performance of an innovative model based on mid-infrared (MIR) spectroscopy for the diagnosis of NASH.MethodsSeverely obese patients who underwent a bariatric procedure at the University Hospital of Nice, France (n = 395) were prospectively recruited. The clinico-biological characteristics were measured prior to surgery. Liver biopsies were collected during the surgical procedure and assessed by a pathologist. A training group (316 patients, NASH: 16.8%) and a validation group (79 patients, NASH: 16.5%) were randomly defined. MIR spectra were acquired by fiber evanescent wave spectroscopy, using chalcogenide glass fiber optic sensors and a spectrometer. This absorption spectroscopic technique delivers a spectrum that identifies the molecular composition of a sample, defining a patient's metabolic fingerprint.ResultsThe areas under the receiver operating curve (AUROC) for the diagnosis of NASH were 0.82 and 0.77 in the training and validation groups, respectively. The best threshold was 0.15, which was associated with a sensitivity of 0.75 and 0.69, and a specificity of 0.72 and 0.76. Negative predictive values of 0.94 and 0.93 and positive predictive values of 0.35 and 0.36, as well as correctly classified patient rates of 72% and 75% were obtained in the training and validation groups, respectively. A composite model using aspartate aminotransferase level, triglyceride level and waist circumference alongside the MIR spectra led to an increase in AUROC (0.88 and 0.84 for the training and validations groups, respectively).ConclusionsMIR spectroscopy provides good sensitivity and negative predictive values for NASH screening in patients with severe obesity.Lay summaryThere is an urgent need for tools to non-invasively diagnose and monitor non-alcoholic steatohepatitis (NASH). This study evaluates the performance of a new tool for fast NASH diagnosis based on mid-infrared (MIR) spectroscopy. Using serum samples from severely obese patients who underwent a bariatric procedure, which enabled a concomitant liver biopsy to be performed, the MIR spectroscopy model performed well in screening patients for NASH compared to a traditional, histological diagnosis.

1034 Efficacy and Safety of Saroglitazar in Nonalcoholic Fatty Liver Disease Patients at 1 Year: An Investigator Initiated Study

INTRODUCTION: Currently there is no drug or therapy approved for NAFLD. Although there are many drugs which have been explored for their usage in NAFLD/NASH. Saroglitazar is one of such novel dual peroxisome proliferator-activated receptors-α/γ agonist drug approved for diabetic dyslipidemia in India and is being investigated for treatment of NAFLD. In this current observational study we have tried to explore the efficacy of Saroglitazar in NAFLD patients with dyslipidemia. METHODS: This is a single centre, single arm, open label study of Saroglitazar conducted in northern India. Obese/overweight patients having Fatty Liver (on USG), elevated transaminases and dyslipidemia with or without type 2 diabetes were enrolled. All the patients were given Saroglitazar 4 mg once daily for at least 1 year. Patients with concomitant liver disease due to other etiologies (alcohol, viral etc.) were excluded. The laboratory parameters and LSM reports at baseline and 1 year were compared using t test. RESULTS: A total of 64 patients with mean age of 41.95 ± 8.56 years were enrolled in the study. The ratio of male to female was 84.38 (N:54): 15.62 (N:10). Out of 64 patients 17 Diabetic, 30 Non- diabetic and 17 were Prediabetic. The baseline and follow up of aspartate aminotransferase (AST), alanine aminotransferase (ALT), Total Cholesterol, triglycerides (TG) and liver stiffness measurement values were given in Table 1. There was a consistent and significant reduction in Total Cholesterol, TG, ALT, AST and LSM. There were no reported adverse events pertaining to Hypoglycemia. CONCLUSION: Saroglitazar was found to be safe and effective in management of NAFLD patients in this interim analysis of 12 months follow up. It is a potential option and need further exploration for management of dyslipidemia and NAFLD in non diabetic patients.

Antibiotic prophylaxis of purulent and septical complications during surgical treatment of complicated gallstone disease on background of liver cirrhosis

Purpose of the study. The goal of this investigation was to determine the main risk factors in development of purulent and septical complications during surgical treatment of complicated gallstone disease on background of liver cirrhosis.&#x0D; Materials and methods. We retrospectively reviewed medical records of 247 patients who undergone treatment in minimally invasive surgery centre of Zhytomyr regional clinical hospital during 2009–2018. All patients with complicated gallstone disease were divided in two groups: group 1 – patients with concomitant liver cirrhosis – 79(31,98%), and group 2 – patients without liver cirrhosis – 168 (68,02%). Theinclusion criteria were presents of complicated gallstone disease (acute calculous cholecystitis, choledocholithiasis with obstructive jaundice and Mirizzi syndrome), and verified liver cirrhosis. Patients with oncological history, immunodeficiency and morbid obesity were excluded. Liver cirrhosis was staged by Child-ТurcotteРugh system. In all cases patient’s condition was assessed by APACHE II scoring system and patients with cirrhotic lesion were additionally analyzed by MELD score. Acute calculous cholecystitis was diagnosed in 185 patients: group 1 – 68(Child A – 36, Child B – 31, Child C – 1), group 2 – 117 patients. The signs of cholodecholithiasis with obstructive jaundice were present in 49 cases: group 1 – 7 (Child A – 5, Child B – 1, Child C – 1), group 2 – 42. Mirizzi syndrome was verified in 9 cases: group 1 – 2 (Child A – 1, Child B – 1, group 2 – 7.&#x0D; Results and discussion. In all patients treatment was started in conservative way that included detoxic, antibacterial and hepatoprotective components. In group of control early operative tactic in cases with acute calculous cholecystitis was preferred. Antimicrobial prophylaxis was performed in cases of severe and moderate calculous cholecystitits with use of cephalosporines of 2 generation in moderate case, and protected cephalosporines of 3 generation in combination with metronidazol in severe. In main group providing of antimicrobial therapy was performed very carefully, because of higher risk of hepato-renal insufficiency. The early de-escalation therapy was mandatory performed. Purulent complications occurred in 13,2% of patient with liver cirrhosis in comparison with control group with 1,7% of complications.&#x0D; Conclusion. The treatment of complicated gallstone disease in patients with liver cirrhosis is very risky in case of postoperative purulent complications. In case of Child A stage of cirrhosis the treatment is safe, and the incidents of purulent complications is the same like in the absence of cirrhosis. Administration of antibiotics in cirrhotic should be very careful because of higher risk of hepato-renal insufficiency. The early de-escalation therapy should be mandatory performed. The «gold» standard of empirical antimicrobial therapy is the use of cephalosporines of 2 and 3 generation.

Bile duct involvement by hepatocellular carcinoma: A rare occurrence and poor prognostic indicator in bile duct brushing samples.

Hepatocellular carcinoma (HCC) rarely involves the biliary tree and may be inadvertently sampled on bile duct brushings (BDBs). The pathology archives of 5 institutions were searched for BDBs with HCC involvement. A total of 17 BDBs from 14 patients were obtained. There was a male:female ratio of 6:1; the median age of the patients was 59.5years (range, 22-80years). The median hepatic tumor size was 6.2cm (range, 2.2-13.0cm). HCC risk factors included viral hepatitis (5 patients), cirrhosis (5 patients), hemochromatosis (1 patient), and alcoholic steatohepatitis (1 patient). Jaundice with elevated bilirubin, liver enzymes, and α-fetoprotein was common. Endoscopic retrograde cholangiopancreatography demonstrated bile duct dilatation, polypoid intraductal masses (5 samples), clots/debris (2 samples), or strictures (4 samples). All BDBs had single and clustered large cells with naked atypical nuclei, granular cytoplasm, high nuclear/cytoplasmic ratios, and nuclei with prominent macronucleoli. Less common findings included clear/microvesicular cytoplasm (35%), papillae (29%), and anisonucleosis (35%). Classic HCC features (widened trabeculae [35%], endothelial wrapping [24%], multinucleation [24%], and cytoplasmic bile pigment [35%]) were uncommon. A total of 11 BDBs were diagnosed as malignant (10 with HCC and 1 with cholangiocarcinoma), 2 were diagnosed as atypical, and 1 BDB was diagnosed as negative; approximately two-thirds were found to have polysomy on fluorescence in situ hybridization. Approximately 71% of patients died of disease at a median of 3.5months. HCC may extend into the intrahepatic and/or extrahepatic biliary tree, causing masses and/or strictures that may be sampled on BDB. Although cytologically malignant, the classic features of HCC are uncommon, which can cause misdiagnosis. Cytopathologists should be mindful of this differential when evaluating BDBs, particularly when concomitant liver masses and/or HCC risk factors are present. Because of the associated high mortality and rapid rate of death, its presence should be conveyed clearly in pathology reports.

Occupational exposure to vinyl chloride and liver diseases.

Portal hypertension, liver fibrosis, and angiosarcoma of the liver (ASL) have been reported among workers exposed to vinyl chloride monomer (VCM) since the 1970s. In 2007, the International Agency for Research on Cancer established the association of VCM with hepatocellular carcinoma (HCC), though only on the basis of the few cases available. Thereafter, recent reports from the United States cohort and a European sub-cohort of vinyl chloride workers provided compelling evidence of a strong association between cumulative VCM exposure and HCC risk. Further areas of research include the risk of liver cancer at lower levels of exposure and different patterns of risk of ASL and HCC with the time since exposure. The evidence of interaction between VCM exposure and other known liver carcinogens such as alcohol and chronic viral infection provides clues for the health surveillance of exposed workers. Notably, also the risk of VCM-associated chronic liver disease is modulated by alcohol consumption, viral infection, and genetic polymorphism. A counter-intuitive finding from cohort studies of exposed workers is the lower mortality from liver cirrhosis with respect to the general population; this can be attributed to the healthy worker effect and to the selection of liver cancer as the cause of death in the presence of concomitant chronic liver disease. Studies designed to overcome these intricacies confirmed an association between cumulative VCM exposure and the risk of liver cirrhosis.

Role of Regulatory T Cell and Effector T Cell Exhaustion in Liver-Mediated Transgene Tolerance in Muscle

The pro-tolerogenic environment of the liver makes this tissue an ideal target for gene replacement strategies. In other peripheral tissues such as the skeletal muscle, anti-transgene immune response can result in partial or complete clearance of the transduced fibers. Here, we characterized liver-induced transgene tolerance after simultaneous transduction of liver and muscle. A clinically relevant transgene, α-sarcoglycan, mutated in limb-girdle muscular dystrophy type 2D, was fused with the SIINFEKL epitope (hSGCA-SIIN) and expressed with adeno-associated virus vectors (AAV-hSGCA-SIIN). Intramuscular delivery of AAV-hSGCA-SIIN resulted in a strong inflammatory response, which could be prevented and reversed by concomitant liver expression of the same antigen. Regulatory T cells and upregulation of checkpoint inhibitor receptors were required to establish and maintain liver-mediated peripheral tolerance. This study identifies the fundamental role of the synergy between Tregs and upregulation of checkpoint inhibitor receptors in the liver-mediated control of anti-transgene immunity triggered by muscle-directed gene transfer.

Baseline risk factors determine lack of biochemical response after SVR in chronic hepatitis C patients treated with DAAs.

Liver function tests (alanine aminotransferase, ALT; gamma-glutamyltransferase, GGT) not always normalize after elimination of hepatitis C virus (HCV) by direct acting antivirals (DAAs), possibly indicating concomitant non-viral liver diseases. We analysed factors determining the biochemical response (normalized ALT/GGT) of DAA therapy in a large real-world cohort. The German Hepatitis C-Registry is a national multicenter registry study. Normal ALT was defined ≤35U/L (female) and ≤50U/L (male) or, according to AASLD, ≤19U/L (female) and ≤30U/L (male), normal GGT ≤40U/L (female) and ≤60U/L (male). At baseline, ALT was elevated in 3705/4946 (74.9%), ALT (AASLD) in 4669/4946 (94.4%) and GGT in 3018/4906 (61.5%). In this study, 97% of patients achieved SVR12. At week 12 after end of therapy, ALT was elevated in 451/4946 (9.1%), ALT according to AASLD in 1906/4946 (38.5%) and GGT in 863/4879 (17.7%). Persistently elevated ALT after DAA therapy was independently associated with high body mass index (BMI), age <70years, liver cirrhosis, diabetes, alcohol consumption and not achieving SVR12. Using the stricter AASLD criteria, opioid substitution and male sex were additional predictors. Higher GGT at week 12 was associated with high BMI, age >70years, liver cirrhosis, diabetes, alcohol consumption, opioid substitution and non-SVR. Importantly, persistently elevated liver tests after treatment, particularly GGT, were associated with hepatic decompensation and mortality during 4-years follow-up. Risk factors at baseline (obesity, diabetes, liver cirrhosis, alcohol consumption) are independently associated with persistently elevated liver function tests after SVR, indicating that these patients warrant further hepatological follow-up. German Clinical Trials Register (DRKS; ID DRKS00009717).

Role of peroxisome proliferator-activated receptors in the control of alcohol dependence and concomitant liver pathology

The article is aimed to summarize the scattered data on the role of peroxisome proliferator-activated receptors (PPAR) and the possibility of using PPAR’s agonists for treatment of alcohol dependence and alcoholic liver disease. Earlier it was shown that some PPAR agonists can reduce ethanol consumption and preference in rodents. Several hypotheses considering the antialcoholic activity of PPAR agonists and the roles of PPAR in the development of alcohol dependence were discussed. In light of these data, the therapeutic potential of PPARs agonists as an agent for the treatment of alcoholism, has been reviewed.

Management of betablocked patients after sustained virological response in hepatitis C cirrhosis.

BACKGROUNDCurrent guidelines do not address the post–sustained virological response management of patients with baseline hepatitis C virus (HCV) cirrhosis and oesophageal varices taking betablockers as primary or secondary prophylaxis of variceal bleeding. We hypothesized that in some of these patients portal hypertension drops below the bleeding threshold after sustained virological response, making definitive discontinuation of the betablockers a safe option.AIMTo assess the evolution of portal hypertension, associated factors, non-invasive assessment, and risk of stopping betablockers in this population.METHODSInclusion criteria were age > 18 years, HCV cirrhosis (diagnosed by liver biopsy or transient elastography > 14 kPa), sustained virological response after direct-acting antivirals, and baseline oesophageal varices under stable, long-term treatment with betablockers as primary or secondary bleeding prophylaxis. Main exclusion criteria were prehepatic portal hypertension, isolated gastric varices, and concomitant liver disease. Blood tests, transient elastography, and upper gastrointestinal endoscopy were performed. Hepatic venous pressure gradient (HVPG) was measured five days after stopping betablockers. Betablockers could be stopped permanently if gradient was < 12 mmHg, at the discretion of the attending physician.RESULTSSample comprised 33 patients under treatment with propranolol or carvedilol: median age 64 years, men 54.5%, median Model for End-Stage Liver Disease (MELD) score 9, Child-Pugh score A 77%, median platelets 77.000 × 103/µL, median albumin 3.9 g/dL, median baseline transient elastography 24.8 kPa, 88% of patients received primary prophylaxis. Median time from end of antivirals to gradient was 67 wk. Venous pressure gradient was < 12 mmHg in 13 patients (39.4%). In univariate analysis the only associated factor was a MELD score decrease from baseline. On endoscopy, variceal size regressed in 19/27 patients (70%), although gradient was ≥ 12 mmHg in 12/19 patients. The elastography area under receiver operating characteristic for HVPG ≥ 12 mmHg was 0.62. Betablockers were stopped permanently in 10/13 patients with gradient < 12 mmHg, with no bleeding episodes after a median follow-up of 68 wk.CONCLUSIONPortal hypertension dropped below the bleeding threshold in 39% of patients more than one year after antiviral treatment. Endoscopy and transient elastography are inaccurate for reliable detection of this change. Stopping betablockers permanently seems uneventful in patients with a gradient < 12 mmHg.