As the central organ of metabolism, the liver plays a pivotal role in the regulation of the synthesis and metabolism of various nutrients within the body. Ferroptosis, as a newly discovered type of programmed cell death caused by the accumulation of iron-dependent lipid peroxides, is involved in the physiological and pathological processes of a variety of acute and chronic liver diseases. Ferroptosis can accelerate the pathogenetic process of acute liver injury, metabolic associated fatty liver disease, alcoholic liver disease, viral hepatitis, and autoimmune hepatitis; while it can slower disease progression in advanced liver fibrosis and hepatocellular carcinoma. This suggests that targeted regulation of ferroptosis may impact the occurrence and development of various liver diseases. This article reviews the latest research progress of ferroptosis in various liver diseases, including acute liver injury, metabolic associated fatty liver disease, alcoholic liver disease, viral hepatitis, autoimmune hepatitis, liver fibrosis and hepatocellular carcinoma. It aims to provide insights for the prevention and treatment of acute and chronic liver diseases through targeting ferroptosis.
Humans ; Liver Diseases/etiology* ; Ferroptosis/physiology* ; Liver Neoplasms/pathology* ; Carcinoma, Hepatocellular/pathology* ; Liver Cirrhosis/etiology* ; Liver/pathology* ; Hepatitis, Autoimmune/metabolism* ; Liver Diseases, Alcoholic/metabolism*

Adult ; Female ; Gene Expression ; Glomerulonephritis, Membranous ; etiology ; genetics ; pathology ; Hepatitis B ; complications ; Hepatitis B virus ; genetics ; metabolism ; Humans ; Male ; Middle Aged ; Mutation ; Receptors, Phospholipase A2 ; genetics ; metabolism ; Trans-Activators ; genetics ; metabolism ; Viral Regulatory and Accessory Proteins ; genetics ; metabolism

BACKGROUND/AIMS: To determine factors predictive of discordance in staging liver fibrosis using liver biopsy (LB) and acoustic radiation force impulse (ARFI) elastography in patients with chronic hepatitis B (CHB). METHODS: Consecutive patients with CHB who underwent LB and ARFI elastography on the same day from November 2010 to March 2013 were prospectively recruited from three tertiary hospitals. RESULTS: We analyzed 105 patients (median age of 47 years). The F0-1, F2, F3, and F4 fibrosis stages were identified in 27 (25.7%), 27 (25.7%), 21 (20.0%), and 30 (28.6%) patients, respectively. The areas under the receiver operating characteristics curves for ARFI elastography in assessing ≥F2, ≥F3, and F4 was 0.814, 0.848, and 0.752, respectively. The discordance of at least one stage between LB and ARFI was observed in 68 patients (64.8%) and of at least two stages in 16 patients (15.2%). In a multivariate analysis, advanced fibrosis stage (F3-4) was the only factor that was negatively correlated with one-stage discordance (p=0.042). Moreover, advanced fibrosis stage was negatively (p=0.016) correlated and body mass index (BMI) was positively (p=0.006) correlated with two-stage discordance. CONCLUSIONS: Advanced fibrosis stage (F3-4) was a predictor of nondiscordance between LB and ARFI elastography; BMI also influenced the accuracy of ARFI elastography.
Body Mass Index ; Elasticity Imaging Techniques/*methods ; Female ; Hepatitis B, Chronic/*complications ; Humans ; Liver/diagnostic imaging/pathology ; Liver Cirrhosis/*diagnostic imaging/etiology ; Male ; Middle Aged ; Multivariate Analysis ; Predictive Value of Tests ; Prospective Studies ; ROC Curve ; Republic of Korea

Tenofovir disoproxil fumarate (TDF) is effective against chronic hepatitis B (CHB) infection and its use is increasing rapidly worldwide. However, it has been established that TDF is associated with renal toxicity in human immunodeficiency virus-infected patients, while severe or symptomatic TDF-associated nephrotoxicity has rarely been reported in patients with CHB. Here we present two patients with TDF-associated nephrotoxicity who were being treated for CHB infection. The first patient was found to have clinical manifestations of proximal renal tubular dysfunction and histopathologic evidence of acute tubular necrosis at 5 months after starting TDF treatment. The second patient developed acute kidney injury at 17 days after commencing TDF, and he was found to have membranoproliferative glomerulonephritis with acute tubular injury. The renal function improved in both patients after discontinuing TDF. We discuss the risk factors for TDF-associated renal toxicity and present recommendations for monitoring renal function during TDF therapy.
Acute Kidney Injury/etiology ; Aged ; Antiviral Agents/adverse effects/therapeutic use ; Creatinine/blood ; Glomerular Filtration Rate ; Hepatitis B, Chronic/*drug therapy ; Humans ; Kidney Tubules/pathology ; Male ; Microscopy, Electron ; Middle Aged ; Necrosis ; Risk Factors ; Tenofovir/adverse effects/*therapeutic use

Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease characterized by hepatocellular inflammation, necrosis, and fibrosis, which can progress to cirrhosis and fulminant hepatic failure. The standard treatment for AIH includes corticosteroids alone or in combination with azathioprine. Although most patients achieve remission using the standard regimen, some patients do not respond due to either drug intolerance or refractory disease; in such cases alternative immunosuppressive agents should be explored. The second-line therapies are cyclophilin inhibitors such as cyclosporine A or tacrolimus, and nowadays mycophenolate mofetil (MMF) is widely used if azathioprine-based therapies are not tolerated. Although these are recommended as an alternative to the first-line regimen, there is insufficient evidence for the efficacy of second-line therapies, with the evidence based mainly on expert opinion. Therefore, we report an AIH patient receiving the standard regimen in whom remission did not occur due to side effects to azathioprine, but was successfully treated with MMF in combination with corticosteroids as an alternative to the standard regimen.
Alanine Transaminase/analysis ; Alopecia/etiology ; Antibiotics, Antineoplastic/*therapeutic use ; Aspartate Aminotransferases/analysis ; Azathioprine/adverse effects ; Female ; Hepatitis, Autoimmune/*drug therapy/pathology ; Humans ; Liver/enzymology/pathology ; Middle Aged ; Mycophenolic Acid/*therapeutic use ; Pancytopenia/etiology ; Prednisolone/therapeutic use

Autochthonous hepatitis E virus (HEV) is an emerging pathogen in developed countries, and several cases of acute HEV infection have been reported in South Korea. However, there have been no reports on HEV-associated Guillain-Barré syndrome (GBS) in Korea. We recently experienced the case of a 58-year-old Korean male with acute HEV infection after ingesting raw deer meat. Persistent cholestasis was resolved by the administration of prednisolone. At 2.5 months after the clinical presentation of HEV infection, the patient developed weakness of the lower limbs, and was diagnosed with GBS associated with acute hepatitis E. To our knowledge, this is the second report on supportive steroid therapy for persistent cholestasis due to hepatitis E, and the first report of GBS in a Korean patient with acute HEV infection.
Acute Disease ; Alanine Transaminase/blood ; Antibodies, Viral/blood ; Aspartate Aminotransferases/blood ; Bilirubin/analysis ; Cholestasis/*drug therapy ; Guillain-Barre Syndrome/complications/*diagnosis ; Hepatitis E/*diagnosis/etiology ; Hepatitis E virus/immunology ; Humans ; Immunoglobulin M/blood ; Liver/pathology ; Male ; Middle Aged ; Prednisolone/therapeutic use ; Republic of Korea ; Steroids/*therapeutic use

BACKGROUND/AIMS: We investigated factors associated with the disease progression and development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients during long-term oral nucleos(t)ide analog (NA) therapy. METHODS: This retrospective study included 524 naive CHB patients who received oral NA therapy for more than 48 weeks between January 2003 and December 2007. The primary outcome was 5-year cumulative probability of disease progression and HCC development. Disease progression was defined as cirrhosis development, cirrhotic complications, HCC or liver-related mortality. RESULTS: For the 524 patients, the cumulative probabilities of disease progression and HCC development at 1, 2, 3, 4 and 5 years were 1.1%, 6.3%, 9.0%, 11.6%, and 16.2% and 0.2%, 1.8%, 3.6%, 5.8%, and 9.3%, respectively. In multivariate analysis, age >50 years (hazard ratio [HR], 1.05) and cirrhosis (HR, 2.95) were significant factors for disease progression. Similarly, age >50 years (HR, 1.05), family history of HCC (HR, 5.48), and cirrhosis (HR, 17.16) were significant factors for HCC development. Importantly, longer duration (>12 months) of maintained virological response (<20 IU/mL) reduced the risks of disease progression (HR, 0.19) and HCC development (HR, 0.09). CONCLUSIONS: Longer duration of maintained virological response significantly reduces the risk of disease progression or HCC development in CHB patients undergoing long-term oral NA therapy.
Adult ; Age Factors ; Antiviral Agents/*administration & dosage ; Carcinoma, Hepatocellular/epidemiology/etiology ; *Disease Progression ; Female ; Hepatitis B, Chronic/complications/*drug therapy/*pathology ; Humans ; Liver Cirrhosis/epidemiology/etiology ; Liver Neoplasms/epidemiology/etiology ; Male ; Middle Aged ; Proportional Hazards Models ; Retrospective Studies ; Time

Inflammation is one of the most prominent characteristic features of chronic liver disease, liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Most of HCC cases develop in patients with cirrhosis and cirrhosis develops in patients with chronic liver inflammation. Therefore, there is no doubt that there exist some strong connection among inflammation, fibrosis, and cancer. In fact, chronic unresolved inflammation is associated with persistent hepatic injury and concurrent regeneration, leading to sequential development of fibrosis, cirrhosis, and eventually HCC. This review will discuss the common mechanism of inflammation and fibrosis in chronic liver diseases, and then demonstrate why HCC develops in inflammatory and fibrotic conditions.
Carcinoma, Hepatocellular/*etiology ; Gram-Negative Bacteria/growth & development ; Hepatitis, Chronic/*complications/metabolism/microbiology ; Humans ; Hypoxia ; *Inflammation ; Lipopolysaccharides/metabolism ; Liver/metabolism/pathology ; Liver Cirrhosis/*complications ; Liver Neoplasms/*etiology ; Toll-Like Receptors/metabolism

BACKGROUND/AIMS: The optimal management of patients exhibiting a partial virologic response (PVR) to entecavir (ETV) has not been determined . The aim of this study was to determine the long-term efficacy of prolonged ETV monotherapy in treatment-naive chronic hepatitis B (CHB) patients exhibiting a PVR to ETV therapy. METHODS: This study included 364 treatment-naive CHB patients treated with ETV for > or =48 weeks and who received continuous ETV monotherapy for > or =96 weeks. PVR was defined as a decrease in serum hepatitis B virus (HBV) DNA of more than 2 log10 IU/mL from baseline but with detectable HBV DNA by real-time PCR assay at week 48. RESULTS: Fifty-two of the 364 patients (14.3%) showed a PVR. Among them, 41 patients received continuous ETV monotherapy for > or =96 weeks (median duration 144 weeks, range 96-312 weeks), and 40 of these patients (95%) achieved a virologic response (VR, HBV DNA <20 IU/mL) during prolonged ETV monotherapy (median duration 78 weeks, range 60-288 weeks). The cumulative probabilities of a VR at weeks 96, 144, and 192 from treatment initiation were 78.0%, 92.7%, and 95.1%, respectively. The VR rate was 97.2% (35/36) in HBeAg-positive patients and 100% (5/5) in HBeAg-negative patients. In multivariate analysis, HBeAg positivity (odds ratio [OR], 9.231; 95% confidence interval [CI], 1.03-82.91; P=0.047) and a high baseline HBV DNA level (OR, 0.170; 95% CI, 0.08-0.37; P=0.000) were independently associated with a delayed virologic response. No patient developed genotypic resistance to ETV during follow-up. CONCLUSIONS: Long-term ETV monotherapy is effective for achieving a VR in treatment-naive CHB patients exhibiting a PVR to ETV. HBeAg positivity and high baseline HBV DNA level were independently associated with a delayed virologic response.
Adult ; Aged ; Antiviral Agents/*therapeutic use ; DNA, Viral/blood ; Drug Administration Schedule ; Female ; Genotype ; Guanine/*analogs & derivatives/therapeutic use ; Hepatitis B e Antigens/blood ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/*drug therapy/pathology/virology ; Humans ; Liver Cirrhosis/etiology/radiography/ultrasonography ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Real-Time Polymerase Chain Reaction ; Retrospective Studies ; Tomography, X-Ray Computed ; Treatment Outcome

BACKGROUND/AIMS: Chronic hepatitis C (CHC) is a major comorbidity in patients with hemophilia. However, there are no published data on the efficacy of antiviral therapy in Korea. We assessed the safety and efficacy of combination therapy with peginterferon alpha-2a plus ribavirin for CHC in hemophilia. METHODS: Patients (n=115) were enrolled between March 2007 and December 2008. Seventy-seven patients were genotype 1 or 6, and 38 patients were genotype 2 or 3. We evaluated rapid virologic responses (RVRs), early virologic response (EVRs), end-of-treatment response (ETRs), sustained virologic response (SVRs), and relapses. Safety evaluations included adverse events and laboratory tests. RESULTS: Eleven patients were excluded from the study because they had been treated previously. Among the remaining 104 treatment-naive patients, RVR was achieved in 64 (60.6%), ETR was achieved in 95 (91.3%), and SVR was achieved in 89 (85.6%). Relapse occurred in eight patients (8.9%). Common adverse events were hair loss (56.7%) and headache (51.0%). Common hematologic adverse events were neutropenia (22.1%), anemia (27.9%), and thrombocytopenia (3.8%). However, there were no serious adverse events such as bleeding. RVR was the only predictor of SVR in multivariate analysis. CONCLUSIONS: Peginterferon alpha-2a plus ribavirin combination treatment produced a favorable response rate in CHC patients with hemophilia without serious adverse events.
Adult ; Aged ; Antiviral Agents/adverse effects/*therapeutic use ; Drug Therapy, Combination ; Fatigue/etiology ; Female ; Genotype ; Headache/etiology ; Hemophilia A/*complications ; Hepacivirus/genetics ; Hepatitis C, Chronic/complications/*drug therapy/virology ; Humans ; Interferon-alpha/adverse effects/*therapeutic use ; Liver/pathology ; Male ; Middle Aged ; Neutropenia/etiology ; Polyethylene Glycols/adverse effects/*therapeutic use ; RNA, Viral/blood ; Recombinant Proteins/adverse effects/therapeutic use ; Recurrence ; Republic of Korea ; Ribavirin/adverse effects/*therapeutic use ; Treatment Outcome