Gut Microbiota and Neuroinflammation in Acute Liver Failure and Chronic Liver Disease.

Acute liver failure and chronic liver disease are associated with a wide spectrum of neurological changes, of which the best known is hepatic encephalopathy (HE). Historically, hyperammonemia, causing astrocyte swelling and cerebral oedema, was considered the main etiological factor in the pathogenesis of cerebral dysfunction in patients with acute and/or chronic liver disease. However, recent studies demonstrated a key role of neuroinflammation in the development of neurological complications in this setting. Neuroinflammation is characterized by activation of microglial cells and brain secretion of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6, which alter neurotransmission, leading to cognitive and motor dysfunction. Changes in the gut microbiota resulting from liver disease play a crucial role in the pathogenesis of neuroinflammation. Dysbiosis and altered intestinal permeability, resulting in bacterial translocation and endotoxemia, are responsible for systemic inflammation, which can spread to brain tissue and trigger neuroinflammation. In addition, metabolites derived from the gut microbiota can act on the central nervous system and facilitate the development of neurological complications, exacerbating clinical manifestations. Thus, strategies aimed at modulating the gut microbiota may be effective therapeutic weapons. In this review, we summarize the current knowledge on the role of the gut-liver-brain axis in the pathogenesis of neurological dysfunction associated with liver disease, with a particular focus on neuroinflammation. In addition, we highlight emerging therapeutic approaches targeting the gut microbiota and inflammation in this clinical setting.

Gut microbiota modulation in patients with non-alcoholic fatty liver disease: Effects of current treatments and future strategies.

Non-alcoholic fatty liver disease (NAFLD) is frequently associated with metabolic disorders, being highly prevalent in obese and diabetic patients. Many concomitant factors that promote systemic and liver inflammation are involved in NAFLD pathogenesis, with a growing body of evidence highlighting the key role of the gut microbiota. Indeed, the gut-liver axis has a strong impact in the promotion of NAFLD and in the progression of the wide spectrum of its manifestations, claiming efforts to find effective strategies for gut microbiota modulation. Diet is among the most powerful tools; Western diet negatively affects intestinal permeability and the gut microbiota composition and function, selecting pathobionts, whereas Mediterranean diet fosters health-promoting bacteria, with a favorable impact on lipid and glucose metabolism and liver inflammation. Antibiotics and probiotics have been used to improve NAFLD features, with mixed results. More interestingly, medications used to treat NAFLD-associated comorbidities may also modulate the gut microbiota. Drugs for the treatment of type 2 diabetes mellitus (T2DM), such as metformin, glucagon-like peptide-1 (GLP-1) agonists, and sodium-glucose cotransporter (SGLT) inhibitors, are not only effective in the regulation of glucose homeostasis, but also in the reduction of liver fat content and inflammation, and they are associated with a shift in the gut microbiota composition towards a healthy phenotype. Even bariatric surgery significantly changes the gut microbiota, mostly due to the modification of the gastrointestinal anatomy, with a parallel improvement in histological features of NAFLD. Other options with promising effects in reprogramming the gut-liver axis, such as fecal microbial transplantation (FMT) and next-generation probiotics deserve further investigation for future inclusion in the therapeutic armamentarium of NAFLD.

SIRT in 2025.

Selective internal radiation therapy represents an endovascular treatment option for patients with primary liver malignancies, in different clinical stages. Potential applications of this treatment are in early-stage hepatocellular carcinoma, as a curative option, or in combination with systemic treatments in intermediate and advanced-stages. This review, based on existing literature and ongoing trials, will focus on the future of this treatment in patients with hepatocellular carcinoma, in combination with systemic treatments, or with the use of new devices and technological developments; it will also describe new potential future indications and structural and organizational perspectives.

Durvalumab: an investigational agent for unresectable hepatocellular carcinoma.

INTRODUCTION: Programmed death 1 (PD1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte associated protein 4 (CTLA-4) are proteins involved in the modulation of immune response, which are upregulated in hepatocellular carcinoma (HCC) tumor microenvironment (TME). Immune checkpoint inhibitors (ICIs) are a new class of drugs that counteract immunological tolerance to cancer cells. Despite the aggressiveness of HCC and its poor prognosis, only a few tyrosine kinase inhibitors (TKIs) and ICIs have been approved for patients with advanced disease. AREAS COVERED: We analyze the current knowledge on Durvalumab, a human antibody against PD-L1 its pharmacodynamics, and pharmacokinetics. We provide a description of its application in HCC, illustrating clinical trials that have demonstrated the safety and efficacy in this setting, either as monotherapy or in combination with other ICIs or TKIs, or as adjuvant treatment. EXPERT OPINION: Durvalumab is a promising drug that could extend the landscape of approved treatments for HCC. The clinical safety profile of Durvalumab was well manageable and comparable to other ICIs, with a low incidence of severe immune-related adverse events (irAEs). The importance of personalized therapy according to tumor characteristics is emerging, but very little is known about factors that could influence the efficacy of ICIs.

High-risk HPV positivity is a long-term risk factor for recurrence after cervical excision procedure in women living with HIV.

OBJECTIVE: To evaluate the risk factors for recurrence of high-grade disease after cervical excision in women living with HIV (WLWH), with a specific interest in the role of high-risk (HR-) HPV positivity. METHODS: Multicentric retrospective study conducted on WLWH who underwent cervical excision between January 1987 and June 2017 in six Italian institutions. The rate of high-grade recurrence was determined. Risk factors for recurrence and HR-HPV positivity were determined with the Log-rank test and Cox proportional hazards regression models. RESULTS: A total of 271 WLWH were included in the final analysis. A high-grade recurrence was found in 58 (21.4%) patients. Age 41 years or more at inclusion and HR-HPV positivity during follow up were independently associated with a higher risk of disease recurrence with relative risks of 4.15 (95% confidence interval [CI] 2.01-8.58, P < 0.001) and 5.18 (95% CI 2.12-12.67, P < 0.01), respectively. Age 41 years or more (relative risk 1.75, 95% CI 1.01-3.04, P = 0.047) resulted as a risk factor for HR-HPV positivity during follow up. CONCLUSION: HR-HPV positivity is a risk factor for recurrence after cervical excision in WLWH. Women older than 41 years may benefit from a long-term yearly follow up. Future studies regarding HPV vaccination after treatment in WLWH may be useful, considering the protective role of the higher probability of HPV negativity in vaccinated women.

Migraine and cluster headache show impaired neurosteroids patterns.

BACKGROUND: Perturbation of neuronal excitability contributes to migraine. Neurosteroids modulate the activity of γ-aminobutyric acid A and N-methyl-d-aspartate receptors, and might be involved in the pathogenesis of migraine. Here, we measured plasma levels of four neurosteroids, i.e., allopregnanolone, epiallopregnanolone, dehydroepiandrosterone and deydroepiandrosterone sulfate, in patients affected by episodic migraine, chronic migraine, or cluster headache. METHODS: Nineteen female patients affected by episodic migraine, 51 female patients affected by chronic migraine, and 18 male patients affected by cluster headache were recruited to the study. Sex- and age-matched healthy control subjects (31 females and 16 males) were also recruited. Patients were clinically characterized by using validated questionnaires. Plasma neurosteroid levels were measured by liquid chromatography-tandem mass spectrometry. RESULTS: We found disease-specific changes in neurosteroid levels in our study groups. For example, allopregnanolone levels were significantly increased in episodic migraine and chronic migraine patients than in control subjects, whereas they were reduced in patients affected by cluster headache. Dehydroepiandrosterone and dehydroepiandrosterone sulfate levels were reduced in patients affected by chronic migraine, but did not change in patients affected by cluster headache. CONCLUSION: We have shown for the first time that large and disease-specific changes in circulating neurosteroid levels are associated with chronic headache disorders, raising the interesting possibility that fluctuations of neurosteroids at their site of action might shape the natural course of migraine and cluster headache. Whether the observed changes in neurosteroids are genetically determined or rather result from exposure to environmental or intrinsic stressors is unknown. This might also be matter for further investigation because stress is a known triggering factor for headache attacks in both migraineurs and cluster headache patients.