• adrenal incidentaloma
• computed tomography
• hepatosteatosis
• mild autonomous cortisol secretion
• nonalcoholic fatty liver disease

• Humans
• Non-alcoholic Fatty Liver Disease/diagnostic imaging
• Non-alcoholic Fatty Liver Disease/epidemiology
• Non-alcoholic Fatty Liver Disease/blood
• Male
• Female
• Middle Aged
• Hydrocortisone/blood
• Tomography, X-Ray Computed
• Prevalence
• Adult
• Aged
• Adrenal Gland Neoplasms/blood
• Adrenal Gland Neoplasms/epidemiology
• Adrenal Gland Neoplasms/diagnostic imaging
• Risk Factors

• Animals
• Adenosine Triphosphate/metabolism
• Adenosine Triphosphate/analysis
• Hypochlorous Acid/analysis
• Hypochlorous Acid/metabolism
• Mice
• Inflammation/metabolism
• Fluorescent Dyes/chemistry
• Liver/metabolism
• Liver/pathology
• Hepatocytes/metabolism
• Mice, Inbred C57BL
• Male
• Ions/chemistry

• COVID-19
• Hospital charges
• Inpatient resource utilization
• Metabolic dysfunction-associated steatotic liver disease
• Prevalence

• computed tomography
• diagnostic performance
• hepatic fat
• magnetic resonance image
• radiation

• Humans
• Protons
• Retrospective Studies
• Tomography, X-Ray Computed/methods
• Liver/diagnostic imaging
• Liver/pathology
• Fatty Liver/diagnostic imaging
• Algorithms
• Magnetic Resonance Imaging/methods

• cirrhosis
• nonalcoholic fatty liver disease
• noninvasive assessment

• Alcoholic hepatitis histology score (AHHS)
• Batts-Ludwig
• Ishak
• Liver biopsy
• MAFLD
• METAVIR
• NAFLD activity score (NAS)
• Repeat biopsy

• inflammation
• insulin resistance
• non-alcoholic fatty liver disease
• oxidative stress
• platelet-activating factor

• Yunnan Province Applied Basic Research Project

• Fructose
• Inflammatory markers
• Non-alcoholic fatty liver

• Elasticity imaging techniques
• Inflammation
• Magnetic resonance imaging
• Nonalcoholic fatty liver disease

• Biomarkers
• Elasticity Imaging Techniques
• Fibrosis
• Humans
• Liver/diagnostic imaging
• Liver/pathology
• Liver Cirrhosis/diagnostic imaging
• Liver Cirrhosis/pathology
• Magnetic Resonance Imaging
• Non-alcoholic Fatty Liver Disease/diagnostic imaging
• Non-alcoholic Fatty Liver Disease/pathology
• Prospective Studies
• Retrospective Studies

• R37 EB001981 NIBIB NIH HHS
• R01 DK088925 NIDDK NIH HHS
• U01DK061718 NIDDK NIH HHS
• R01 EB001981 NIBIB NIH HHS
• R01 DK083380 NIDDK NIH HHS
• R01 DK100651 NIDDK NIH HHS
• U01 DK061718 NIDDK NIH HHS
• K24 DK102595 NIDDK NIH HHS
• K23 DK090303 NIDDK NIH HHS
• R01 EB017197 NIBIB NIH HHS
• K23DK090303, R01DK083380, R01DK088925, R01DK100651, K24DK102595, R01DK106419 NIDDK NIH HHS
• R01 DK106419 NIDDK NIH HHS

An excess fat in the liver enhances the susceptibility to hepatic cancer. We found that Armcx3, a protein only known to date to play a role in neural development, is strongly increased in mouse liver in response to lipid availability and proliferation-inducing insults. In patients, the levels of hepatic Armcx3 are also increased in conditions of high exposure of the liver to fat. We wanted to determine the role of Armcx3 in the hepatocarcinogenesis favored by a high-fat diet. We generated mice with genetically driven suppression of Armcx3, and we found that they were protected against experimentally induced hepatic cancer, especially in conditions of a high-fat diet. Armcx3 was also found to promote hepatic cell proliferation through the interaction with Sox9, a known proliferation factor in hepatocellular carcinoma. Armcx3 is identified as a novel factor in meditating propensity to liver cancer in conditions of high hepatic lipid insults.

ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly upregulated in mouse liver in response to high lipid availability, and that hepatic ARMCX3 is upregulated in patients with NAFLD and hepatocellular carcinoma (HCC). Mice were subjected to ARMCX3 invalidation (inducible ARMCX3 knockout) and then exposed to a high-fat diet and diethylnitrosamine-induced hepatocarcinogenesis. The effects of experimental ARMCX3 knockdown or overexpression in HCC cell lines were also analyzed. ARMCX3 invalidation protected mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis. ARMCX3 invalidation promoted apoptotic cell death and macrophage infiltration in livers of diethylnitrosamine-treated mice maintained on a high-fat diet. ARMCX3 downregulation reduced the viability, clonality and migration of HCC cell lines, whereas ARMCX3 overexpression caused the reciprocal effects. SOX9 was found to mediate the effects of ARMCX3 in hepatic cells, with the SOX9 interaction required for the effects of ARMCX3 on hepatic cell proliferation. In conclusion, ARMCX3 is identified as a novel molecular actor in liver physiopathology and carcinogenesis. ARMCX3 downregulation appears to protect against hepatocarcinogenesis, especially under conditions of high dietary lipid-mediated hepatic insult.

• Alex3
• HCC
• NAFLD
• SOX9
• lipotoxicity
• obesity

• Complications
• Imaging
• Liver cancer
• Liver fibrosis

Chronic hepatitis B patients in Taiwan with no or limited liver injury are not reimbursed for antiviral treatment by the Taiwan National Health Insurance (NHI). Innovative fibrosis marker, age-adjusted Fibrosis-4 Index (FIB4-AA), was implemented to evaluate the tendency of liver fibrosis in these patients.

The FIB-4 indices of 256 antiviral treatment-naïve chronic hepatitis B patients at Kaohsiung Medical University Hospital from 2003 to 2019 were reviewed. The difference in initial FIB-4 and last FIB4-AA was treated as a categorical variable, representing the tendency of liver fibrosis in each individual aside from ageing. Logistic regression was implemented to evaluate the three parameters most dependent on increment of FIB4-AA: e seroconversion, body mass index (BMI) and initial FIB-4 index.

The yearly FIB-4 growth rate of an individual without chronic hepatitis was lower than that of the study group (0.0237 vs 0.0273 for males, 0.02 vs 0.0288 for females). Patients undergoing or completing e seroconversion were less prone to increment of FIB4-AA (p=0.036, OR 0.524). Logistic regression revealed that BMI ≥25 kg/m² significantly less increment of FIB4-AA (p=0.001, OR 0.383, 95% CI 0.212 to 0.690), while patients with initial FIB-4 <1.29 were prone to increasing liver FIB4-AA (p=0.000, OR 3.687, 95% CI 1.999 to 6.797).

Chronic hepatitis B patients not meeting the reimbursement criteria of the Taiwan NHI are prone to increment of liver fibrosis marker. Overweight is associated with less increment of fibrosis marker, while initial FIB-4 <1.29 is associated with increasing fibrosis marker.

• hepatic fibrosis
• hepatitis B
• obesity

• Alanine Transaminase/blood
• Amino Acids/deficiency
• Amino Acids/metabolism
• Animals
• Cell Adhesion/genetics
• Choline/metabolism
• Diet/veterinary
• Disease Models, Animal
• Endothelial Cells/cytology
• Endothelial Cells/drug effects
• Endothelial Cells/metabolism
• Inflammation/genetics
• Lipogenesis/genetics
• Liver/metabolism
• Liver/pathology
• Male
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/etiology
• Protective Agents/chemistry
• Protective Agents/pharmacology
• Protective Agents/therapeutic use
• Triglycerides/metabolism
• Tumor Necrosis Factor-alpha/genetics
• Tumor Necrosis Factor-alpha/metabolism

• National Research Foundation of Korea
• National Research Foundation of Korea (KR)

• dyslipidemia
• nomogram
• nonalcoholic fatty liver disease

• Adult
• Asian People
• China/epidemiology
• Cohort Studies
• Female
• Humans
• Male
• Middle Aged
• Nomograms
• Non-alcoholic Fatty Liver Disease/epidemiology
• Non-alcoholic Fatty Liver Disease/ethnology
• Non-alcoholic Fatty Liver Disease/etiology
• Retrospective Studies

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) is a major cause of liver fibrosis and cirrhosis. Accurate assessment of liver fibrosis is important for predicting disease outcomes and assessing therapeutic response in clinical practice and clinical trials. Although noninvasive tests such as transient elastography and magnetic resonance elastography are preferred where possible, histological assessment of liver fibrosis via semiquantitative scoring systems remains the current gold standard. Collagen proportionate area provides more granularity by measuring the percentage of fibrosis on a continuous scale, but is limited by the absence of architectural input. Although not yet used in routine clinical practice, advances in second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy imaging show great promise in characterising architectural features of fibrosis at the individual collagen fiber level. Quantification and calculation of different detailed variables of collagen fibers can be used to establish algorithm-based quantitative fibrosis scores (e.g., qFibrosis, q-FPs), which have been validated against fibrosis stage in NAFLD. Artificial intelligence is being explored to further refine and develop quantitative fibrosis scoring methods. SHG-microscopy shows promise as the new gold standard for the quantitative measurement of liver fibrosis. This has reaffirmed the pivotal role of the liver biopsy in fibrosis assessment in NAFLD, at least for the near-future. The ability of SHG-derived algorithms to intuitively detect subtle nuances in liver fibrosis changes over a continuous scale should be employed to redress the efficacy endpoint for fibrosis in NASH clinical trials; this approach may improve the outcomes of the trials evaluating therapeutic response to antifibrotic drugs.

• Biopsy
• Fibrosis
• Nonalcoholic fatty liver disease

• EZH2
• NAFLD
• NASH
• epigenetics
• liver fibrosis

• Drug Delivery Systems
• Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors
• Enhancer of Zeste Homolog 2 Protein/metabolism
• Humans
• Liver/metabolism
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/metabolism

In patients with nonalcoholic fatty liver disease (NAFLD), liver fibrosis is the predictive factor for liver-related events and prognosis. This retrospective study aimed to evaluate longitudinal changes in the FIB-4 index and to determine a strategy for diagnosing and following patients with NAFLD using this index. We analyzed the FIB-4 index at baseline and after 1 and 5 years in 272 consecutive patients with biopsy-proven NAFLD. Of these, 52 patients underwent serial biopsies. The change in the FIB-4 index was correlated with changes in the fibrosis stage among these patients (p = 0.048). The median FIB-4 index was 1.64 at baseline, 1.45 at 1 year, and 1.74 at 5 years. The negative predictive value for advanced fibrosis at a low cutoff point was 90.4/90.1 at baseline/1 year. Its specificity at a high cutoff point increased from 65.0% at baseline to 82.3% at 1 year. Multivariate analysis identified the FIB-4 index at 1 year as a predictive factor for a FIB-4 index > 2.67 at 5 years. A FIB-4 index < 1.30 was acceptable for excluding advanced fibrosis at baseline. In contrast, to evaluate and predict advanced liver fibrosis with the FIB-4 index at a high cutoff point, we should use the index at 1 year after appropriate therapy.

• FIB-4 index
• liver fibrosis
• nonalcoholic fatty liver disease

• Echographic analysis
• Endothelial dysfunction
• ICAM-1
• Obesity

• Anatomy, Cross-Sectional
• Animals
• Endothelium, Vascular/diagnostic imaging
• Endothelium, Vascular/pathology
• Endothelium, Vascular/physiopathology
• Heart/diagnostic imaging
• Heart/physiopathology
• Intercellular Adhesion Molecule-1/metabolism
• Liver/diagnostic imaging
• Liver/physiopathology
• Male
• Musculoskeletal Diseases/diagnosis
• Musculoskeletal Diseases/etiology
• Musculoskeletal Diseases/pathology
• Musculoskeletal Diseases/physiopathology
• Musculoskeletal System/diagnostic imaging
• Musculoskeletal System/pathology
• Musculoskeletal System/physiopathology
• Myocardium/pathology
• Obesity/complications
• Obesity/diagnosis
• Obesity/physiopathology
• Rats
• Rats, Sprague-Dawley
• Ultrasonography
• Vascular Diseases/diagnosis
• Vascular Diseases/etiology
• Vascular Diseases/pathology
• Vascular Diseases/physiopathology
• Ventricular Dysfunction, Left/diagnosis
• Ventricular Dysfunction, Left/etiology
• Ventricular Dysfunction, Left/pathology
• Ventricular Dysfunction, Left/physiopathology

• Instituto Mexicano del Seguro Social

To examine in vitro acoustic property of nonalcoholic fatty disease in mouse and human liver to identify nonalcoholic steatohepatitis (NASH).

The acoustic impedance (× 10⁶ kg/m²/s) was measured in 35 free fatty acids (FFAs, 500 mmol/L) and histologically-diagnosed liver samples of twelve mice (four control, four simple steatosis [SS], and four NASH) and eight humans (two control, three SS, and three NASH), using 80-MHz acoustic microscopy. The sum of percentage (SP) composition of FFAs (SP-FFAs) was also assessed.

Median impedance of all FFAs was 0.7 (5 FFAs with impedance 0.7); 17 FFAs with impedance < 0.7 were classified as low-impedance group; and, 13 FFAs with impedance > 0.7 were classified as high-impedance group. The median impedance of the mouse liver decreased from control (1.715), to SS (1.68), to NASH (1.635) (control versus NASH, p = 0.039 without significant differences for the other comparisons, p ≥ 0.1). Similarly, the median impedance of human liver showed decreased from control (1.825), to SS (1.788), to NASH (1.76) (control versus SS, p = 0.023; control versus NASH, p = 0.003; SS versus NASH, p = 0.050). The ratio of SP-FFAs between the low-impedance and high-impedance groups showed an increase in both mice and humans, with significant differences in mice (control versus SS, p < 0.001; control versus NASH, p < 0.001; SS versus NASH, p = 0.003), without significant differences in humans (p ≥ 0.671).

Lower acoustic impedance based on the intrahepatic composition of FFAs may be characteristic of NASH.

• Acoustic impedance tests
• Fatty acids
• Liver
• Nonalcoholic fatty liver disease
• Ultrasonography

• Bariatric surgery
• NAFLD
• Sleeve gastrectomy

Liver fibrosis consists in the accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells. This is commonly the result of chronic liver injury repair and represents an important health concern. As liver biopsy is burdened with many drawbacks, not surprisingly there is great interest to find new reliable noninvasive methods. Among the many are new potential fibrosis biomarkers under study, some of the most promising represented by the growth arrest-specific gene 6 (Gas6) serum protein and its family of tyrosine kinase receptors, namely, Tyro3, Axl, and MERTK (TAM). Gas6/TAM system (mainly, Axl and MERTK) has in fact recently emerged as an important player in the progression of liver fibrosis. This review is aimed at giving an overall perspective of the roles played by these molecules in major chronic liver diseases. The most promising findings up to date acknowledge that both Gas6 and its receptor serum levels (such as sAxl and, probably, sMERTK) have been shown to potentially allow for easy and accurate measurement of hepatic fibrosis progression, also providing indicative parameters of hepatic dysfunction. Although most of the current scientific evidence is still preliminary and there are no in vivo validation studies on large patient series, it still looks very promising to imagine a possible future prognostic role for these biomarkers in the multidimensional assessment of a liver patient. One may also speculate on a potential role for this system targeting (e.g., with small molecule inhibitors against Axl) as a therapeutic strategy for liver fibrosis management, always bearing in mind that any such therapeutic approach might face toxicity.

• Adipose Tissue, Beige/metabolism
• Animals
• Benzothiepins/pharmacology
• Bile Acids and Salts/metabolism
• Biomarkers
• Disease Models, Animal
• Energy Metabolism/drug effects
• Glycosides/pharmacology
• Lipid Metabolism/drug effects
• Lipid Regulating Agents/pharmacology
• Male
• Mice
• Mice, Knockout
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/etiology
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/pathology
• Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors
• Risk Factors
• Symporters/antagonists & inhibitors

Hepatic iron deposition is seen in cases of chronic hepatitis and cirrhosis, and is a hallmark of a poorer prognosis. Iron deposition is also found in non-alcoholic steatohepatitis (NASH) patients. We have now developed a mouse model of NASH with hepatic iron deposition by combining a methione- and choline-deficient (MCD) diet with an iron-overload diet. Using this model, we evaluated the effects of human placenta extract (HPE), which has been shown to ameliorate the pathology of NASH. Four-week-old male C57BL/6 mice were fed the MCD diet with 2% iron for 12 weeks. In liver sections, iron deposition was first detected around the portal vein after 1 week. From there it spread throughout the parenchyma. Biliary iron concentrations were continuously elevated throughout the entire 12-week diet. As a compensatory response, the diet caused elevation of serum hepcidin, which accelerates excretion of iron from the body. Accumulation of F4/80-positive macrophages was detected within the sinusoids from the first week onward, and real-time PCR analysis revealed elevated hepatic expression of genes related inflammation and oxidative stress. In the model mice, HPE treatment led to a marked reduction of hepatic iron deposition with a corresponding increase in biliary iron excretion. Macrophage accumulation was much reduced by HPE treatment, as was the serum oxidation-reduction potential, an index of oxidative stress. These data indicate that by suppressing inflammation, oxidative stress and iron deposition, and enhancing iron excretion, HPE effectively ameliorates iron overload-induced liver injury. HPE administration may thus be an effective strategy for treating NASH.

• Molecular biology

• Clinical trial
• Nonalcoholic fatty liver disease
• Nonalcoholic steatohepatitis

• Chalcones/therapeutic use
• Cholesterol Ester Transfer Proteins/genetics
• Clinical Trials as Topic
• Enzyme Inhibitors/therapeutic use
• Humans
• Lipase/genetics
• Membrane Proteins/genetics
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/epidemiology
• Non-alcoholic Fatty Liver Disease/pathology
• Propionates/therapeutic use
• Severity of Illness Index

Oxidative stress is recognized as a cancer-initiating stress response in the digestive system. It is produced through mitochondrial respiration and induces DNA damage, resulting in cancer cell transformation. However, recent findings indicate that oxidative stress is also a necessary anticancer response for destroying cancer cells. The oxidative stress response has also been reported to be an important step in increasing the anticancer response of newly developed molecular targeted agents. Oxidative stress might therefore be a cancer-initiating response that should be downregulated in the precancerous stage in patients at risk of cancer but an anticancer cell response that should not be downregulated in the postcancerous stage when cancer cells are still present. Many commercial antioxidant agents are marketed as “cancer-eliminating agents” or as products to improve one’s health, so cancer patients often take these antioxidant agents. However, care should be taken to avoid harming the anticancerous oxidative stress response. In this review, we will highlight the paradoxical effects of oxidative stress and antioxidant agents in the digestive system before and after carcinogenesis.

• antioxidant
• cancer
• oxidative stress
• reactive oxygen species

This study aims to determine the relationship between the different factors associated with the severity of Fibroscan with CAP findings among patients with Type 2 diabetes and fatty liver.

This is a cross-sectional study. Seven hundred four Fibroscan with Controlled Attenuation Parameter (CAP) results were electronically retrieved from a diagnostic center. 285 charts of diabetic patients with fatty liver on ultrasound were reviewed. 164 patients with fatty liver on ultrasound and Fibroscan with CAP were included in the study. Several factors were analysed in relation to the severity of Fibroscan with CAP findings in the study group.

Fifty five point five percent (55.5%) (91/164) had significant fibrosis and cirrhosis. Hepatic steatosis prevalence was 96% (158/164). Diabetes >5 years (OR 1.75), HbA1c >7% (OR 2.25) and high SGPT levels (OR 2.39) were associated with liver fibrosis and cirrhosis. BMI >25 kg/m2 (OR 1.45), triglyceride levels >150 mg/dl (OR 1.31) and HbA1c >7% (OR 1.74) were associated with hepatic steatosis.

Factors associated with the severity of hepatic fibrosis, cirrhosis and steatosis included above normal BMI, disease duration of >5 years, poor glycemic control and elevated levels of ALT, and serum triglycerides.

• NAFLD
• transient elastography
• type 2 diabetes

To investigate [¹¹C]acetate PET-surrogate parameter of fatty acid synthase activity—as suitable tool for diagnosis and monitoring of liver steatosis.

In this retrospective study, data were obtained from 83 prostatic carcinoma patients from 1/2008 to 1/2014. Mean HU was calculated from unenhanced CT of all patients from liver with liver HU less than 40 as threshold for liver steatosis. SUV_max of the liver and of the blood pool in thoracic aorta (as background for calculation of a liver/background ratio [SUV_l/b]) was measured. t test was used with a P < 0.05 considered as statistically significant difference and ROC analysis was used for calculating specificity and sensitivity.

19/83 patients (20%) had diagnosis of hepatic steatosis according to CT. Uptake of [¹¹C]acetate was significantly higher in patients with hepatic steatosis as compared to control group (SUV_max 7.96 ± 2.0 vs. 5.48 ± 2.3 [P < 0.001]). There was also a significant correlation between both SUV_max (r = − 0.52, P < 0.001) and SUV_l/b (r = − 0.59, P < 0.001) with the density (HU) of the liver. In ROC analysis for detection of liver steatosis SUV_max (threshold: 5.86) had a sensitivity of 94% and specificity of 69% with an AUC of 0.81. Increasing body mass index is correlated with the severity of steatosis.

We showed for the first time that hepatic steatosis associates with increased [¹¹C]acetate uptake. Also, severity of steatosis correlates with [¹¹C]acetate uptake. [¹¹C]acetate uptake PET seems promising for the assessment of liver steatosis.

The online version of this article (10.1007/s00261-018-1558-4) contains supplementary material, which is available to authorized users.

• Liver
• Liver steatosis
• NAFLD
• PET
• [11C]acetate

• Humans
• Liver/diagnostic imaging
• Magnetic Resonance Imaging
• Non-alcoholic Fatty Liver Disease/diagnostic imaging
• Tomography, X-Ray Computed
• Ultrasonography

Volixibat is a potent inhibitor of the apical sodium-dependent bile acid transporter in development for the treatment of nonalcoholic steatohepatitis. This phase 1, open-label study investigated the absorption, distribution, metabolism, and excretion of [¹⁴C]-volixibat in heathy men.

Eligible men (n = 8) aged 18–50 years (body mass index 18.0–30.0 kg/m²; weight >50 kg) received a single oral dose of [¹⁴C]-volixibat 50 mg containing ~5.95 µCi radioactivity. The primary objectives were to assess the pharmacokinetics of [¹⁴C]-volixibat and to determine the total radioactivity in whole blood, plasma, urine, and feces at pre-selected time points over 6 days. The secondary objectives were to characterize metabolites and to assess the safety and tolerability.

Low concentrations of volixibat (range 0–0.179 ng/mL) were detected in plasma up to 8 h following administration; the pharmacokinetic parameters could not be calculated. No radioactivity was observed in plasma or whole blood. The percentage (mean ± standard deviation) of total radioactivity in urine was 0.01 ± 0.007%. The vast majority (92.3 ± 5.25%) of volixibat was recovered in feces (69.2 ± 33.1% within 24 h). Unchanged volixibat was the only radioactive component detected in feces. Adverse events were mild in severity and mostly gastrointestinal. Changes in laboratory values were not clinically meaningful.

Following oral administration, [¹⁴C]-volixibat was excreted unchanged from the parent compound almost exclusively via fecal excretion, indicating that the drug is minimally absorbed. Consistent with other studies, adverse events were primarily gastrointestinal in nature.

ClinicalTrials.gov identifier NCT02571192.

The online version of this article (doi:10.1007/s13318-017-0429-7) contains supplementary material, which is available to authorized users.

• Adolescent
• Adult
• Benzothiepins/analysis
• Benzothiepins/blood
• Benzothiepins/pharmacokinetics
• Benzothiepins/urine
• Carbon Radioisotopes/pharmacokinetics
• Feces/chemistry
• Glycosides/analysis
• Glycosides/blood
• Glycosides/pharmacokinetics
• Glycosides/urine
• Healthy Volunteers
• Humans
• Male
• Middle Aged
• Young Adult

• Shire Human Genetic Therapies Inc. (Lexington, MA, USA)

Bangladesh is one of the countries facing huge burden of hepatocellular carcinoma (HCC). Hepatocellular carcinoma is the third commonest cancer in the country and it is just behind to cancer of the lung and cancer of the stomach. Hepatitis B virus (HBV) is responsible for 66% of HCC in Bangladesh. Presumptive prevalence of HBV and hepatitis C virus (HCV) may be as high as 5.4 and 0.84%, respectively, in Bangladesh, and liver diseases occupied 8 to 12% of admission in medicine wards of Public Medical College. In this mini review, I would like to highlight the impact of HBV and HCV in the development of HCC and the management of HCC from a Bangladesh perspective.

How to cite this article: Noor-E-Alam SM. Management of Hepatocellular Carcinoma: Bangladesh Perspective. Euroasian J Hepato-Gastroenterol 2018;8(1):52-53.

• Bangladesh
• Innovative cancer therapy
• Liver cancer
• Management.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world affecting almost one-fourth of the population. It may progress to nonalcoholic steatohepatitis (NASH), cirrhosis, end-stage liver disease, and liver cancer in the long run. Besides, it may make the natural history in other chronic liver diseases worse too. Furthermore, patients of NAFLD more often suffer from metabolic syndrome, ischemic heart disease, and extrahepatic malignancies than others, leading to a lower overall survival than the general population. Obesity and sedentary lifestyle are among the most important risk factors for NAFLD apart from increasing age, male sex, and certain genetic factors. Due to the rising incidence, possible adverse consequences, and the futile available treatment options, prevention is the key to tackle this health menace. Spreading awareness, adopting a healthy lifestyle with appropriate dietary modifications, regular physical activity are the cornerstones for challenging this unfolding monster.

How to cite this article: Nath P, Singh SP. Nonalcoholic Fatty Liver Disease: Time to Take the Bull by the Horns. Euroasian J Hepato-Gastroenterol 2018;8(1):47-51.

• Awareness
• Lifestyle change
• Nonalcoholic fatty liver disease
• Prevention.

Accumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat.

Overweight and obese adults were randomised 3:1 to double-blind volixibat or placebo, respectively, for 12 days. Volixibat was initiated at a once-daily dose of 20 mg, 40 mg or 80 mg. Based on the assessment of predefined safety events, volixibat dosing was either escalated or reduced. Other dose regimens (titrations and twice-daily dosing) were also evaluated. Assessments included safety, tolerability, stool hardness, faecal bile acid (FBA) excretion, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and lipids.

All 84 randomised participants (volixibat, 63; placebo, 21) completed the study, with no serious adverse events at doses of up to 80 mg per day (maximum assessed dose). The median number of daily bowel evacuations increased from 1 (range 0–4) to 2 (0–8) during volixibat treatment, and stool was looser with volixibat than placebo. Volixibat was minimally absorbed; serum levels were rarely quantifiable at any dose or sampling time point, thereby precluding pharmacokinetic analyses. Mean daily FBA excretion was 930.61 μmol (standard deviation [SD] 468.965) with volixibat and 224.75 μmol (195.403) with placebo; effects were maximal at volixibat doses ≥20 mg/day. Mean serum C4 concentrations at day 12 were 98.767 ng/mL (standard deviation, 61.5841) with volixibat and 16.497 ng/mL (12.9150) with placebo. Total and low-density lipoprotein cholesterol levels decreased in the volixibat group, with median changes of − 0.70 mmol/L (range − 2.8 to 0.4) and − 0.6990 mmol/L (− 3.341 to 0.570), respectively.

This study indicates that maximal inhibition of bile acid reabsorption, as assessed by FBA excretion, occurs at volixibat doses of ≥20 mg/day in obese and overweight adults, without appreciable change in gastrointestinal tolerability. These findings guided dose selection for an ongoing phase 2 study in patients with non-alcoholic steatohepatitis.

ClinicalTrials.gov identifier: NCT02287779 (registration first received 6 November 2014).

The online version of this article (10.1186/s40360-018-0200-y) contains supplementary material, which is available to authorized users.

• Apical sodium-dependent bile acid transporter (ASBT)
• Cholesterol
• LUM002
• Non-alcoholic fatty liver disease
• Non-alcoholic steatohepatitis
• Obesity
• SHP626
• Volixibat

Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002).

Participants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker).

Sixty-one individuals were randomised (HVs: placebo, n = 12; volixibat, n = 38; T2DM: placebo, n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6–3.2 times higher in HVs (643.73–1239.3 μmol/24 h) and ~8 times higher in T2DM (1786.0 μmol/24 h) than with placebo (HVs: 386.93 μmol/24 h; T2DM: 220.00 μmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3–5.3-fold from baseline to day 28 in HVs and by twofold in T2DM.

Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013).

The online version of this article (10.1186/s12876-017-0736-0) contains supplementary material, which is available to authorized users.

• Apical sodium-dependent bile acid transporter
• Bile acids
• Clinical pharmacology
• LUM002
• Non-alcoholic fatty liver disease
• Non-alcoholic steatohepatitis
• Phase 1 clinical trial
• SHP626
• Type 2 diabetes mellitus
• Volixibat

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world. The complete natural history of NAFLD is unknown because few high‐quality follow‐up studies have been conducted. Our aim was to find variables predicting disease severity through an extended follow‐up with serial biopsies. In a prospective cohort study, 129 patients who enrolled between 1988 and 1993 were asked to participate in a follow‐up study on two occasions; biochemical, clinical, and histologic data were documented. The mean time between biopsies was 13.7 (±1.7) and 9.3 (±1.0) years, respectively. At the end of the study period, 12 patients (9.3%) had developed end‐stage liver disease and 34% had advanced fibrosis. Out of the 113 patients with baseline low fibrosis (<3), 16% developed advanced fibrosis. Fibrosis progression did not differ among the different stages of baseline fibrosis (P = 0.374). Fifty‐six patients (43%) had isolated steatosis, of whom 9% developed advanced fibrosis (3 patients with biopsy‐proven fibrosis stage F3‐F4 and 2 patients with end‐stage liver disease). Fibrosis stage, ballooning, and diabetes were more common in patients who developed end‐stage liver disease; however, there were no baseline clinical, histologic, or biochemical variables that predicted clinical significant disease progression. Conclusion: NAFLD is a highly heterogeneous disease, and it is surprisingly hard to predict fibrosis progression. Given enough time, NAFLD seems to have a more dismal prognosis then previously reported, with 16% of patients with fibrosis stage <3 developing advanced fibrosis and 9.3% showing signs of end‐stage liver disease. (Hepatology Communications 2018;2:199–210)

The purpose of this review is to summarize the latest knowledge on the natural history of non-alcoholic fatty liver disease (NAFLD). The review focuses on mortality, liver-related complications, and histological course.

Studies during the last decade have established NAFLD as a potentially progressive liver disease. Age and diabetes are the strongest clinical predictors of progressive disease. Fibrosis stage is the most important histological variable to predict mortality and liver-related complications. So far, no study has been able to show that non-alcoholic steatohepatitis at baseline predicts mortality or future liver-related complications when adjusting for fibrosis.

The outlines of the natural history of NAFLD have become clearer during the last decade. There is limited data on factors that predict clinical progression. Prospective longitudinal studies are needed to help us predict worse outcome in individual patients.

• Liver histology
• Mortality
• Natural history
• Non-alcoholic fatty liver disease
• Non-alcoholic steatohepatitis
• Prognosis

• Linköping University

• Coronary disease
• Liver fibrosis
• Magnetic resonance imaging
• Multidetector computed tomography
• Non-alcoholic fatty liver disease

Non-alcoholic steatohepatitis (NASH) is a severe form of fatty liver disease that is defined by the presence of inflammation and fibrosis, ultimately leading to cirrhosis and hepatocellular carcinoma. Treatment with human placental extract (HPE) reportedly ameliorates the hepatic injury. We evaluated the effect of HPE treatment in a mouse model of NASH. In the methione- and choline-deficient (MCD) diet-induced liver injury model, fibrosis started from regions adjacent to the sinusoids. We administered the MCD diet with high-salt loading (8% NaCl in the drinking water) to mice deficient in the vasoprotective molecule RAMP2 for 5 weeks, with or without HPE. In both the HPE and control groups, fibrosis was seen in regions adjacent to the sinusoids, but the fibrosis was less pronounced in the HPE-treated mice. Levels of TNF-α and MMP9 expression were also significantly reduced in HPE-treated mice, and oxidative stress was suppressed in the perivascular region. In addition, HPE dose-dependently increased survival of cultured endothelial cells exposed to 100 μM H₂O₂, and it upregulated expression of eNOS and the anti-apoptotic factors bcl-2 and bcl-xL. From these observations, we conclude that HPE ameliorates NASH-associated pathologies by suppressing inflammation, oxidative stress and fibrosis. These beneficially effects of HPE are in part attributable to its protective effects on liver sinusoidal endothelial cells. HPE could thus be an attractive therapeutic candidate with which to suppress progression from simple fatty liver to NASH.

• Health Sciences
• Metabolism
• Pathology
• Pharmaceutical science

• CD36
• Chylomicron
• MTTP
• Non-alcoholic fatty liver disease
• Saturated fatty acids

• Hepatocellular carcinoma
• Metabolic syndrome
• Non-alcoholic fatty liver disease
• Steatohepatitis
• Steatosis

Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD). The minimal pathologic criteria for NASH include hepatic steatosis, ballooning degeneration, and lobular inflammation. The resolution of NASH, which relies on the loss of ballooning degeneration, is subject to sampling and observer variability in pathologic interpretation. Ballooning is associated with advanced hepatic fibrosis in cross‐sectional studies but is not a predictor of mortality in NAFLD. Fibrosis staging, while still subject to some sampling variability, has less observer variability and is a robust predictor of liver‐related mortality in NAFLD. In this study, we hypothesize that, regardless of the diagnosis of NASH, the presence of steatofibrosis (steatosis accompanied by fibrosis) regardless of other pathologic features can also be a robust predictor of mortality in NAFLD. We used our previously reported cohort of patients with NAFLD with liver biopsies and long‐term mortality follow‐up. Cox proportional hazard models were used to determine the predictors of overall and liver‐related mortality. Of 209 enrolled NAFLD subjects, 97 can be classified as having steatofibrosis. During follow‐up (median 150 months), 64 (30.6%) patients died, with 18 (8.6%) from liver‐related causes. Adjusted for age, both diagnostic categories of NASH and steatofibrosis were significantly and similarly associated with liver‐related mortality (adjusted hazard ratio [aHR], 9.9; 95% confidence interval (CI), 1.3‐74.9; P = 0.027; aHR, 6.7; 95% CI, 1.5‐29.8; P = 0.013, respectively). However, only steatofibrosis showed independent association with overall mortality (aHR, 1.76; 95% CI, 1.02‐3.05; P = 0.043). Conclusion: Steatofibrosis and NASH are similarly associated with liver‐related mortality, but only steatofibrosis is associated with overall mortality in patients with NAFLD. Given the inherent observer variability in ballooning degeneration, a key diagnostic component of NASH, we suggest that steatofibrosis should be considered a viable diagnostic classification for NAFLD subjects at risk or adverse outcomes and provides a simpler endpoint for clinical trials of therapeutic agents. (Hepatology Communications 2017;1:421–428)

• NAFLD/NASH
• antioxidants
• astaxanthin
• chemokine
• fibrosis
• inflammation
• insulin resistance
• macrophage/Kupffer cells
• β-cryptoxanthin

• Antioxidants/therapeutic use
• Carotenoids/therapeutic use
• Cryptoxanthins/therapeutic use
• Humans
• Insulin Resistance/immunology
• Liver/immunology
• Liver/metabolism
• Liver/pathology
• Macrophages
• Non-alcoholic Fatty Liver Disease/etiology
• Non-alcoholic Fatty Liver Disease/immunology
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/therapy
• Oxidative Stress
• Xanthophylls/therapeutic use

• Non-alcoholic steatohepatitis
• estrogen receptor β
• inflammation
• liver cirrhosis
• metabolic diseases
• non-alcoholic fatty liver disease
• obesity

The association between circulating microRNA-122 (miR-122) and histopathological features of nonalcoholic fatty liver disease (NAFLD) remains unclear.

The association of serum miR-122 levels with histopathological features of NAFLD (steatosis, ballooning, lobular inflammation, and stage, as histological components of nonalcoholic steatohepatitis) was examined in serial liver biopsies from 36 hepatocellular carcinoma (HCC)-free Japanese patients with histopathologically-proven NAFLD. The median interval between first and second liver biopsies was 4.6 years.

In patients who showed improvement of histopathological scores (steatosis, ballooning, and stage), serum miR-122 levels were significantly lower at second biopsy than first biopsy. In patients who showed no improvement, the changes at second biopsy were not different from those at first biopsy. There were significant and strong associations between serum miR-122 ratio (ratio of level at second biopsy to that at first biopsy) and changes in histopathological scores (of steatosis, lobular inflammation, and stage). There were also significant and strong associations between serum miR-122 ratio and changes in other clinical parameters, including aspartate aminotransferase and alanine aminotransferase.

Longitudinal examination of serial liver biopsies showed the association of serum miR-122 with histopathological features of HCC-free NAFLD patients.

The online version of this article (doi:10.1186/s12876-016-0557-6) contains supplementary material, which is available to authorized users.

• Circulating
• Longitudinal observation
• Nonalcoholic fatty liver disease
• Nonalcoholic steatohepatitis
• Serial liver biopsy
• microRNA-122