Prospective randomized pilot study of Y90+/-sorafenib as bridge to transplantation in hepatocellular carcinoma.

BACKGROUND & AIMS: To investigate the safety and adverse event profile of sorafenib plus radioembolization (Y90) compared to Y90 alone in patients awaiting liver transplantation. METHODS: 20 patients with HCC were randomized to Y90 alone (Group A) or Y90+sorafenib (Group B). Adverse events, dose reductions, and peri-transplant complications were assessed. RESULTS: All patients in the sorafenib group necessitated dose reductions. Seventeen of 20 patients underwent liver transplantation; median time-to-transplant was 7.8 months (range: 4.2-20.3) and similar between groups (p = 0.35). In the sorafenib group, there were 4/8 peri-transplant (<30 days) biliary complications (p = 0.029) and 3/8 acute rejections (p = 0.082); there were none in the Y90-only group. Survival rates were 70% (Group A) and 72% (Group B) at 3 years (p = 0.57). CONCLUSIONS: The addition of sorafenib to Y90 necessitated dose reductions in all patients awaiting transplantation. Preliminary data suggest that the combination was associated with more peri-transplant biliary complications and potentially trended towards more acute rejections. Caution should be exercised when considering sorafenib in the transplant setting. Further investigation is warranted.

Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: A randomized controlled trial.

Innovative non-pharmacological lifestyle strategies to treat non-alcoholic fatty liver disease (NAFLD) are critically needed. This study compared the effects of alternate day fasting (ADF) combined with exercise to fasting alone, or exercise alone, on intrahepatic triglyceride (IHTG) content. Adults with obesity and NAFLD (n = 80, 81% female, age: 23-65 years) were randomized to 1 of 4 groups for 3 months: combination of ADF (600 kcal/2,500 kJ "fast day" alternated with an ad libitum intake "feast day") and moderate-intensity aerobic exercise (5 session per week, 60 min/session); ADF alone; exercise alone; or a no-intervention control group. By month 3, IHTG content was significantly reduced in the combination group (-5.48%; 95% CI, -7.77% to -3.18%), compared with the exercise group (-1.30%; 95% CI, -3.80% to 1.20%; p = 0.02) and the control group (-0.17%; 95% CI, -2.17% to 1.83%; p < 0.01) but was not significantly different versus the ADF group (-2.25%; 95% CI, -4.46% to -0.04%; p = 0.05). Body weight, fat mass, waist circumference, and alanine transaminase (ALT) levels significantly decreased, while insulin sensitivity significantly increased in the combination group compared with the control group. Lean mass, aspartate transaminase (AST), HbA1c, blood pressure, plasma lipids, liver fibrosis score, and hepatokines (fetuin-A, FGF-21, and selenoprotein P) did not differ between groups. Combining intermittent fasting with exercise is effective for reducing hepatic steatosis in patients with NAFLD but may offer no additional benefit versus fasting alone.

Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial.

INTRODUCTION: The burden of non-alcoholic steatohepatitis (NASH) is growing and current pharmacologic treatments are limited by side effects and inconsistent efficacy. Pilot studies suggest that pentoxifylline (PTX) can reduce liver injury in patients with NASH. OBJECTIVE: We sought to determine the tolerability of PTX and its effect on aminotransferases and liver histology in patients with NASH. MATERIAL AND METHODS: Thirty patients with biopsy proven NASH were randomized in a 2:1 fashion to receive 1,200 mg PTX or placebo for 12 months. Metabolic parameters, aminotransferases, liver histology and hepatic gene expression changes were compared. RESULTS: At baseline the groups were similar. Adverse events were mild, most frequently headache and abdominal cramps, and did not differ between groups (p = NS). After 12 months, ALT and AST decreased from 92 ± 12 IU/L to 67 ± 13 IU/L and 67 ± 6 IU/L to 47 ± 6 IU/L (p < 0.05), respectively in patients treated with PTX. No significant effect was seen with placebo. Steatosis and cellular ballooning improved in the PTX group (p < 0.05), whereas no histological feature of steatohepatitis improved with placebo. However, between groups comparison of both biochemical and histological features were nonsignificant. CONCLUSION: Pentoxifylline is safe, well tolerated and improves transaminases and histology in patients with NASH when compared to baseline and may be a reasonable therapeutic modality for the treatment of NASH. However PTX failed to reduce transaminases compared to placebo and did not positively affect any of the metabolic markers postulated to contribute to NASH. Although animal data and small pilot studies in humans have suggested that PTX may be effective as a treatment for NASH, translating this therapy to clinical practice may prove challenging.

Colonic leiomyoma mimicking a liver tumor: an unusual diagnosis after en-block robotic resection.

Colonic leiomyomas are rare. Their clinical presentation ranges from asymptomatic polyps detected on endoscopy to large symptomatic abdominopelvic masses. Imaging findings are usually non-specific, and percutaneous biopsy might help with differential diagnosis. However, radical surgery with negative margins is ultimately needed to rule out malignancy. We describe an uncommon presentation of a colonic leiomyoma mimicking a right hepatic lobe tumor on preoperative imaging. The robotic approach allowed a precise abdominal exploration with confirmation of colonic and hepatic infiltration and subsequent oncological en-block resection. Surgeons operating on hepatic tumors close to the right colic flexure should be aware of this diagnosis.

Practical considerations when treating chronic hepatitis E in solid organ transplant recipients.

Hepatitis E virus (HEV) can lead to chronic infections in immunosuppressed patients. The use of ribavirin to treat chronic HEV has been well-established in case reports and guidelines. However, practical approaches to the use of this antiviral treatment in a post-transplant patient, including drug interactions, dosing adjustments, and monitoring parameters, are lacking. Thus, we present our real-world approach to the use of ribavirin to treat chronic HEV in a solid organ transplant recipient.

Trans fat feeding results in higher serum alanine aminotransferase and increased insulin resistance compared with a standard murine high-fat diet.

Diets high in trans fats are associated with an increased risk of cardiovascular disease and components of the metabolic syndrome. The influence of these toxic fatty acids on the development of nonalcoholic fatty liver disease has not been significantly examined. Therefore, we sought to compare the effect of a murine diet high in trans fat to a standard high-fat diet that is devoid of trans fats but high in saturated fats. Male AKR/J mice were fed a calorically identical trans fat diet or standard high-fat diet for 10 days, 4 wk, and 8 wk. Serum alanine aminotransferase (ALT), lipid, insulin, and leptin levels were determined and the quantitative insulin-sensitivity check index (QUICKI) was calculated as a measure of insulin resistance. Additionally, hepatic triglyceride content and gene expression of several proinflammatory genes were assessed. By 8 wk, trans fat-fed mice exhibited higher ALT values than standard high-fat-fed mice (126 +/- 16 vs. 71 +/- 7 U/l, P < 0.02) despite similar hepatic triglyceride content at each time point. Trans fat-fed mice also had increased insulin resistance compared with high-fat-fed mice at 4 and 8 wk with significantly higher insulin levels and lower QUICKI values. Additionally, hepatic interleukin-1beta (IL-1beta) gene expression was 3.6-fold higher at 4 wk (P < 0.05) and 5-fold higher at 8 wk (P < 0.05) in trans fat-fed mice compared with standard high-fat-fed mice. Trans fat feeding results in higher ALT values, increased insulin resistance, and elevated IL-1beta levels compared with standard high-fat feeding.

Modern Management of Acute Liver Failure.

Acute liver failure is a rare but life-threatening disease that can lead to progressive encephalopathy, intracranial hypertension, and multiorgan failure. In the developed world, the most common cause remains acetaminophen overdose, but there are still many cases in which there is acute liver failure of unknown etiology. The mainstay of acute liver failure management remains supportive care in the critical care setting. If supportive treatment does not stabilize the disease process, the patient may require emergent liver transplantation. This article summarizes the current management of acute liver failure.

Obesity and nonalcoholic fatty liver disease: current perspectives.

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common cause of chronic liver disease due to an increase in the prevalence of obesity. The development of NASH leads to an increase in morbidity and mortality. While the first line of treatment is lifestyle modifications, including dietary changes and increased physical activity, there are no approved pharmacological treatment agents for NAFLD and NASH currently. Due to its complex pathophysiology, different pathways are under investigation for drug development with the focus on metabolic pathways, inflammation, and slowing or reversing fibrosis. There are several agents advancing in clinical trials, and promising results have been seen with drugs that affect hepatic steatosis, inflammation, and fibrosis. This review will provide an overview on NAFLD and some of the mechanisms of disease that are being targeted with pharmacologic agents.

Atypical Presentation of Cardiac Tamponade as a Cause of Acute Liver Injury: Case Report and Review of Literature.

Pericardial tamponade is a rare cause of acute liver injury due to the compressive effects of an effusion resulting in a poor cardiac output which ultimately leads to ischemia-induced injury. We present a patient with chronic hepatitis C infection and end-stage renal disease who was transferred to our center for further evaluation and management of acute liver injury after presenting to an outside hospital with left upper quadrant abdominal pain, nausea and vomiting. The patient was discovered to have tamponade physiology on transthoracic echocardiogram as an underlying cause of his acute liver injury despite lack of clinical tamponade features. He required pericardiocentesis which eventually led to resolution of the acute liver injury and he was discharged home on day twelve after full recovery. We review the existing literature regarding the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of ischemic hepatitis, which is associated with high mortality; therefore early recognition and treatment of the underlying cause are paramount.

Clinical Assessment and Management of Portal Hypertension.

The development of portal hypertension in a patient with cirrhosis portends a poor prognosis. Untreated or progressive portal hypertension has serious clinical outcomes, which are often fatal. It is important to recognize portal hypertension early to delay progression and to treat complications of portal hypertension as they arise. This review will focus on the clinical assessment and management of portal hypertension.

Liver function tests in identifying patients with liver disease.

BACKGROUND AND AIMS: Many patients with liver disease come to medical attention once they have advanced cirrhosis or acute decompensation. Most often, patients are screened for liver disease via liver function tests (LFTs). There is very limited published data evaluating laboratory values with biopsy-proven stages of hepatic fibrosis. We set out to evaluate whether any correlation exists between routine LFTs and stages of hepatic fibrosis. METHODS: A large retrospective observational study on 771 liver biopsies was conducted for evaluating the stage of fibrosis with AST, ALT, INR, BUN, creatinine, platelets, alkaline phosphatase, bilirubin, and albumin. Mean and 95% confidence intervals were used to describe the distributions of serum markers in different fibrosis stages. Multivariable generalized linear models were used and a two-tailed P-value was calculated. RESULTS: ALT was not statistically significant for any stage, and AST was statistically significant for stage 3 and 4 fibrosis. INR was statistically significant only in stage 4 disease but remained near the upper limit of normal range. Albumin failed to show a clinically relevant association. Platelets remained within normal laboratory range for all stages. The remaining laboratory values failed to show statistical and clinical significance. CONCLUSION: The health care burden from chronic liver disease (CLD) will likely continue to rise, unless clinicians are made aware that normal or near normal laboratory findings may be seen in asymptomatic patients. Earlier identification of asymptomatic patients will allow for treatment with new promising modalities and decrease morbidity and mortality from CLD. Our study shows that laboratory values correlate poorly with liver disease.

Universal Index for Cirrhosis (UIC index): The development and validation of a novel index to predict advanced liver disease.

AIM: The purpose of this study was to create and validate a novel serological diagnostic index to predict cirrhosis of all etiologies. METHODS: This was a retrospective observational study of 771 patients, age >18 years, who underwent a liver biopsy. The stage of fibrosis and routine laboratory values were recorded. The data were randomly separated into 2 datasets (training 50% and testing 50%). A stepwise logistic regression model was used to develop the novel index. The area under the curve of receiver operating characteristic (AUROC) was applied to compare the new index to existing ones (Fibro-Q, FIB4, APRI, AAR), which was also validated in the testing dataset. RESULTS: Variables associated with the presence of cirrhosis were first assessed by univariate analysis then by multivariable analysis, which indicated serum glutamic-oxaloacetic acid transaminase, serum glutamic-pyruvic transaminase, international normalized ratio, albumin, blood urea nitrogen, glucose, platelet count, total protein, age, and race were the independent predictors of cirrhosis (P<0.05). Regression formula for prediction of cirrhosis was generated and a novel index was subsequently created. The diagnostic performance of the novel index for predicting cirrhosis was assessed using the receiver operating characteristic curve. The new index had significantly higher AUROC (0.83, 95% CI: 0.79-0.87) than Fibro-Q (0.80, 95% CI: 0.76-0.85), FIB4 (0.79, 95% CI: 0.74-0.83), APRI (0.74, 95% CI: 0.69-0.78), and AAR (0.72, 95% CI: 0.67-0.78). CONCLUSION: The novel index had the highest AUROC curve when compared with current indices and can be applied to all etiologies of chronic liver disease.

Elbasvir/Grazoprevir Use in Postliver Transplantation Patients on Hemodialysis.

BACKGROUND: Current national hepatitis C virus (HCV) guidelines do not recommend the use of elbasvir (EBR)/grazoprevir (GZR) in postliver transplantation (LT) patients due to drug-drug interactions with immunosuppression agents. However, recommendations do not address the treatment of HCV in renally impaired post-LT patients. Treatment regimens that are recommended for post-LT patients are not safe in patients with severe renal impairment and patients on dialysis. EBR/GZR is approved for use in patients with renal impairment and patients on dialysis, but not in the post-LT setting. METHODS: Authors reviewed the electronic medical records of 3 treatment-naive HCV genotype 1a male post-LT patients on hemodialysis who were treated with EBR/GZR with or without ribavirin for 12 or 16 weeks. RESULTS: No patients had serious adverse drug events during treatment and no patients stopped treatment early or died. Providers monitored immunosuppression levels; both patients who were taking tacrolimus required immunosuppression dose adjustments during HCV treatment. No patients experienced organ rejection. All patients achieved sustained virologic response. CONCLUSIONS: Current HCV guidelines do not address the treatment options for post-LT patients with severe renal impairment or who are on dialysis, nor do published accounts of use of EBR/GZR in this patient population exist. Clinicians may benefit from exposure to real-world cases of HCV treatment in this historically difficult-to-cure patient population. Providers must address drug-drug interactions with EBR/GZR and monitor for changes in immunosuppression levels to ensure safety with its use in post-LT patients.

Microvascular injury in persistent gastric ulcers after yttrium-90 microsphere radioembolization for liver malignancies.

Yttrium-90 microsphere radioembolization ((90)Y MRE) is a therapy for liver malignancies by permanently implanting (90)Y-containing microspheres into tumors via hepatic artery. The etiology of persistent gastric ulcerations in patients presenting months after treatment remains unclear. Three patients who presented with gastric ulceration 4 to 13 months after (90)Y MRE were examined by esophagogastroduodenoscopy and biopsies. Pathological examinations showed multiple (90)Y microspheres scattered within the lamina propria and submucosa. Most of the microspheres were distributed in a linear fashion, consistent with an intravascular location; however, the vascular lumen and endothelial cells were not present. The microspheres were surrounded by fibrotic tissue infiltrated by chronic inflammatory cells and rare neutrophils. Epithelial granulation without pititis and miniaturized glands with intervening fibrosis were noted, compatible with chronic ischemic changes. These findings suggest that the persistent gastric ulceration is a result of localized ischemic injury in response to (90)Y MRE-induced vascular damage.

Successful sofosbuvir-based therapy in HIV/hepatitis C virus coinfected liver transplant recipients with recurrent hepatitis C virus infection.

OBJECTIVE: Recurrent hepatitis C virus (HCV) infection contributes to unfavourable outcomes in HIV/HCV coinfected liver transplant recipients. Direct-acting antiviral (DAA) therapies for HCV offer an opportunity to improve patient and allograft survival in this patient population. We evaluated treatment outcomes with sofosbuvir (SOF)-based DAA therapy among HIV/HCV coinfected liver transplant recipients. DESIGN: Single centre prospective cohort study. METHODS: We identified eight HIV/HCV coinfected liver transplant recipients who were prospectively followed in the Northwestern University Viral Hepatitis Registry and who received SOF-based DAA therapy. We evaluated responses to therapy, including sustained HCV viral response 12 weeks after therapy completion (SVR12) and adverse effects. RESULTS: Seven recipients (87.5%) completed 12 weeks of SOF-based therapy: SOF/simeprevir for genotype 1 (n = 6), SOF/ribavirin for genotype 2 (n = 1). Of persons who completed therapy, all achieved SVR12. Strategies for the management of expected and observed drug interactions consequent to the addition of simeprevir to preexisting complex medication regimens included modifications of HIV antiretroviral regimens (n = 4) and tacrolimus dosing (n = 4) and frequent monitoring of tacrolimus trough levels. Minor adverse effects were observed after DAA initiation. One episode of allograft rejection and one death occurred that were deemed unlikely related to HCV therapy. CONCLUSION: High rates of HCV treatment success and no treatment-limiting adverse effects were observed in this HIV/HCV liver transplant cohort. Complex drug interactions were successfully managed in the context of multidisciplinary specialty care. Further studies are needed to assess the long-term effects of DAA therapy on patient and allograft survival among HIV/HCV coinfected liver transplant recipients.

Obesity and the liver: nonalcoholic fatty liver disease.

The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) parallels the rise of obesity and its complications. NAFLD is a common cause of cirrhosis and a leading indication for liver transplant. Genetic susceptibility, dietary composition, and exercise habits influence the development of NAFLD, and insulin resistance results in widespread metabolic perturbations with a net effect of triglyceride accumulation in the liver. Some patients will develop hepatocyte cellular injury and fibrosis of the liver, which can progress to cirrhosis and require liver transplant. Treatments targeting the pathophysiological mechanisms of NAFLD exist, but carry some potential risk and are not universally effective. Weight loss and lifestyle changes remain the most effective and safest approach, but sustainable change is difficult for most patients to achieve. Future work will continue to focus on developing effective and safe interventions to prevent the development of advanced liver disease, whereas efforts in the public health domain continue to combat obesity.