Setting Of Chronic Liver Disease Research Articles

Chronic Liver Disease and the Detection of Hepatocellular Carcinoma by [(18)F]fluorocholine PET/CT.

Positron emission tomography (PET) using the radiopharmaceutical tracer fluorine-18 fluorocholine (FCh) can elucidate tumors based on differences in choline phospholipid metabolism between tumor and surrounding tissue. The feasibility of detecting hepatocellular carcinoma (HCC) using FCh PET has been shown despite constitutively high parenchymal choline metabolism in the liver. Since HCC frequently develops in the setting of chronic liver disease, we comparatively evaluated FCh PET/CT between cirrhotic and non-cirrhotic patients with HCC to investigate the effects of hepatic dysfunction on tumor detection and the tumor-to-background ratio (TBR) of FCh uptake. FCh PET/CT was performed prospectively in 22 consecutive patients with HCC (7 newly diagnosed, 15 previously treated). Of these 22 patients, 14 were cirrhotic and 8 non-cirrhotic. Standardized uptake value (SUV) measurements were obtained by region of interest analysis of the PET images. Tumor FCh uptake and the TBR were compared between cirrhotic and non-cirrhotic patients. Liver lesions were confirmed to be HCC by biopsy in 10 patients and by Barcelona criteria in 4 patients. There was correspondingly increased liver tumor FCh uptake in 13/14 of those patients, and iso-intense tumor FCh uptake (TBR 0.94) in one non-cirrhotic patient with newly diagnosed HCC. FCh PET/CT also showed metastatic disease without local tumor recurrence in 2 previously treated patients, and was negative in 6 treated patients without tumor recurrence by radiographic and clinical follow-up. Tumor maximum SUV ranged from 6.4 to 15.3 (mean 12.1) and liver TBR ranged from 0.94 to 2.1 (mean 1.6), with no significant differences between cirrhotic and non-cirrhotic patients (SUVmax 11.9 vs. 12.2, p = 0.83; TBR 1.71 vs. 1.51, p = 0.29). Liver parenchyma mean SUV was significantly lower in cirrhotic patients (6.4 vs. 8.7, p < 0.05). This pilot study supports the general feasibility of HCC detection by FCh PET/CT. However, a broad range of tumor FCh uptake was observed, and lower liver parenchymal uptake of FCh was noted in cirrhotic patients as compared to non-cirrhotic patients. Incorporating tissue profiling into future liver imaging trials of FCh PET may help determine the molecular basis of the observed variations in tumor and hepatic FCh uptake.

Syndrome métabolique, stéatopathie hépatique non alcoolique (NASH) et carcinome hépatocellulaire : des liaisons bien dangereuses...

Obesity and the metabolic syndrome are fast-growing epidemics associated with an increased risk for many types of cancer. In the liver, inflammatory and angiogenic changes due to insulin resistance and fatty liver disease are associated with an increased incidence of liver cancer. Regardless of underlying liver disease, cirrhosis remains the most important risk factor for hepatocellular carcinoma (HCC) although cases of HCC arising without cirrhosis do not exclude the possibility of a direct carcinogenesis secondary to non-alcoholic fatty liver disease. Moreover, metabolic syndrome and its different features may also increase the risk of HCC in the setting of chronic liver diseases of other causes, such as viral hepatitis or alcohol abuse. Taking into account all these data, it is necessary to better determine the risk of developing HCC in patients with metabolic syndrome to improve the screening guidelines and develop prophylactic treatments in this setting.

Liver transplantation for hepatocellular carcinoma: how far have we come and what is the future?

Liver transplantation is the best treatment for hepatocellular carcinoma in the setting of chronic liver disease, completely removing malignancy and underlying diseased liver tissue. Technical aspects of liver transplantation have improved over the years, along with outcomes. But challenges continue in the areas of expanding existing indications for transplant with limited organ supply, calling for optimization of patient selection and the development of alternative or adjunctive treatment options. Expansion of existing transplant criteria will help identify patients most likely to have good outcomes. Locoregional and systemic treatments showing therapeutic promise are being investigated for use in achieving acceptable oncologic effect. Improvements in post-transplant treatment and continued attempts to enlarge the donor pool will continue to provide avenues for further improvements in outcomes.

Current surgical treatment strategies for hepatocellular carcinoma in North America.

Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in the setting of chronic liver disease. Many patients do not initially manifest any symptoms of HCC and present late when cure with surgical resection or transplantation is no longer possible. For this reason, patients at high risk for developing HCC are subjected to frequent screening processes. The surgical management of HCC is complex and requires an inter-disciplinary approach. Hepatic resection is the treatment of choice for HCC in patients without cirrhosis and is indicated in some patients with early cirrhosis (Child-Pugh A). Liver transplantation has emerged in the past decade as the standard of care for patients with cirrhosis and HCC meeting Milan criteria and in select patients with HCC beyond Milan criteria. Loco-regional therapy with transarterial chemoembolization, transarterial embolization, radiofrequency ablation and other similar local treatments can be used as neo-adjuvant therapy to downstage HCC to within Milan criteria or as a bridge to transplantation in patients on transplant wait list.

Relationship between hepatocellular carcinoma, metabolic syndrome and non-alcoholic fatty liver disease: Which clinical arguments?

Obesity and the metabolic syndrome are growing epidemics associated with an increased risk for many types of cancer. In the liver, inflammatory and angiogenic changes due to insulin resistance and fatty liver disease are associated with an increased incidence of liver cancer. Regardless of underlying liver disease, cirrhosis remains the most important risk factor for hepatocellular carcinoma (HCC) although are cases of HCC arising without cirrhosis raise the possibility of a direct carcinogenesis secondary to Non-alcoholic Fatty Liver Disease (NAFLD). Moreover, metabolic syndrome and its different features may also increase the risk of HCC in the setting of chronic liver diseases of other causes such as viral hepatitis or alcohol abuse. Taking into account all these data, it is necessary to better determine the risk of developing HCC in patients with metabolic syndrome to improve the screening guidelines and develop prophylactic treatments in this setting.

Multiphase Multi–Detector Row Computed Tomography in the Setting of Chronic Liver Disease and Orthotopic Liver Transplantation

The objectives of this study were to explore utilization of multi-detector row computed tomography (MDCT) in screening for hepatocellular carcinoma (HCC) and to modify a liver CT protocol with a goal of dose reduction. An electronic mail survey querying HCC surveillance practices was sent. One hundred forty consecutive patients referred for HCC indications underwent 4-phase MDCT of the liver. The unenhanced and delayed phases were evaluated by 3 readers for identification of HCC and reader confidence. The estimated effective dose (ED) was calculated. Computed tomography is primarily used to screen for HCC. Average estimated ED was 35.5 mSv. Unenhanced phase did not add to reader confidence; delayed phase increased confidence in 47% of cases. Thirty-two percent of the screening population had cumulative ED of greater than 200 mSv. Multi-detector row CT of the liver is used frequently in screening for HCC. Unenhanced phase imaging does not add to HCC detection and may be eliminated to reduce radiation dose.

HCC and NASH: How strong is the clinical demonstration?

Obesity and the metabolic syndrome (MS) are growing epidemics associated with an increased risk for many types of cancer. In the liver, inflammatory and angiogenic changes due to insulin resistance and fatty liver disease are associated with an increased incidence of liver cancer. Regardless of underlying liver disease, cirrhosis remains the most important risk factor for hepatocellular carcinoma (HCC) although rare cases of HCC arising without cirrhosis raise the possibility of a direct carcinogenesis secondary to nonalcoholic fatty liver disease (NAFLD). Moreover, MS and its different features may also increase the risk of HCC in the setting of chronic liver diseases of other causes such as viral hepatitis or alcohol abuse. Taking into account all these data, it is necessary to better determine the risk of developing HCC in patients with MS to improve the screening guidelines and develop prophylactic treatments in this setting.

Sleep Disorders in Chronic Liver Disease

Sleep-related complaints and disturbances are increasingly recognized in the setting of chronic liver disease and have recently been shown to be an important prognostic factor in patients with advanced chronic liver disease. This article reviews the literature surrounding sleep disturbances and disorders in a variety of types of chronic liver disease. This includes the association of sleep disturbances with hepatitis C and antiviral therapy, primary biliary cirrhosis, and Wilson disease as well as the circadian rhythm abnormalities present in cirrhosis and hepatic encephalopathy. The association between chronic liver disease, particularly nonalcoholic fatty liver disease, and sleep-disordered breathing is also reviewed in detail.

Human Chorionic Gonadotropin (HCG) Secreting Hepatocellular Carcinoma

Purpose: To describe an unusual case of a Human Chorionic Gonadotropin (HCG) secreting hepatocellular carcinoma. Case: 47 year old woman with co-morbidities including end-stage liver disease secondary to hepatitis C and hepatocellular carcinoma presented with fatigue and nausea. She denied any fever, chills, dyspnea, chest pain, abdominal pain, diarrhea or dysuria. On physical exam she had scleral icterus, ascites and jaundiced skin. Laboratory tests revealed a platelet count of 96,000 th/ul, albumin of 1.9 g/dl, total bilirubin of 10.5 mg/dl, AST of 104 u/l and ALT of 34 u/l. Surprisingly, a urine HCG done as part of standard screening prior to imaging tests was positive so a quantitative measure was done which showed an HCG of 113 mIU/ml. A pelvic ultrasound showed a non gravid uterus. A computed tomography (CAT) scan was then done which showed a 2.4 x 2.0 cm hypodense lesion in the caudate lobe of the liver, cirrhotic morphology of the liver, enlargement of the spleen, ascites, cholelithiasis and low attenuation material in a dilated main portal vein extending into the right and left portal veins concerning for portal vein thrombosis. She underwent a liver transplantation and splenectomy. Pathology showed a dominant tumor nodule in the caudate lobe and diffuse small multifocal cirrhosis-like hepatocellular carcinoma nodules involving about 25% of the liver. The tumor nodules showed variable differentiation from moderate to poor with giant cells. Staining of the tumor was positive for HCG. The spleen showed passive venous congestion and the distal pancreas showed hemorrhage, focal pancreatitis and fat necrosis. There was also an unsuspected organizing thrombus with tumor embolization seen in the portal vein. The HCG level measured two weeks after transplant normalized to < 1.0 mIU/ml and remained normal during follow up. Discussion: Hepatocellular carcinoma is an aggressive tumor that often occurs in the setting of chronic liver disease and cirrhosis. It commonly secretes alpha-fetoprotein and in case reports has been shown to secrete parathyroid hormone and other hormones. This case is novel in that HCG has not been reported before in this setting. The utility of this marker in terms of treatment prognosis remains to be determined. We report a case of an HCG secreting tumor in which the level of HCG normalized after transplantation.

Detoxification as a treatment goal in hepatic failure

Acute liver failure (ALF) is a dramatic clinical syndrome with high mortality because of cerebral oedema (type A hepatic encephalopathy) and multi-organ failure. With intensive care medicine and emergent liver transplantation being the mainstay of treatment, alternatives to transplantation are increasingly needed. Ammonia has been recognised as a major toxin in patients with ALF. It can be effectively removed by haemodialysis, haemofiltration and artificial liver support (a combination of extracorporeal toxin absorption and haemodialysis). Previous studies of extracorporeal detoxification, however, have either not specifically targeted ammonia or were hampered by poor biocompatibility and obsolete pathophysiological assumptions, ultimately failing to improve the prognosis. Moreover, most patients were treated only late after the emergence of advanced HE and multi-organ failure, while detoxification should prevent these complications. Acute-on-chronic liver failure (AOCLF) occurs in the setting of chronic liver disease and has an equally poor prognosis. Here, the goals of extracorporeal blood detoxification are renal support and haemodynamic stabilisation in order to support recompensation. Patients with AOCLF, unfortunately, are at a risk for treatment-related complications including bleeding, thrombocytopenia, hypotension and acute renal failure, making biocompatibility a critical issue. Peritoneal dialysis could possibly emerge as a more biocompatible way of treating refractory hepatorenal syndrome. This article will critically analyse the pathophysiological concepts and goals of extracorporeal detoxification in acute and chronic liver diseases.

Case Definition and Phenotype Standardization in Drug-Induced Liver Injury

Drug-induced liver injury (DILI) is the most frequent reason cited for the withdrawal of approved drugs from the market and accounts for up to 15% of the cases of acute liver failure. Investigators around the globe have begun to identify and study patients with DILI; several large registries and tissue banks are being established. In order to gain the maximum scientific benefit from these efforts, the definitions and terminology related to the clinical phenotypes of DILI must be harmonized. For this purpose, an international DILI Expert Working Group of clinicians and scientists reviewed current DILI terminology and diagnostic criteria so as to develop more uniform criteria that would define and characterize the spectrum of clinical syndromes that constitute DILI. Consensus was established with respect to the threshold criteria for definition of a case as being DILI, the pattern of liver injury, causality assessment, severity, and chronicity. Consensus was also reached on approaches to characterizing DILI in the setting of chronic liver diseases, including autoimmune hepatitis (AIH).

The role of the renin–angiotensin system in liver fibrosis

Hepatic fibrosis, which is characterized by progressive inflammation and deposition of extracellular matrix components, is a common response to chronic liver disease. Hepatic fibrogenesis is a dynamic process that involves several liver cell types including hepatic stellate cells and Kupffer cells. In addition, recent evidence indicates that bile duct epithelial cells (i.e. cholangiocytes) also participate in the progression of biliary fibrosis that is observed during chronic cholestatic liver diseases, such as primary sclerosing cholangitis. To date, there are no effective treatments for hepatic fibrosis. Several recent studies have demonstrated that the renin-angiotensin system (RAS) plays a key role in hepatic fibrosis. Therapies targeting the RAS may represent a promising paradigm for the prevention and treatment of hepatic fibrosis in the setting of chronic liver disease. In this review, we provide a comprehensive update on the role of RAS in the pathogenesis of hepatic fibrosis in both animal models and human studies. We will discuss the profibrotic mechanisms activated by the RAS and the cell types involved. Studies that have utilized angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors to modulate the RAS in order to ameliorate hepatic fibrosis will also be discussed. Although the cumulative evidence supports the potential for the use of ARBs and ACE inhibitors as treatment for hepatic fibrosis, extensive studies of the effectiveness of RAS therapeutics are necessary in patients with chronic liver disease.

Abstract 2133: Phenylenebis(1,2-ethanediyl)bisisoselenourea (PBISe), a novel selenium drug for the treatment of hepatocellular cancer (HCC)

Abstract Hepatocellular cancer (HCC) is an aggressive tumor that frequently arises in a setting of chronic liver disease and cirrhosis. Appearing 20 to 30 years from initial insult, it is more likely to be discovered in its late stage. The median survival following diagnosis is approximately 6 to 20 months. Although the definitive treatment is tumor resection, most patients are not eligible because of tumor extent or underlying liver dysfunction. Alternative chemopreventive approach in reducing HCC mortality is to be explored. Earlier we have shown the efficacy of PBISe against colon adenocarcinoma and metastatic melanoma with a negligible systemic toxicity in animal studies. In the present study, we intend to demonstrate the chemotherapeutic effects of PBISe on the human HCC. We analyzed the role of PBISe and the underlying mechanism in HCC. PBISe in our study suppressed cell growth, and induce apoptosis. Evaluation of PBISe was performed in vitro on human SK-HEP-1, HepG2, C3A and HUH-7 cells by cellular viability, caspase 3/7 activity, annexin-V expression, DNA fragmentation by Tunnel, cell cycle analysis and AKT, ERK, STAT, SAPK/JNK phosphorylation. PBISe promotes apoptosis by upregulating caspase 3/7, annexin-V, and cPARP. Increased DNA fragmentation was observed with PBISe in all the HCC cell lines tested. PBISe also mediated the cellular proliferation by AKT signaling and downstream pPRAS40 by inducing the cell cycle arrest at G2-M phase. Decreased pERK, pSTAT and pAKT shows that PBISe has a potential to target several signaling pathways. Overall our results suggest that PBISe is a potent chemotherapeutic agent with novel properties for the treatment of HCC. The chemotherapeutic effect of PBISe in the murine HCC model will be discussed. Supported by Penn State Deans Feasibility Grant to H.R.T, NIH RO3 CA 137763-01 to D. D., NIH KO8 417-67HY to K.S.O.C. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2133. doi:10.1158/1538-7445.AM2011-2133

Hepatocellular Carcinoma: Prevention and Therapy

Hepatocellular carcinoma (HCC) is an aggressive malignancy of the liver and occurs most often in the setting of chronic liver disease. The most common acquired causes for this are chronic viral hepatitis infections (mostly HBV and HCV), and alcohol. Other causes include nonalcoholic fatty liver disease-related nonalcoholic steatohepatitis, autoimmune liver disease, and biliary diseases. In addition, certain heritable diseases like hemochromatosis and α-1-antitrypsin deficiency can also lead to HCC. Therefore, prevention of HCC can be achieved by preventing and controlling these problems. For treatment, curative modalities are surgical resection and liver transplantation. However, most patients are not candidates for these surgical maneuvers, and outcomes are poor. New therapeutic developments have brought some improvement with both local and systemic disease control.

Thrombin generation in plasma from patients with cirrhosis supplemented with normal plasma: considerations on the efficacy of treatment with fresh-frozen plasma

Cirrhosis is characterized by a complex coagulation defect leading to the prolongation of the prothrombin and activated partial thromboplastin times (PT and APTT). Arbitrary PT cut-off values are still used as a yardstick to guide treatment with fresh-frozen plasma (FFP) or other pro-coagulant agents in patients undergoing invasive procedures. No randomized studies on the FFP efficacy are available, and are unlikely to be carried out because of their complex organization. An interim solution could be to evaluate the in vitro thrombin generation in plasmas from patients with cirrhosis when mixed with appropriate amounts of pooled normal plasma (PNP). The PT, APTT and thrombin generations in the presence of thrombomodulin were examined in 58 patients with cirrhosis and 24 healthy subjects both before and after mixing their plasmas with PNP at a proportion of 4 + 1 (patient + PNP), chosen to mimic in vivo conditions when patients are treated with 10 ml/kg of FFP. The PT and APTT, which were abnormal in the majority of unmixed patient plasmas were shortened considerably, but did not normalize completely when mixed with PNP. Thrombin generation, which was already within normal limits in all unmixed patient plasmas, remained essentially unchanged after mixing with PNP. In conclusion, thrombin generation in patients with cirrhosis does not appreciably change after in vitro addition of PNP despite PT and APTT shortening would suggest otherwise. These results question the validity of the PT as a stand-alone test to guide transfusion of FFP in the setting of chronic liver disease.

Weight History influences the Development of Cirrhosis in Chronic Liver Disease

Purpose: Weight and lifestyle play important roles in the development of many diseases. The aim of this study is to evaluate weight and lifestyle in the development of cirrhosis in the setting of chronic liver disease. Methods: Using the Weight and Lifestyle Instrument and clinical variables, collected on consecutive patients at the Penn State Hershey Medical Center a data base was created. Univariate and Multivariate analysis was performed. Results: A total of sixty-six patients did not have cirrhosis (non-cirrhosis) and 28 had cirrhosis. Obesity was similar between cirrhosis and non-cirrhosis. The time spent with BMI >30 was greater in cirrhosis then in non-cirrhosis (19.1 vs. 11.4 years). In the cirrhosis group 61% were obese for more than 15 years whereas in the non-cirrhosis group only 33% (P=0.01). The cirrhosis cases showed a pattern of lifetime gaining or shifting weights more often than non-cirrhosis (p=0.01), more often gained or lost a total of 80 pounds in their lifetime (p=0.005) and more often showed any form of weight shifting (p=0.02). In the final model the variables that predicted cirrhosis were platelet count, alcohol use of at least 20 grams daily and the time in years spent obese. Conclusion: These findings suggest that patients with liver disease should be counseled to remain lean (BMI <30). When patients with liver disease are overweight they should be counseled to lose weight and then maintain the lower weight. Patients with chronic liver disease need to be counseled against weight shifts.Table: Logistic regression model: independent predictors of cirrhosisTable: Odds of cirrhosis as time spent obese with chronic liver disease

Coagulopathy Does Not Protect Against Venous Thromboembolism in Hospitalized Patients With Chronic Liver Disease

It is uncertain whether pathologically prolonged international normalized ratio (INR) seen in chronic liver disease (CLD) protects against venous thromboembolism (VTE). Previous studies reported VTE incidence of 0.5% to 1.9% in patients with CLD. We sought to evaluate VTE incidence among hospitalized patients with CLD according to INR levels. This was a retrospective cohort study performed at a tertiary university hospital. We included all adult patients admitted with a primary diagnosis of CLD over a 7-year period. The primary outcome was the development of VTE during hospital stay. Patients were divided into quartiles according to their highest admission INR. VTE events and prophylaxis rates were compared among INR quartiles. During the allotted 7-year period, we included 190 patients. Of these, 12 developed VTE events, yielding a VTE incidence of 6.3%. There was no significant difference in the incidence of VTE between INR quartiles. Hospital mortality rates were higher in the higher INR quartiles than in the lower ones (P < .001), but hospital length of stay was not significantly different. Of the patients with documented VTE, one (4.2%) was Child-Pugh stage A, three (4.6%) were stage B, and eight (8.0%) were stage C (P = .602). VTE prophylaxis was not used in 75% of patients. An elevated INR in the setting of CLD does not appear to protect against the development of hospital-acquired VTE. The notion that "auto-anticoagulation" protects against VTE is unfounded. Use of DVT prophylaxis was extremely low in this population.

Current Management of Hepatocellular Cancer

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, being the fifth most frequent cancer worldwide. It usually occurs in the setting of chronic liver disease and has a poor prognosis if untreated. Following the diagnosis, this disease requires multidisciplinary management. Orthotopic liver transplantation is theoretically the best treatment for early, unresectable HCC. However, the major practical obstacle is the extreme shortage of organs, which makes this a practical option only in selected patients. In this report we describe new advancements in diagnosis, classification, and treatment that have emerged in the field of HCC in recent years.

Infiltrating hepatocellular carcinoma into the duodenum presenting with upper gastrointestinal bleeding

Hepatocellular carcinoma (HCC) is a primary tumor of the liver that usually develops in the setting of chronic liver disease and cirrhosis. Extrahepatic spread is found in 10 % – 20 % of patients at the time of diagnosis and is more common in tumors over 5 cm in diameter [1]. Direct invasion of the gastrointestinal tract is rare and reported to occur in 0.5 % – 2 % of cases [2]. We present a case of HCC directly invading the duodenal bulb with resultant upper gastrointestinal bleeding.

Safety and efficacy of sorafenib in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is frequently diagnosed in the setting of chronic liver disease and cirrhosis. The median survival after diagnosis is dismal. The treatment options that may offer cure are either resection or liver transplantation. Unfortunately most patients are not eligible for either treatment modality at diagnosis because of advanced stage and underlying liver dysfunction. Until recently, there was no effective systemic therapy for patients with advanced HCC. Sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor and Raf, has shown antitumor activity in patients with advanced HCC in phase III trials. Although objective response is not common, sorafenib promotes disease stabilization and improves overall survival. Sorafenib is well tolerated with a favorable toxicity profile. In this article we review the efficacy and safety data for sorafenib in patients with advanced HCC.