Background and Aims: Accumulated evidence has shown that chronic liver inflammation is one of the main risks of hepatocellular carcinoma (HCC), and E167K variant of the transmembrane 6 superfamily member 2 (TM6SF2) plays an important role in the progression of chronic liver diseases and HCC. The aim of this study was to explore effects of the TM6SF2 E167K variant on expression of the inflammatory cytokines TNF-α, IL-2, IL-6 and IL-8 in the HCC cell line HEPA 1-6.

Methods: HEPA 1-6 cells were infected with lentivirus containing either the TM6SF2 E167K variant or TM6SF2 wild-type, or control plasmids. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were conducted to analyze the expression of the inflammatory cytokines TNF-α, IL-2, IL-6 and IL-8. A t-test was used for statistical analysis.

Results: Compared with the control group and TM6SF2 overexpression group, the relative expression of IL-2 and IL-6 mRNAs were significantly elevated in the TM6SF2 E167K overexpression group (p < 0.05). The relative mRNA expression of IL-8 in the TM6SF2 and TM6SF2 E167K overexpression groups were increased compared to the control group (p < 0.05). No obvious differences were observed for the expression of TNF-α in each group. The expression of TNF-α, IL-2, IL-6 and IL-8 that was tested by western blotting showed the same trends as the qRT-PCR results.

Conclusions: In conclusion, the E167K variant of the TM6SF2 gene could promote the expression of inflammatory cytokines IL-2 and IL-6 in HEPA 1-6 cells, suggesting that the TM6SF2 E167K variant may accelerate the progression of HCC.

Background and Aims: Drug-induced liver injury with autoimmune features (AI-DILI) mimics the clinical presentation, and laboratory and pathologic features of idiopathic autoimmune hepatitis (AIH). We aimed to identify histopathologic hallmarks to differentiate these entities.

Methods: All liver biopsies archived for the past 10 years were reviewed retrospectively to identify cases of recently detected liver injury associated with predominantly lymphoplasmacytic interphase hepatitis, positive markers for liver autoimmunity, and negative tests for viral hepatitis. Twenty cases were divided into AIH (n = 12) or AI-DILI (n = 8) groups. Blind qualitative evaluation of necroinflammatory changes and liver fibrosis were performed according to the Scheuer scoring system. Cellular densities were determined using ImageJ (V1.51t, National Institutes of Health, Bethesda, MD, USA). Fibrosis was assessed on Masson trichrome-stained slides, and collagen deposition was estimated following a protocol of color deconvolution.

Results: Necroinflammatory changes as well as densities (portal and lobular) of neutrophils and eosinophils, intracellular cholestasis, and regenerative changes did not differ between the two groups (P ≥ 0.05). Neutrophil densities but not eosinophils showed a positive correlation with the severity of hepatocellular damage (r = 0.6 and 0.58, vs. alanine aminotransferase, P < 0.05). Ceroid-laden macrophages but not histiocytic aggregates appeared to be more common in AI-DILI (P < 0.05). AIH patients presented more often with evidence of chronic damage, including higher scores of fibrosis and collagen deposition, in comparison to AI-DILI (P < 0.05).

Conclusions: Although there is no histologic feature pathognomonic for AI-DILI or AIH, advanced stages of liver fibrosis can be used to support the diagnosis of AIH in some cases. Definitive diagnosis of AI-DILI requires follow-up and demonstration of complete remission after drug withdrawal with no need for immunosuppression.

Post-stroke depression (PSD) is a common and complex post-stroke neuropsychiatric disorder, which not only delays functional recovery but also increases mortality, and which currently lacks effective drug therapy. The pathogenesis of PSD is associated with impairment of the subcortical neural circuits and alterations of synaptic plasticity and neurotransmitters, but the exact mechanisms of PSD remain unknown. Our previous work indicates that the death-associated protein kinase 1 (DAPK1) mediates neuronal death after stroke. Genetic deletion of DAPK1 gene or blocking DAPK1 signal in the PSD mouse model can not only alleviate cerebral ischemic injury but also relieve PSD-like behaviors. Our previous work has also demonstrated the following results. First, the neural circuit of dorsal CA1 (dCA1) to medial prefrontal cortex (mPFC) (dCA1-mPFC) is selectively impaired after stroke. Second, the DAPK1 signal is involved in the impairment of dCA1-mPFC neural circuit after stroke. Third, genetic deletion of the DAPK1 gene or blocking of the DAPK1 signal alleviates the injury of dCA1-mPFC neural circuit after stroke and improves PSD-like behaviors. In conclusion, we hypothesize that activated DAPK1 signal after stroke induces apoptosis in the hippocampal dCA1 neurons, leading to loss of the dCA1-mPFC glutamatergic projections, synaptic injury, decrease of glutamate release, inhibition of mPFC neurons, and finally onset of PSD. We hope to further replenish the mechanisms of PSD and provide new insights for PSD treatment.

Lambl’s excrescences have a low prevalence in the general population. Although they occur most frequently in adults over 60 years-old, pediatric cases have been described. The cases in adulthood are associated with ischemic stroke, but in childhood they are asymptomatic. The aim of reporting on this case series is to show the association or coexistence of Lambl’s excrescences with some congenital heart diseases (CHDs), of which there are no known descriptive case series in adults or children. We present 17 patients (8 females), with a mean age of 23.7 years; among these cases, 64.7% were under 18 years-old. We found that 94% of the Lambl’s excrescences were located on the aortic valve. In 47% (8 cases), they coincided with a CHD (with 6 of those individuals being under 18 years-old). We propose the hypothesis that Lambl’s excrescences could have a congenital origin or coexist with CHD. No complications were found throughout the follow-up. Lambl’s excrescences could be more frequent than currently reported in the literature, and more research should be done on their significance in CHD-associated stroke.

Autoimmune hepatitis (AIH) is a cause of chronic, immune-mediated liver injury which without treatment may progress to end-stage liver disease. The disease state, characterized by elevations in liver enzymes, autoantibodies, and interface hepatitis on histology, has been noted to be induced by a wide range of insults. Medications, most commonly minocycline and nitrofurantoin, have long been established as potential inducers of AIH. Recently, biologics, powerful immune-modulators, have also been reported to induce AIH. We conclude that there is an association between administration of biologics in the development of AIH, and whether the relationship is causal will require appropriate studies in the future.

Background and Aims: Acute kidney injury (AKI) occurs commonly in patients with acute-on-chronic liver failure (ACLF). However, there are scant data regarding the impact of AKI on survival in ACLF. We performed a prospective study to evaluate the impact of AKI on survival in ACLF.

Methods: This study was conducted in ACLF patients hospitalized in the Gastroenterology Department of Sriram Chandra Bhanja Medical College (India) between October 2016 and February 2018. Demographic, clinical and laboratory parameters were recorded, and outcomes were compared between patients with and without AKI and between patients with persistent AKI and AKI reversal at 48 h.

Results: We screened 439 chronic liver disease patients as per the Asian Pacific Association for the Study of the Liver criteria and found that 113 (25.7%) of them had ACLF and 78 (69%) of them had AKI as per the Acute Kidney Injury Network criteria. ACLF patients with AKI had reduced 28-day survival (44.9% vs. 74.3%; p = 0.004) and 90-day survival (25.6% vs. 51.4%; p = 0.007), in comparison to ACLF patients without AKI. However, when comparison was made between AKI reverters and AKI persisters at 48 h, survival was comparable for both at 28 days and 90 days. Further, about one-tenth of ACLF patients with AKI died within 48 h of hospitalization.

Conclusions: Over two-thirds of ACLF patients had AKI. Although ACLF itself is a predictor of reduced survival, a very small increase in serum creatinine further worsens survival. Importantly, AKI at admission is a better predictor of early mortality in ACLF patients since recovery from AKI at 48 h does not improve survival.

In the present article the effects of drug binding (both specific and nonspecific) in the porous arterial wall following stent-based drug delivery from drug-eluting stents (DESs) are investigated. A three-phase (free, extracellular matrix-bound, and specific receptor-bound) second-order nonlinear saturable reversible binding model is considered in order to describe the binding process with the constituents of the porous arterial wall. Although, there are currently some precise forms of a drug binding model in the arterial tissue in the literature, analyzed by various authors. The specific interest in this present context is in assessing to what extent modelling of specific and nonspecific binding within a single-layered homogeneous porous arterial wall is possible. A novel axi-symmetric model of drug delivery from three stent struts has been developed and is presented.

The governing equations of motion together with the physiologically realistic boundary conditions are tackled numerically by an explicit finite-difference scheme in staggered grids.

Results include the influence of the significant model parameters, such as Peclet numbers (PeT, Pe1 and Pe2), Damköhler numbers (Da1 and Da2) and time-dependent release kinetics as well as constant release kinetics. Consistency of the proposed approach is shown graphically.

As the porosity (εw) increases, the effective as well as the true diffusivity increases, which eventually leads to expedition of the diffusion process. In a porous media, diffusion takes place in confined tortuous pores and its progression is impeded as the tortuosity increases. The present simulation also demonstrates a decrease in the mean concentration of free as well as extracellular matrix-bound and SR-bound drug with increasing tortuosity. The present observation may be justified in the sense that as the tortuosity increases so too does the effective distance over which diffusion has to take place (i.e. the progression of diffusion is impeded, which eventually lowers the mean concentration of all drug forms).

Gut microbiota changes play a key role in the pathogenesis of hepatic encephalopathy (HE). Fecal microbiota transplantation (FMT) is an efficient way to manipulate the gut microbiota. This review collects the experimental and clinical evidence that supports the use of FMT in the treatment of HE. Animal experiments showed that the blood ammonia level, mortality and cognitive impairment were decreased when animals with HE were transplanted with the selected gut microbiota or the fecal material from human donor. Successful clinical application of FMT for treating HE was first reported in 2016. A subsequent randomized clinical trial demonstrated further that FMT from a “rationally selected donor” reduced hospitalizations and improved cognition and dysbiosis in patients with recurrent HE. Possible underlying mechanisms of FMT treating HE include restoration of the impaired gut-liver-brain axis, as well as reduction of ammonia production, systemic inflammation and blood-brain barrier permeability.

Background and Aims: Hepatic encephalopathy is a liver disease complication with significant mortality and costs. The aim of this study was to evaluate the relative performance of facilities based on their teaching status and transplant capability by correlating their connections to mortality, cost, and length of stay from 2007 to 2014.

Methods: The Nationwide Inpatient Sample database was utilized to collect information on (USA) American patients admitted with a primary diagnosis of hepatic encephalopathy from 2007–2014. Hospitals were placed into one of four categories using their teaching and transplant status. Using regression analysis, mortality, length of stay and cost adjusted rate ratios were calculated.

Results: The study revealed that teaching transplant centers had a mortality risk ratio of 0.783 (95% confidence interval (CI): 0.750–0.819, p < 0.001). Blacks had the highest mortality risk ratio, of 1.273 (95%CI: 1.217–1.331, p < 0.001). Furthermore, teaching transplant hospitals had a cost rate ratio of 1.226 (95%CI: 1.214–1.238, p < 0.001) and a length of stay rate ratio of 1.104 (95%CI: 1.093–1.115, p < 0.001).

Conclusions: It appears that admission to transplant facilities for hepatic encephalopathy is associated with reduced mortality but increased costs and longer stay independent of transplantation. Moreover, factors impacting black mortality should also be examined more closely.

Procalcitonin (PCT) is a widely used biomarker for the diagnosis of bacterial infections. It is produced by various organs and the liver is considered to be the most important site of production. Severe liver dysfunction has been shown to influence PCT levels. Patients with no sources of infection who have liver disease are observed to have increased serum levels of PCT, thereby reducing the diagnostic utility and value within this particular patient subset. Here, we have summarized the relationship between PCT and liver disease, including liver cirrhosis, liver failure, and liver transplantation.

Background and Aims: Intoxications by aliphatic halogenated hydrocarbons (AHH), used as effective solvents, are rare and may cause life-threatening liver injury. Patients with acute intoxications by AHH received an innovative treatment.

Methods: Analyzed were data of 60 patients intoxicated by AHH, such as dichloromethane (n = 3), chloroform (n = 2), carbon tetrachloride (n = 12), 1,2-dichloroethane (n = 18), 1,1,2-trichloroethane (n = 2), trichloroethylene (n = 2), tetrachloroethylene (n = 13) or mixed AHH chemicals (n = 8), who received a new treatment consisting of CO2-induced hyperventilation to accelerate toxin removal via the lungs.

Results: Added to the inspiration air at a flow rate of 2–3 Liter min−1, CO2 increased the respiratory volume up to 25–30 Liter min−1, ensuring forced AHH exhalation. This CO2-induced hyperventilation therapy was commonly well tolerated by the 60 patients and lasted for 106.0±10.5 hours. In most cases, initially increased liver test results of aminotransferases normalized quickly under the therapy, and liver histology obtained at completion of the therapy revealed, in the majority of patients, normal findings or fatty changes, and rarely severe single cell necrosis but no confluent liver cell necrosis. Despite therapy, clinical outcome was unfavorable for 4/60 patients (6.7%) of the study cohort, due to single or combined risk factors. These included late initiation of the CO2-induced hyperventilation therapy, intentional intoxication, uptake of high amounts of AHH, concomitant ingestion of overdosed drugs, consumption of high amounts of alcohol, and history of alcohol abuse.

Conclusions: For intoxications by AHH, effective therapy approaches including forced hyperventilation to increase toxin removal via the lungs are available and require prompt initiation.

Biliary atresia (BA) is a childhood disease which manifests with abnormal narrowing, blockage or complete absence of bile ducts within the liver. Many possible etiologies have been reported for the development of BA, including congenital, perinatal and acquired conditions. Since the 1970’s, there has been increasing evidence linking BA development to viral perinatal infections. The viral vectors most commonly implicated include members of the herpesviridae family (cytomegalovirus and Epstein-Barr virus) as well as those of the reoviridae family (reovirus and rotavirus). While extensive work has been done on a murine model of disease, the current review focuses primarily on evidence from human studies of viral vectors in children afflicted with BA.