Minimal Steatosis Research Articles

Bile acid disorders and intestinal barrier dysfunction are involved in the development of fatty liver in laying hens

The pathogenesis of fatty liver is highly intricate. The role of the gut-liver axis in the development of fatty liver has gained increasing recognition in recent years. This study was conducted to explore the role of bile acid signaling and gut barrier in the pathogenesis of fatty liver. A total of 100 “Jing Tint 6” laying hens, 56-week-old, were used and fed basal diets until 60 weeks of age. At the end of the experiment, thirty individuals were selected based on the degree of hepatic steatosis. The hens with minimal hepatic steatosis (< 5 %) were chosen as healthy controls, while those with severe steatosis (> 33 %) in the liver were classified as the fatty liver group. Laying hens with fatty liver and healthy controls showed significant differences in body weight, liver index, abdominal fat ratio, feed conversion ratio (FCR), albumin height, Haugh unit, and biochemical indexes. The results of bile acid metabolomics revealed a clear separation in hepatic bile acid profiles between the fatty liver group and healthy controls, and multiple secondary bile acids were decreased in the fatty liver group, indicating disordered bile acid metabolism. Additionally, the mRNA levels of farnesoid X receptor (FXR) and genes related to bile acid transport were significantly decreased in both the liver and terminal ileum of hens with fatty liver. Moreover, the laying hens with fatty liver exhibited significant decreases in ileal crypt depth, the number of goblet cells, and the mRNA expression of tight junction-related proteins, alongside a significant increase in ileal permeability. Collectively, these findings suggest that disordered bile acids, suppressed FXR-mediated signaling, and impaired intestinal barrier function are potential factors promoting the development of fatty liver. These insights indicate that regulating bile acids and enhancing intestinal barrier function may become new preventive and therapeutic strategies for fatty liver in the near future.

Future of U.S. living donor liver transplant: Donor and recipient criteria, transplant indications, transplant oncology, liver paired exchange, and non-directed donor graft allocation.

In the United States, living donor liver transplant (LDLT), from both directed and nondirected living donors, has expanded over the past several years. LDLT is viewed as an important opportunity to expand the overall donor pool for liver transplantation (LT), shorten waiting times for a life-prolonging LT surgery, and reduce LT waitlist mortality. The LT community's focus on LDLT expansion in the United States is fostering discussions around future opportunities, which include the safe expansion of donor and recipient candidate eligibility criteria, broadening indications for LDLT including applications in transplant oncology, developing national initiatives around liver paired exchange, and maintaining vigilance to living donor and recipient candidate risk/benefit equipoise. Potential opportunities for expanding living liver donor and recipient candidate criteria include using donors with more than minimal hepatic steatosis, evaluating older donors, performing LDLT in older recipients to facilitate timely transplantation, and providing candidates who would benefit from an LT, but may otherwise have limited access (ie, lower MELD scores), an avenue to receive a life-prolonging organ. Expansion opportunities for LDLT are particularly robust in the transplant oncology realm, including leveraging LDLT for patients with advanced HCC beyond Milan, intrahepatic cholangiocarcinoma, and nonresectable colorectal cancer liver metastases. With ongoing investment in the deliberate growth of LDLT surgical expertise, experience, and technical advances in the United States, the LT community's future vision to increase transplant access to more patients with end-stage liver disease and selected oncology patients may be successfully realized.

Cardiac surgery and acute hepatitis B - Use of the Seraph™ 100 hemofilter.

We present a case of a 55-year-old male, presenting with angina symptoms with electrocardiographic changes and a panfocal systolic murmur radiating to the carotids. He had a primary HBV infection 8 months ago, without antiviral treatment. Echocardiography showed critical aortic valve stenosis (area: 0.53 cm2/m2). No coronary lesions were found on coronary angiography. Blood analysis revealed AST/GOT of 96 U/L and ALT/GPT 150 U/L. The serological profile revealed positive IgM anti-HBc, anti-HBc, anti-HBs and anti-HBe antibodies, with an increasing viral load (VL). The abdominal ultrasound identified mild hepatic fibrosis (F3) with minimal steatosis. Mechanical aortic prosthetic valve replacement was performed under CPB. The Seraph™ 100 filter was incorporated into the CPB circuit to reduce the risk of HBV contamination, infection and liver failure. The postoperative VL was monitored (Table 1). Liver function tests showed peak levels of bilirubin 0.66 mg/dL, AST/GOT 58 U/L, ALT/GPT 74 U/L at 6 hours post-surgery, with recovery of normal ranges at 48 hours post-surgery.

The structure of liver damage in patients with acute decompensated heart failure, the prognostic role of steatosis and liver density

Abstract Funding Acknowledgements None. Aim To study the spectrum of liver damage in patients with acute decompensated heart failure (ADHF). Materials and methods Included were 566 patients hospitalized with ADHF, NYHA class II–IV, 66% men, mean age 72,4±11,4 years. All patients underwent laboratory and instrumental examination, the degree of steatosis and liver density were determined by transient elastometry methods, with an assessment of the controlled ultrasound attenuation parameter (CAP - Controlled Attenuation Parameter, S, dB/m) using a device according to standard methods. CAP values &amp;lt;294 dB/m with steatosis degree 0 - S0, 295-309 dB/m - S1, 310-330 dB/m - S2, ≥331 dB/m - S3. Liver density was used: ≤5,8 kPa – normal liver density, ≥5,9 – stage F1, ≥7,2 kPa – F2, ≥9,5 kPa – F3, ≥12,5 kPa – F4. Laboratory manifestations of liver damage were considered to be increased aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase and alkaline phosphatase. Results The incidence of hepatic steatosis (≥S1) among patients with ADHF was 29%. Among patients with liver steatosis, minimal steatosis (S1) was detected in 19% of cases, moderate steatosis (S2) - 28,6%, severe steatosis S3 - 52,4%. In patients with steatosis, the frequency of laboratory indicators of liver damage was 53%, and in patients without steatosis - 49,2%. Liver density ≥ F1 was observed in 79,5% of patients. Stage F1 was diagnosed in 10,4% of cases, F2 - in 11%, F3 - 12,7%, F4 - 44,5%. However, no relationship was found between the severity of steatosis and liver density (p&amp;gt;0,05). Multivariate Cox regression analysis showed that extremely low CAP values (&amp;lt;234 dB/m) were associated with a worse prognosis and higher risk of HF mortality during the 3-year follow-up period (adjusted hazard ratio (aHR) 1,57 95% confidence interval (CI) 1,08–2,31, p=0,019) after adjustment for established risk factors and potential confounders. The presence of increased liver density &amp;gt;15,9 kPa was also associated with a worse prognosis of the risk of death from HF during the 3-year follow-up period by Cox multivariate analysis (aHR 1,24, 95% CI 1,01–1,52, p= 0,040). Conclusion Thus, extremely low CAP values (&amp;lt;234 dB/m) and the presence of a marked increase in liver density (&amp;gt;15,9 kPa) were associated with a worse prognosis in patients with ADHF during the 3-year follow-up period.

Hepatocellular carcinoma in patients cured of chronic hepatitis C: Minimal steatosis.

Successful treatment of hepatitis C reduces liver inflammation and fibrosis; however, patients remain at risk of developing hepatocellular carcinoma (HCC). To identify risk factors for new-onset HCC in patients cured of hepatitis C. Imaging, histological, and clinical data on patients whose first HCC was diagnosed >12 months of post-SVR were analyzed. Histology of 20 nontumor tissues was analyzed in a blinded manner using the Knodel/Ishak/HAI system for necroinflammation and fibrosis/cirrhosis stage and the Brunt system for steatosis/steatohepatitis. Factors associated with post-SVR HCC were identified by comparison with HALT-C participants who did not develop post-SVR HCC. Hepatocellular carcinoma was diagnosed in 54 patients (45 M/9F), a median of 6 years of post-SVR [interquartile range (IQR) =1.4-10y] at a median age of 61 years (IQR, 59-67). Approximately one-third lacked cirrhosis, and only 11% had steatosis on imaging. The majority (60%) had no steatosis/steatohepatitis in histopathology. The median HAI score was 3 (1.25-4), indicating mild necroinflammation. In a multivariable logistic regression model, post-SVR HCC was positively associated with non-Caucasian race (p=0.03), smoking (p=0.03), age > 60 years at HCC diagnosis (p=0.03), albumin<3.5g/dL (p=0.02), AST/ALT>1 (p=0.05), and platelets <100 × 103 cells/μL (p < 0.001). Alpha fetoprotein ≥4.75 ng/mL had 90% specificity and 71% sensitivity for HCC occurrence. Noncirrhotic patients had larger tumors (p=0.002) and a higher prevalence of vascular invasion (p=0.016) than cirrhotic patients. One-third of patients with post-SVR HCC did not have liver cirrhosis; most had no steatosis/steatohepatitis. Hepatocellular carcinomas were more advanced in noncirrhotic patients. Results support AFP as a promising marker of post-SVR HCC risk.

A study of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus and its correlation with cardiovascular risk

Background: NAFLD (non-alcoholic fatty liver disease) encompasses a variety of disorders of lipid metabolism ranging from NAFL, NASH to cirrhosis and rarely HCC. A great deal of evidence suggests that the metabolic syndrome predicts incident cardiovascular disease (CVD), so it is possible to hypothesize that NAFLD patients might portend a greater CVD risk and that NAFLD itself might confer a CVD risk above that associated with individual metabolic syndrome risk factors.Methods: 55 T2DM patients were included in current study conducted from August 2019 to September 2021 for assessment of NAFLD using USG abdomen, NAFLD fibrosis score and FIBROSCAN. ASCVD score was used for correlation between CVD risk and NAFLD.Results: Out of 55 patients 42 (76.4%) were having fatty liver based on USG abdomen while 13 (23.4%) patients were having no fatty liver. As far as steatosis is concerned mean CAP (dB/m) was 245±50.89 out of which 24 (43.6%) were having no or minimal steatosis (S0), while 31 (56.4%) were having significant steatosis with 11 (20%), 9 (16.4%) and 11 (20%) having S1, S2 and S3 grade of steatosis respectively. 15 patients out of 55 were of F0 grade while 19 (34.5%), 9 (16.4%), 7 (12.7%) and 5 (9.1%) were of grade F1, F2, F3 and F4 respectively. There was a positive statistically significant (p≤0.001) association of ASCVD risk score with NAFLD fibrosis score and fibroscan: E (KPa). Conclusions: Our study found that the prevalence of NAFLD was quite higher in patients with T2DM based on both USG abdomen (76.4%) and transient elastography (steatosis-56.4% and fibrosis-65.5%) and a statistically significant association between fibrosis and ASCVD score with higher fibrosis associated with higher 10 years ASCVD score.

S2454 Eosinophilic Cholangitis – An Uncommon Cause of Elevated Liver Enzymes

INTRODUCTION: Eosinophilic cholangitis (EC) is a rare disease with only a few cases reported. It is known to cause an obstructive pattern of abnormal liver function enzymes due to eosinophilic infiltration along the biliary channels. We present a case of a young woman who was found to have EC without biliary strictures on liver biopsy. CASE DESCRIPTION/METHODS: A 42 year old woman with history of hypertension presented with a rash of 1 week after eating salmon. Vitals were normal except for a heart rate of 120. Physical exam was notable for bilateral conjunctival injection, erythematous rash on face, chest, and upper extremities, desquamating rash on fingertips (Figure 1), tachycardia with regular rhythm, and a soft, non-tender abdomen with no hepatosplenomegaly. Labs on presentation were notable for a leukocytosis of 10.9 K/uL (neutrophil predominant), total bilirubin 3.8 mg/dL (direct 2.9), ALP 231 U/L, AST 102 U/L, ALT 237 U/L, GGT 314 U/L, ESR 126 U/L, and no eosinophilia. Abdominal ultrasound was unremarkable. Peripheral eosinophilia (0.63 K/uL) developed on day 3 of admission. Liver biopsy revealed severe acute cholangitis with numerous portal eosinophils consistent with eosinophilic cholangitis, without necrosis or fibrosis (Figure 2). Serologic work-up was negative for infectious or autoimmune etiology. Prednisone was started with improvement in liver enzymes and eosinophilia within 2 weeks. DISCUSSION: EC is a rare diagnosis typically associated with biliary strictures. However, no established diagnostic criteria exist. Our case shows biliary strictures are not always associated with EC, and peripheral eosinophilia may be absent on presentation. EC may be an overlapping condition with other causes of sclerosing cholangitis such as IgG4 related cholangiopathy and primary sclerosing cholangitis. Drug Reaction with Eosinophilia and Systemic Symptoms differs by having both a longer duration of liver involvement after initiation of prednisone and histologic features of cytotoxic phenotype with atypical lymphoid infiltrates and erythrophagocytosis. EC is often mistaken for cholangiocarcinoma given the radiographic similarities, with diagnosis established only after biopsy or surgical intervention. These patients may undergo unnecessary procedures for a condition that can be medically treated with high dose steroids. Thus, EC should be on the differential for a patient presenting with rash and acutely abnormal liver enzymes in a cholestatic or mixed pattern, with or without presence of biliary strictures.Figure 1.: Desquamating rash on fingertips.Figure 2.: (Percutaneous Liver Biopsy): Clinicopathologically consistent with eosinophilic cholangitis. A) dense portal inflammation rich in eosinophils, B) acute cholangitis with numerous portal eosinophils, and C) minimal lobular steatosis and no necrosis or fibrosis.

S2426 Segmental Atrophy Associated With Overestimation of Fibrosis by Transient Elastography

INTRODUCTION: Hepatic atrophy, although rare, may be a potential confounder of transient elastography results. Atrophy can result from tumor or cirrhosis but can also be due to etiologies associated with diversion of portal venous blood flow. We present a case of overestimation of fibrosis by transient elastography in a patient with left hepatic lobe atrophy. CASE DESCRIPTION/METHODS: A 60 year old overweight male with hypertension and hyperlipidemia was referred for evaluation of elevated transaminases. Initial laboratory investigation noted AST 62 U/L, ALT 110 U/L, alkaline phosphatase (ALP) 160 U/L, total bilirubin 0.7 mg/dL, platelet count 172,000/microliter and albumin 4.2 g/dL. He was advised to stop taking high intensity atorvastatin and abstain from alcohol consumption, though alcohol intake was one glass of wine nightly. Repeat testing demonstrated AST 39 U/L, ALT 58 U/L, ALP 98 U/L and total bilirubin 0.9mg/dL. An abdominal ultrasound was obtained and showed cavernous transformation of the portal vein (PV) with gastrosplenic varices. Computed tomography of the abdomen (Image 1) confirmed these findings and also revealed atrophy of the left hepatic lobe. The etiology of chronic PV thrombus was explored. Protein C and S, and antithrombin III were within reference range. Anticardiolipin antibody was negative. JAK2 and Factor V Leiden mutations were negative. Given risk factors for non-alcoholic fatty liver disease, we decided to evaluate the extent of fibrosis with transient elastography during the patient's office visit. FibroScan measured liver stiffness at 21.1 kPa, correlating with F4 fibrosis. No overt confounders were identified. To confirm the diagnosis of cirrhosis, the patient underwent a percutaneous liver biopsy. The sample obtained was from the right liver lobe and was adequate for interpretation, over 2cm in length. It showed minimal macrovesicular steatosis without features of steatohepatitis and no significant portal or lobular inflammation. Trichrome stain revealed stage 1 fibrosis with patchy perisinusoidal fibrosis. DISCUSSION: We concluded that the patient did not have cirrhosis, and that chronic PV thrombus contributed to left hepatic lobe atrophy. The etiology of chronic PV thrombus remains elusive. FibroScan results were likely confounded by the atrophic left hepatic lobe. Our case highlights the importance of confirming cirrhosis with liver biopsy in particular subsets of patients given the many implications in the patient’s monitoring and prognosis with a diagnosis of cirrhosis.Image 1.: Atrophy of the Left Hepatic Lobe.

2066 Much Ado About Nothing: Isolated Raised ALP in IBD Patients Due to Macrocomplex

INTRODUCTION: Macro-Alkaline Phosphatase (ALP) is a rare benign condition characterised by increased plasma ALP activity due to an immunoglobulin-bound form of ALP. Due to an autoimmune process, antibodies can be generated against any of the enzymes, leading to the formation of “macroenzymes”, which interferes with the correct laboratory measurement of the native enzymes. These have been identified for several enzymes including alkaline phosphatase (ALP), amylase, AST, creatine kinase, γ-glutamyl transferase and lactate dehydrogenase. CASE DESCRIPTION/METHODS: 51-year-old woman with a long-standing history of ulcerative colitis and psoriasis presented for establishing care. She reported alternating diarrhea and constipation and musculoskeletal pains but no jaundice or itching. Her labwork showed normal levels of AST, ALT and total bilirubin but raised ALP (190 units/L, UNL-103). Hepatic origin of raised ALP was confirmed with mildly elevated GGT (42 U/L, UNL- 37). Repeat labs done at monthly intervals showed persistently elevated ALP ranging between 140-240 U/L. She underwent extensive workup to rule out an obstructive pathology, including a USG and MRCP which were unremarkable and liver biopsy which showed preserved hepatic architecture with minimal steatosis. Fractionation of her ALP via gel electrophoresis showed Macro-ALP complexes. She was followed up for a period of 2 years, with persistently elevated ALP but no obstructive symptoms or liver dysfunction. DISCUSSION: Isolated raised ALP is a common finding seen in up to 16% of hospitalized patient. However, this becomes concerning in patients with IBD due to its association with disorders of the hepatobiliary system, particularly Primary Sclerosing Cholangitis, seen in upto 5% of IBD patients The mean time from the development of symptoms of IBD to the diagnosis of PSC was 2.3 months. The biochemical parameters are consistent with cholestasis. Our patient was beyond the time frame for the development of PSC and showed no symptoms of signs of cholestasis. Macro-ALP as a cause of persistently elevated ALP has been reported twice earlier in literature. Strategies to identify macro enzymes include polyethylene glycol precipitation,counter-immunoelectrophoresis or gel electrophoresis. In general, the identification of macro-enzyme complexes is important to rule out pathological causes of raised serum enzyme activity and avoid unnecessary and potentially harmful diagnostic investigations.

1387 Late Recurrence of Metastatic Pancreatic Angiomyolipoma in Tuberous Sclerosis Following Bilateral Nephrectomy and Transplant

INTRODUCTION: Angiomyolipomas are typically benign tumors often associated with tuberous sclerosis, most commonly occurring in the kidneys. Some variants have malignant potential. Surgical resection remains the most effective form of treatment; however, recurrence after nephrectomy is rare, especially in the pancreas. CASE DESCRIPTION/METHODS: We report a unique case of a 59-year-old female with tuberous sclerosis who underwent bilateral nephrectomy for malignant, hemorrhagic angiomyolipomas with subsequent renal transplant. Almost 10 years after initial discovery of renal angiomyolipoma, patient presented to gastroenterology clinic with elevated liver function tests and was subsequently referred for endoscopic ultrasound (EUS) to evaluate for biliary obstruction as the etiology. If no obstruction was found, an EUS guided liver biopsy was requested. The EUS showed a normal non-dilated common bile duct (CBD) with no evidence of obstruction. EUS guided liver biopsy was then performed using a 19G core biopsy needle. Incidentally, she was found to have pancreatic tail mass lesion which measured 13 mm in diameter. This was not visualized on her previous surveillance CT scans. EUS fine needle aspiration was performed on the pancreatic tail mass with a 25G needle. The liver biopsy showed mild iron overload and minimal macrovesicular steatosis. The cytology from the pancreatic lesion was reported as an angiomyolipoma. The patient was subsequently referred to surgical oncology for evaluation of distal pancreatectomy. DISCUSSION: This is the second reported case of a pancreatic angiomyolipoma in a tuberous sclerosis patient, however guidelines on surveillance are lacking. Radiological imaging has not been an effective form of detecting pancreatic angiomyolipomas. This case highlights the importance of continued surveillance, and the possible role of EUS in that surveillance, for recurrent angiomyolipoma following nephrectomy in patients with tuberous sclerosis.

Oxidative stress biomarkers in the serum and plasma of patients with non-alcoholic fatty liver disease (NAFLD). Can plasma AGE be a marker of NAFLD? Oxidative stress biomarkers in NAFLD patients

Still little is known about the redox abnormalities in patients with non-alcoholic fatty liver disease (NAFLD). The purpose of the study was to find the relationship between enzymatic and non-enzymatic antioxidants, redox homeostasis and oxidative damage in 67-patients with NAFLD. The study population was divided into patients with non-alcoholic fatty liver (early NAFLD, n = 29) and patients with non-alcoholic steatohepatitis (advanced NAFLD, n = 38). Redox biomarkers: enzymatic antioxidants (Cu − Zn-superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR)); non-enzymatic antioxidants and redox status (reduced glutathione (GSH), total antioxidant capacity (TAC)); and oxidative damage products (total oxidant status (TOS), advanced glycation end products (AGE), malondialdehyde (MDA), and DNA/RNA oxidative damage) were determined in the serum/plasma samples. The activity of SOD, GPx, GR and levels of GSH, TOS, AGE, MDA, and DNA/RNA oxidative damage were significantly elevated in early NAFLD and advanced NAFLD group compared to controls (p < .001). There was a positive correlation between AGE, TAC and ALT activity (R = 0.34, p = .04; R = 0.36, p = .03, respectively) in advanced NAFLD group. Interestingly, ROC analysis for AGE showed good discriminatory ratio for patients with minimal steatosis (BARD score 0–1) vs. moderate steatosis (BARD score 2–4), AUC = 0.76. Plasma AGE can be a potential non-invasive biomarker differentiating NAFLD patients.

Extrapulmonary Hepatic Histoplasmosis Presenting as Chronic Liver Disease: A Case Report

Introduction: Histoplasma capsulatum is the most common endemic mycosis in the United States. Extrapulmonary hepatic histoplasmosis as a primary manifestation is extremely rare. We report a case of histoplasmosis that presented like chronic liver disease with portal hypertension, splenomegaly, esophageal varices, and thrombocytopenia in an immunocompetent adult. Case Description: A 56 year-old Caucasian man from West Virginia who works in construction presented to the hepatology clinic for work up of chronic liver disease. He was initially evaluated by his primary care doctor for complaints of diarrhea and had an EGD performed that revealed esophageal varices. On examination, he was noted to have splenomegaly but no other stigmata of chronic liver disease. A CBC was only remarkable for a platelet count of 86. A CMP was unremarkable with normal liver enzymes. INR was 1.0. Serological work up for liver disease including ceruloplasmin, remote hepatitis panel, iron studies, anti-nuclear antibody, anti-mitochondrial antibody, anti-smooth muscle antibody, and alpha 1 anti-trypsin were normal. A RUQ ultrasound with elastography showed a normal, homogenous liver, splenomegaly and a liver stiffness of F2-F3 indicating moderate fibrosis. EGD was repeated which showed large (>5mm) esophageal varices that were banded. It also revealed moderate portal hypertensive gastropathy. Transjugular liver biopsy was performed that revealed bridging fibrosis with minimal steatosis, no obvious granulomas but loose clusters of histiocytes, and a gomori methenamine silver stain was performed looking for histoplasmosis that highlighted small yeast with budding typical for Histoplasma capsulatum. Histoplasma antibody in the blood was positive. The patient was seen by infectious disease and he was started on oral itraconazole. Discussion: Hepatic histoplasmosis can present as granulomatous hepatitis, as stigmata of portal hypertension, including ascites or varices, or with elevated liver enzymes. The most common hepatic finding on liver biopsy is portal lymphohistiocytic inflammation; discrete hepatic granulomas are seen in less than 20% of involved livers. There are only a few case reports of disseminated histoplasmosis presenting as primary hepatic histoplasmosis. A high clinical suspicion is warranted in patients who present with stigmata of portal hypertension and chronic liver disease with no evidence of cirrhosis, especially if the person lives in or has visited an endemic area.2252 Figure 1. The normal lobular architecture is distorted by bridging fibrosis. The hepatocytes show minimal steatosis. Although well-developed granulomas are not identified, there are loose clusters of histiocytes.

MiR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice

microRNAs were recently suggested to contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a disease lacking specific pharmacological treatments. In that regard, nuclear receptors are arising as key molecular targets for the treatment of nonalcoholic steatohepatitis (NASH). Here we show that, in a typical model of NASH-associated liver damage, microRNA-21 (miR-21) ablation results in a progressive decrease in steatosis, inflammation and lipoapoptosis, with impairment of fibrosis. In a complementary fast food (FF) diet NASH model, mimicking features of the metabolic syndrome, miR-21 levels increase in both liver and muscle, concomitantly with decreased expression of peroxisome proliferator-activated receptor α (PPARα), a key miR-21 target. Strikingly, miR-21 knockout mice fed the FF diet supplemented with farnesoid X receptor (FXR) agonist obeticholic acid (OCA) display minimal steatosis, inflammation, oxidative stress and cholesterol accumulation. In addition, lipoprotein metabolism was restored, including decreased fatty acid uptake and polyunsaturation, and liver and muscle insulin sensitivity fully reinstated. Finally, the miR-21/PPARα axis was found amplified in liver and muscle biopsies, and in serum, of NAFLD patients, co-substantiating its role in the development of the metabolic syndrome. By unveiling that miR-21 abrogation, together with FXR activation by OCA, significantly improves whole body metabolic parameters in NASH, our results highlight the therapeutic potential of nuclear receptor multi-targeting therapies for NAFLD.

The First Case of Total Laparoscopic Living Donor Right Hemihepatectomy in Mainland China and Literature Review

Total laparoscopic living donor right hemihepatectomy (LDRH) has been successfully performed in several transplant centers. Here we report the first LDRH performed in mainland China and review current literature, focusing on perioperative donor evaluation and surgical procedure to secure donor safety. A 47-year-old man volunteered for living donation to his wife who suffered from sclerosing cholangitis-related liver cirrhosis and hepatocellular carcinoma. Donor height is 165 cm and weight is 65 kg, whereas the body mass index is 23.9. The CT volume evaluation showed that the graft-to-body weight ratio was 1.42%, and the remnant liver volume was 36.3% for right graft without middle hepatic vein (MHV). The anatomy of hepatic vein, artery, portal vein, and bile duct was normal. Preoperative liver function tests were normal. Intraoperative biopsy result showed minimal steatosis. A transection was performed along the right side of the MHV. Two branches of MHV (V5 and V8) were <5 mm in diameter, and there was no need for reconstruction in the back table. Hilar dissection was meticulously performed. Right portal vein, hepatic artery, and bile duct were transected above the bifurcation. The right hepatic vein was transected by a laparoscopic linear stapler. The real graft volume was 660 mL, with a revised graft-to-body weight ratio of 1.14%. Warm ischemia time was about 4 minutes. The donor's postoperative course was uneventful. Total LDRH has been proven to be technically feasible in selected adult donors. Following increased experience, it might be a safe and minimally invasive option for adult donors.

Effect of ischaemic preconditioning on recurrence of hepatocellular carcinoma in an experimental model of liver steatosis.

Livers with parenchymal abnormalities tolerate ischaemia-reperfusion (IR) injury poorly. IR injury is a risk factor for hepatocellular carcinoma (HCC) recurrence. This study assessed the link between liver parenchymal abnormalities and HCC recurrence, and evaluated the protective effect of ischaemic preconditioning. C57BL/6 mice were fed a choline-deficient diet for 6 and 12 weeks, or standard chow. Hepatic IR and ischaemic preconditioning were achieved by clamping liver blood inflow. Hepa 1-6 HCC cells were inoculated through the spleen. Thereafter, tumour burden, serum α-fetoprotein and cancer cell aggressiveness were compared among groups. Hepatocellular damage and expression of inflammatory genes (encoding interleukin 6, tumour necrosis factor α, hypoxia inducible factor 1α and E-selectin) were exacerbated after IR injury in mice with severe steatosis. Compared with control livers or those with minimal steatosis, livers exposed to a prolonged choline-deficient diet developed larger tumour nodules and had higher serum α-fetoprotein levels. Non-ischaemic liver lobes from mice with steatosis were not protected from accelerated tumour growth mediated by IR injury. This remote effect was linked to promotion of the aggressiveness of HCC cells. Ischaemic preconditioning before IR injury reduced the tumour burden to the level of that in non-ischaemic steatotic controls. This protective effect was associated with decreased cancer cell motility. Livers with steatosis tolerated IR poorly, contributing to more severe HCC recurrence patterns in mice with increasingly severe steatosis. IR injury also had a remote effect on cancer cell aggressiveness. Ischaemic preconditioning before IR injury reduced tumour load and serum α-fetoprotein levels. Liver ischaemia-reperfusion (IR) injury is associated with organ dysfunction and surgical morbidity. Livers with steatosis tolerate IR injury poorly in the setting of both liver resection and liver transplantation. Ischaemic preconditioning is a simple method to mitigate IR injury. This study shows that ischaemic preconditioning of mouse livers with steatosis reduces ischaemia-mediated tumour growth acceleration. Liver parenchymal abnormalities such as warm IR injury and liver steatosis should be taken into account to predict accurately the risk of liver cancer recurrence after surgical management. Ischaemic preconditioning strategies may hold therapeutic potential not only to mitigate surgical morbidity but also to reduce postoperative recurrence of liver cancer.

Hepatic Deficiency of Augmenter of Liver Regeneration Exacerbates Alcohol-Induced Liver Injury and Promotes Fibrosis in Mice.

Why only a subpopulation (about 15%) of humans develops liver cirrhosis due to alcohol is a critical as yet unanswered question. Liver-specific depletion of augmenter of liver regeneration (ALR) protein in mice causes robust steatosis and hepatocyte apoptosis by 2 weeks; these pathologies regress subsequently with return of ALR expression even at lower than control levels, but the mice develop modest steatohepatitis by 8 weeks. We aimed to investigate whether chronic alcohol ingestion promotes excessive hepatic fibrosis in these ALR-deficient mice. Liver-specific ALR-deficient and wild type (WT) female mice (8–10 weeks old) were placed on 4% alcohol-supplemented or isocaloric diet for 4 weeks. Liver sections were examined for histopathology, and parameters of steatosis and fibrosis were quantified. The mRNA expression of alcohol dehydrogenase-1, acetaldehyde dehydrogenase-1 and cytochrome P450-2E1 increased in WT mice but decreased in ALR-deficient mice upon alcohol ingestion. While alcohol induced steatosis and mild inflammation in WT mice, ALR-deficient mice showed minimal steatosis, strong hepatocellular injury and inflammation, prominent ductular proliferation, and robust fibrosis. Compared to the WT mice, alcohol feeding of ALR-deficient mice resulted in significantly greater increase in hepatic TNFα and TGFβ, and oxidative stress; there was also hepatic iron accumulation, robust lipid peroxidation and mitochondrial DNA damage. Importantly, similar to ALR-deficient mice, lower hepatic ALR levels in human alcoholic liver cirrhosis were associated with increased iron content, reduced expression of alcohol dehydrogenase and acetaldehyde dehydrogenase, and elevated fibrogenic markers. We conclude that ALR deficiency or anomaly can play a critical role in alcohol-induced hepatic fibrosis/cirrhosis, mechanisms of which may involve dysregulation of alcohol metabolism and iron homeostasis, mitochondrial damage and oxidative injury.

Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in the liver

Acyl-CoA thioesterase (Acot)2 localizes to the mitochondrial matrix and hydrolyses long-chain fatty acyl-CoA into free FA and CoASH. Acot2 is expressed in highly oxi-dative tissues and is poised to modulate mitochondrial FA oxidation (FAO), yet its biological role is unknown. Using a model of adenoviral Acot2 overexpression in mouse liver (Ad-Acot2), we show that Acot2 increases the utilization of FA substrate during the daytime in ad libitum-fed mice, but the nighttime switch to carbohydrate oxidation is similar to control mice. In further support of elevated FAO in Acot2 liver, daytime serum ketones were higher in Ad-Acot2 mice, and overnight fasting led to minimal hepatic steatosis as compared with control mice. In liver mitochondria from Ad-Acot2 mice, phosphorylating O₂ consumption was higher with lipid substrate, but not with nonlipid substrate. This increase depended on whether FA could be activated on the outer mitochondrial membrane, suggesting that the FA released by Acot2 could be effluxed from mitochondria then taken back up again for oxidation. This circuit would prevent the build-up of inhibitory long-chain fatty acyl-CoA esters. Altogether, our findings indicate that Acot2 can enhance FAO, possibly by mitigating the accumulation of FAO intermediates within the mitochondrial matrix.

Steatohepatitic hepatocellular carcinoma-a case report with literature review.

We report a case of a 65year old male who presented with complaints of pain right upper abdomen for past 3months. He was a known diabetic and hypertensive. On evaluation he was found to have space occupying lesion in the right lobe of the liver. USG Guided FNC done showed a Hepatocellular Carcinoma with predominant steatosis. He underwent Right Hepetectomy for the same and Histopathological examination revealed a Steatohepatitic Hepatocellular Carcinoma with background liver showing minimal steatosis and no significant fibrosis. This case is reported to provide better insight into the understanding of pathophysiology of metabolic syndrome as an etiological agent for development of HCC.

Fatal Acute Liver Failure in a Kidney-Transplant Recipient

36 Question: A 56-yearold man was transferred from another hospital with a rapid onset of jaundice, ascites and hepatic encephalopathy. He had a 7-year history of idiopathic hemolytic uremic syndrome leading to terminal renal failure, despite treatment with plasmapheresis and glucocorticoids. Cadaveric renal transplantation was performed 5 years previously. Immunosuppression consisted of tacrolimus, mycophenolate mofetil, and prednisolone. Serum tacrolimus trough levels ranged from 7 to 12 ng/mL. Pretransplant checkup including abdominal ultrasonography and liver function tests showed no abnormalities. About 7 months posttransplant, the patient developed anicteric chronic hepatitis with consistently elevated alanine aminotransferase (ALT) and aspartate aminotransferase levels ranging from 90 to 470 U/L, and 60 to 400 U/L, respectively (Figure A). Serologic tests for hepatitis B (HBV), C (HCV), E virus (HEV), Epstein–Barr virus, and cytomegalovirus, autoimmune serology (antinuclear antibody, anti-smooth muscle antibody, anti-mitochondrial antibody, and liver-kidney microsomal antibody-1) as well as HBV and HCV polymerase chain reaction (PCR) analyses from peripheral blood were repeatedly negative. Serum concentrations of a1 antitrypsin, copper, and ceruloplasmin were in the reference range. Liver biopsy showed distinct pericellular fibrosis with incomplete cirrhosis as well as minimal steatosis and mild inflammatory activity suggesting underlying steatohepatitis (Figure B). Iron and copper concentrations in the liver tissue were normal. Right ventricular failure, constrictive pericarditis, and Budd-Chiari syndrome were ruled out. Despite intensive therapy the patient lapsed into hepatic coma and died before liver transplantation could be performed. What is your diagnosis? Look on page 325 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

M2 Kupffer cells promote M1 Kupffer cell apoptosis: A protective mechanism against alcoholic and nonalcoholic fatty liver disease

Alcoholic and nonalcoholic fatty liver disease (ALD and NAFLD) are the predominant causes of liver-related mortality in Western countries. We have shown that limiting classical (M1) Kupffer cell (KC) polarization reduces alcohol-induced liver injury. Herein, we investigated whether favoring alternatively activated M2 KCs may protect against ALD and NAFLD. Ongoing alcohol drinkers and morbidly obese patients, with minimal hepatic injury and steatosis, displayed higher hepatic expression of M2 genes, as compared to patients with more severe liver lesions; individuals with limited liver lesions showed negligible hepatocyte apoptosis but significant macrophage apoptosis. Experiments in mouse models of ALD or NAFLD further showed that BALB/c or resveratrol-treated mice fed alcohol or a high-fat diet displayed preponderant M2 KC polarization, M1 KC apoptosis, and resistance to hepatocyte steatosis and apoptosis, as compared to control C57BL6/J mice. In vitro experiments in isolated KC, peritoneal, and Raw264.7 macrophages demonstrated that M1 macrophage apoptosis was promoted by conditioned medium from macrophages polarized into an M2 phenotype by either interleukin (IL)4, resveratrol, or adiponectin. Mechanistically, IL10 released from M2 cells promoted M1 death, and anti-IL10 antibodies blunted the proapoptic effects of M2-conditioned media. IL10 secreted by M2 KCs promoted selective M1 death by a mechanism involving activation of arginase in high inducible nitric oxide synthase-expressing M1 KCs. In alcohol-exposed mice, neutralization of IL10 impaired M1 apoptosis. These data uncover a novel mechanism regulating the M1/M2 balance that relies on apoptotic effects of M2 KCs towards their M1 counterparts. They suggest that promoting M2-induced M1 KC apoptosis might prove a relevant strategy to limit alcohol- and high fat-induced inflammation and hepatocyte injury.