The latest advances in hepatology were presented in oral and poster presentations. In order to cover the varying subspecialties, the sessions were divided into various sections including 'Acute Liver Failure and Artificial Liver Support', 'Biliary Tract and Immunologic Liver Diseases', 'Cellular and Molecular Biology', 'Clinical and Experimental Hepatobiliary Surgery', 'Hepatotoxicity and Cell Death', 'Transport and Biliary Physiology', 'Viral Hepatitis', 'Evaluation and Treatment of Biliary Disease', 'Necrosis/Apoptosis', 'Portal Hypertension', 'Blood Flow and Vascular Disorders of Cirrhosis', 'Liver Transplantation', 'Fibrogenesis', 'Hepatocellular Carcinoma', 'Metabolism and Genetic Disease', and 'Public Policy, Epidemiology and Decision Analysis'. Drug therapy focused on treatments for viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis, and recurrent viral disease following liver transplant. High dose interferon therapy or various combinations of interferon/ribavirin (ICN Pharmaceuticals Inc) therapy seem to offer the best current therapy for chronic HCV. PEGylated interferon (F Hoffmann-La Roche Ltd) offers hope for treatment and histologic improvement in patients with chronic HCV. Following liver transplantation, combination interferon/ribavirin therapy may also find success, but caution with new potent immunosuppressant monoclonal antibodies is advised. For HBV, intramuscular H-BIG (NABI) appears to be effective and less costly than iv H-BIG administration following liver transplantation. Percutaneous radiofrequency ablation may hold promise over conventional ethanol injection therapy for small hepatocellular carcinoma. Autoimmune hepatitis may respond to tacrolimus therapy whereas budesonide therapy did not provide any advantage to prednisone therapy. For primary biliary cirrhosis, eicosapentate and ursodeoxycholic acid may provide benefit to some patients while silymarin from milk thistle did not provide any additional benefit. In primary sclerosing cholangitis, high dose ursodeoxycholic acid may provide benefit. Ursodeoxycholic acid may also provide benefit for mothers with intrahepatic cholestasis of pregnancy by decreasing pruritus, lowering laboratory values and allowing deliveries to occur closer to term.

Digestive disease week 2000. American Association for the Study of Liver Diseases

非アルコール性脂肪肝炎の治療薬およびバイオマーカーの開発における課題と機会 : 米国肝臓病学会(American Association for the Study of Liver Diseases)と米国食品医薬品局の合同ワークショップの知見と推奨

Ferroptosis is a type of cell death that was described less than a decade ago. It is caused by the excess of free intracellular iron that leads to lipid (hydro) peroxidation. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. Since the 1960s, increased concentration of iron in the central nervous system has been associated with oxidative stress, oxidation of proteins and lipids, and cell death. Here, we review the main mechanisms involved in the process of ferroptosis such as lipid peroxidation, glutathione peroxidase 4 enzyme activity, and iron metabolism. Moreover, the association of ferroptosis with the pathophysiology of some neurodegenerative diseases, namely Alzheimer’s, Parkinson’s, and Huntington’s diseases, has also been addressed.

Ferroptosis Mechanisms Involved in Neurodegenerative Diseases.

Ferroptosis is a form of regulated cell death modality associated with disturbed iron-homeostasis and unrestricted lipid peroxidation. Ample evidence has depicted an essential role for ferroptosis as either the cause or consequence for human diseases, denoting the likely therapeutic promises for targeting ferroptosis in the preservation of human health. Ferritinophagy, a selective form of autophagy, contributes to the initiation of ferroptosis through degradation of ferritin, which triggers labile iron overload (IO), lipid peroxidation, membrane damage, and cell death. In this review, we will delineate the role of ferritinophagy in ferroptosis, and its underlying regulatory mechanisms, to unveil the therapeutic value of ferritinophagy as a target in the combat of ferroptosis to manage metabolic diseases.

Ferritinophagy and ferroptosis in the management of metabolic diseases.

Iron is a critical metal for several vital biological processes. Most of the body’s iron is bound to hemoglobin in erythrocytes. Iron from senescent red blood cells is recycled by macrophages in the spleen, liver and bone marrow. Dietary iron is taken up by the divalent metal transporter 1 (DMT1) in enterocytes and transported to portal blood via ferroportin (FPN), where it is bound to transferrin and taken up by hepatocytes, macrophages and bone marrow cells via transferrin receptor 1 (TfR1). While most of the physiologically active iron is bound hemoglobin, the major storage of most iron occurs in the liver in a ferritin-bound fashion. In response to an increased iron load, hepatocytes secrete the peptide hormone hepcidin, which binds to and induces internalization and degradation of the iron transporter FPN, thus controlling the amount of iron released from the cells into the blood. This review summarizes the key mechanisms and players involved in cellular and systemic iron regulation.

On Iron Metabolism and Its Regulation.

Cellular iron, at the physiological level, is essential to maintain several metabolic pathways, while an excess of free iron may cause oxidative damage and/or provoke cell death. Consequently, iron homeostasis has to be tightly controlled. Under hypoxia these regulatory mechanisms for human macrophages are not well understood. Hypoxic primary human macrophages reduced intracellular free iron and increased ferritin expression, including mitochondrial ferritin (FTMT), to store iron. In parallel, nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy, decreased and was proven to directly regulate FTMT expression. Reduced NCOA4 expression resulted from a lower rate of hypoxic NCOA4 transcription combined with a micro RNA 6862-5p-dependent degradation of NCOA4 mRNA, the latter being regulated by c-jun N-terminal kinase (JNK). Pharmacological inhibition of JNK under hypoxia increased NCOA4 and prevented FTMT induction. FTMT and ferritin heavy chain (FTH) cooperated to protect macrophages from RSL-3-induced ferroptosis under hypoxia as this form of cell death is linked to iron metabolism. In contrast, in HT1080 fibrosarcome cells, which are sensitive to ferroptosis, NCOA4 and FTMT are not regulated. Our study helps to understand mechanisms of hypoxic FTMT regulation and to link ferritinophagy and macrophage sensitivity to ferroptosis.

Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis.

Background Hepatitis B virus (HBV) surface proteins (HBsAg) coat the viral particle and form subviral particles (SVPs). Loss of HBsAg represents a functional cure and is an important treatment goal. Methods We analyzed the impact of the HBV genotypes A-E and pre-S mutations on SVP expression in hepatitis B virus e antigen (HBeAg)-negative chronic HBV-infected patients. A HBV genome harboring a preS1-deletion was analyzed in hepatoma cells. Results We observed a genotype-specific ratio of the 3 surface proteins (SHBs/MHBs/LHBs), reflecting differences in the morphology and composition of SVPs. Deletions/mutations in the preS1/preS2 domain, detected in released viral genomes, did not affect the molecular weight of MHBs and LHBs in these patients. In contrast, LHB molecular weight was altered in vitro using an HBV genome harboring a preS1-deletion derived from one of these patients. Conclusion Differences in composition of SVPs may result in genotype-specific immunogenicity and pathogenesis. In the patients with preS-mutations, secreted HBsAg and released viral genomes cannot be derived from the same genetic source. As viral genomes are derived from covalently closed circular DNA (cccDNA), HBsAg is presumably derived from integrated DNA. This important HBsAg source should be considered for novel antiviral strategies in HBeAg-negative chronic HBV-infected patients.

Divergent preS Sequences in Virion-Associated Hepatitis B Virus Genomes and Subviral HBV Surface Antigen Particles From HBV e Antigen-Negative Patients.

Objective Hormone treatment is an important part of gender reassignment therapy in gender dysphoria. Previous data about efficacy and safety are commonly based on small cohorts or they comprise former cohorts under meanwhile obsolete therapy regimes. Our objective was to investigate these topics in a large cohort of individuals under guideline-based treatment. Design/methods Cohort study of medical files of n = 155 male-to-female (transwomen) and n = 233 female-to-male transgender persons (transmen) of an Endocrine outpatient clinic between 2009 and 2017. Results Median time to reach amenorrhoea in transmen under testosterone monotherapy was 3 months, regardless of whether testosterone undecanoat or gel was used. Transmen with higher levels of hemoglobin 3-4 months after onset of GAHT had a greater chance to reach amenorrhea early, whereas testosterone levels showed no significant correlation (hemoglobin: HR: 1.639; 95% CI: 1.036-2.591, P = 0.035; testosterone: HR: 0.999; 95% CI: 0.998-1.001, P = 0.490). Estradiol levels (ρ -0.117; P = 0.316) had no significant influence on breast development in transwomen. Testosterone levels (ρ -0.398; P < 0.001) and FAI (ρ 0.346; P = 0.004) were significantly negatively correlated with reached Tanner stage. Liver values and blood lipids showed an alignment to reference range of the required sex in both groups. Relevant elevations of liver values were rare (2.44% in transmen, 4.23% in transwomen) and transient in most cases. Most relevant side effects were acne (44.8%), respectively erythrocytosis (up to 5.6%) in transmen and venous thrombembolism (1.9%) in transwomen. Conclusions Gender-affirming hormone therapy in accordance with current clinical practice guidelines is efficient and safe.

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Safety and rapid efficacy of guideline-based gender-affirming hormone therapy: an analysis of 388 individuals diagnosed with gender dysphoria.

Background/aims Signaling of Gs protein-coupled receptors (GsPCRs) is accomplished by stimulation of adenylyl cyclase, causing an increase of the intracellular cAMP concentration, activation of the intracellular cAMP effectors protein kinase A (PKA) and Epac, and an efflux of cAMP, the function of which is still unclear. Methods Activation of adenylyl cyclase by GsPCR agonists or cholera toxin was monitored by measurement of the intracellular cAMP concentration by ELISA, anti-phospho-PKA substrate motif phosphorylation by immunoblotting, and an Epac-FRET assay in the presence and absence of adenosine receptor antagonists or ecto-nucleotide phosphodiesterase/pyrophosphatase2 (eNPP2) inhibitors. The production of AMP from cAMP by recombinant eNPP2 was measured by HPLC. Extracellular adenosine was determined by LC-MS/MS, extracellular ATP by luciferase and LC-MS/MS. The expression of eNPP isoenzymes 1-3 was examined by RT-PCR. The expression of multidrug resistance protein 4 was suppressed by siRNA. Results Here we show that the activation of GsPCRs and the GsPCRs-independent activation of Gs proteins and adenylyl cyclase by cholera toxin induce stimulation of cell surface adenosine receptors (A2A or A2B adenosine receptors). In PC12 cells stimulation of adenylyl cyclase by GsPCR or cholera toxin caused activation of A2A adenosine receptors by an autocrine signaling pathway involving cAMP efflux through multidrug resistance protein 4 and hydrolysis of released cAMP to AMP by eNPP2. In contrast, in PC3 cells cholera toxin- and GsPCR-induced stimulation of adenylyl cyclase resulted in the activation of A2B adenosine receptors. Conclusion Our findings show that stimulation of adenylyl cyclase causes a remarkable activation of cell surface adenosine receptors.

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Activation of Adenylyl Cyclase Causes Stimulation of Adenosine Receptors

Background: Chronic hepatitis C virus (HCV) infections are causally linked with metabolic comorbidities such as insulin resistance, hepatic steatosis, and dyslipidemia. However, the clinical impact of HCV eradication achieved by direct-acting antivirals (DAAs) on glucose and lipid homeostasis is still controversial. The study aimed to prospectively investigate whether antiviral therapy of HCV with DAAs alters glucose and lipid parameters. Methods: 50 patients with chronic HCV who were treated with DAAs were screened, and 49 were enrolled in the study. Biochemical and virological data, as well as noninvasive liver fibrosis parameters, were prospectively collected at baseline, at the end of treatment (EOT) and 12 and 24 weeks post-treatment. Results: 45 of 46 patients achieved sustained virologic response (SVR). The prevalence of insulin resistance (HOMA-IR) after HCV clearance was significantly lower, compared to baseline (5.3 ± 6.1 to 2.5 ± 1.9, p < 0.001), which is primarily attributable to a significant decrease of fasting insulin levels (18.9 ± 17.3 to 11.7 ± 8.7; p = 0.002). In contrast to that, HCV eradication resulted in a significant increase in cholesterol levels (total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL-C) levels) and Controlled Attenuated Score (CAP), although BMI did not significantly change over time (p = 0.95). Moreover, HOMA-IR correlated significantly with noninvasive liver fibrosis measurements at baseline und during follow-up (TE: r = 0.45; p = 0.003, pSWE: r = 0.35; p = 0.02, APRI: r = 0.44; p = 0.003, FIB-4: r = 0.41; p < 0.001). Conclusion: Viral eradication following DAA therapy may have beneficial effects on glucose homeostasis, whereas lipid profile seems to be worsened.

https://www.mdpi.com/2077-0383/9/9/2702/pdf

Antonia Mondorf

Papers

Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis.

Divergent preS Sequences in Virion-Associated Hepatitis B Virus Genomes and Subviral HBV Surface Antigen Particles From HBV e Antigen-Negative Patients.

Safety and rapid efficacy of guideline-based gender-affirming hormone therapy: an analysis of 388 individuals diagnosed with gender dysphoria.

Activation of Adenylyl Cyclase Causes Stimulation of Adenosine Receptors

Hepatitis C Clearance by Direct-Acting Antivirals Impacts Glucose and Lipid Homeostasis.