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*

A 25-year-old woman presented with jaundice, palpitation, and weight loss of 5 kg during a period of 2 weeks. Laboratory tests showed elevated levels of liver enzymes (AST 1,282 IU/L, ALT 1,119 IU/L) and total bilirubin (6.4 mg/dL); negative for hepatitis virus infection; elevated serum levels of triiodothyronine (T3, 3.60 ng/dL), free thyroxine (fT4, 3.82 ng/dL), and lowered serum level of thyroid stimulating hormone (TSH, <0.025 microIU/mL); and positive for thyroid stimulating antibody and anti-mitochondrial antibody (AMA). The liver biopsy findings were consistent with autoimmune hepatitis (AIH). Accordingly, oral steroid therapy was started with 60 mg of prednisolone under the impression of AIH associated with Graves' disease. After a week of steroid therapy, the clinical manifestation showed significant improvement, with normalization of both liver and thyroid functions. Diagnosis of the liver condition of patients who present with hyperthyroidism and liver dysfunction is important, so that appropriate therapy can be promptly initiated.
Adult ; Alanine Transaminase/analysis ; Antibodies, Antinuclear/blood ; Aspartate Aminotransferases/analysis ; Bilirubin/blood ; Female ; Graves Disease/complications/*diagnosis/drug therapy ; Hepatitis, Autoimmune/complications/*diagnosis/drug therapy ; Humans ; Immunoglobulins, Thyroid-Stimulating/blood ; Liver/enzymology/metabolism/pathology ; Prednisolone/therapeutic use ; Steroids/therapeutic use ; Thyrotropin/blood

BACKGROUND/AIMS: Overlap syndrome of autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) (AIH-PBC overlap syndrome) is a rare disease that has not been clearly characterized in Korean patients. This study investigated the clinical features of AIH-PBC overlap syndrome compared with those of AIH and PBC alone. METHODS: This retrospective cohort study included 158 consecutive patients who were diagnosed as AIH (n=61), PBC (n=81), or AIH-PBC overlap syndrome (n=9) based on the Paris and the International Autoimmune Hepatitis Group (IAIHG) criteria from 2001 to 2011 in Korea. We compared the clinical features of these three groups retrospectively, including their biochemical characteristics, treatments, responses, and clinical outcomes. RESULTS: The AIH-PBC overlap syndrome patients exhibited biochemical characteristics of both AIH and PBC, and showed a similar response to ursodeoxycholic acid (UDCA) monotherapy as for the PBC patients. However, the response of AIH-PBC overlap syndrome patients to UDCA and steroid combination therapy was worse than the response of AIH patients to steroid-based therapy (P=0.024). Liver cirrhosis developed more rapidly in AIH-PBC overlap syndrome patients than in AIH patients group (P=0.013), but there was no difference between AIH-PBC overlap syndrome patients and PBC patients. The rates of developing hepatic decompensation did not differ significantly between the groups. CONCLUSIONS: The AIH-PBC overlap syndrome patients exhibited a worse response to UDCA and steroid combination therapy and a faster cirrhotic progression compared with AIH patients.
Adult ; Aged ; Cohort Studies ; Drug Therapy, Combination ; Female ; Hepatitis, Autoimmune/complications/*diagnosis ; Humans ; Liver/metabolism/pathology ; Liver Cirrhosis, Biliary/complications/*diagnosis/drug therapy ; Male ; Middle Aged ; Republic of Korea ; Retrospective Studies ; Steroids/therapeutic use ; Treatment Outcome ; Ursodeoxycholic Acid/therapeutic use

OBJECTIVETo observe the effects of interferon-alpha combined with saikosaponin on serum T lymphocyte subgroups and hepatic cytokines in mice with immune hepatic injury.

METHODSThe mice were randomly divided into five groups, i. e., the normal control group, the model group, the interferon group, the saikosaponin group, and the interferon combined saikosaponin group. Corresponding medication was given to mice in respective groups for two days. Peripheral blood was collected 8 and 24 h after concanavalin A (Con A) was injected. Serum lymphocyte subgroups, tumor necrosis factor alpha (TNF-alpha), levels of interleukin 18 (IL-18) and IL-10, activities of alanine aminotransferase (ALT) and aspartate transaminase (AST) were detected. Pathological changes of the liver tissue were observed.

RESULTS(1) Compared with the normal control group, serious inflammation and necrosis was significant in the liver tissue of the model group. The serum levels of ALT and AST obviously increased. Meanwhile, the 24-h peripheral blood CD4+ T cell and CD8+ T cell ratios and the hepatic IL-10 level obviously decreased (P < 0.01). The levels of IL-18 and TNF-alpha significantly increased (P < 0.05, P < 0.01). (2) Compared with the model group, dot and lamellar necrosis was dispersedly seen in the liver tissue in the three medication groups. The serum activities of ALT and AST significantly decreased (P < 0.01). Meanwhile, the peripheral blood CD4+ T cell and CD8+ T cell ratios, as well as the hepatic IL-10 level obviously increased (P < 0.01, P < 0.05). The levels of IL-18 and TNF-alpha significantly decreased (P < 0.05, P < 0.01). (3) In the interferon combined saikosaponin group, the 24-h peripheral blood CD4+ T cell and CD8+ T cell ratios increased more obviously than those of the interferon group. The 8- and 24-h IL-18 levels were obviously lower than those of the interferon group, while the 24-h TNF-alpha level significantly decreased more than that of the interferon group (P < 0.05).

CONCLUSIONInterferon-alpha combined saikosaponin could effectively play a role in fighting against the immune hepatic injury.

Animals ; Cytokines ; metabolism ; Hepatitis, Autoimmune ; blood ; metabolism ; Interferon-alpha ; pharmacology ; Liver ; drug effects ; pathology ; Male ; Mice ; Mice, Inbred BALB C ; Oleanolic Acid ; analogs & derivatives ; pharmacology ; Saponins ; pharmacology ; T-Lymphocyte Subsets ; metabolism

OBJECTIVETo observe the expression change of signal regulatory protein alpha1 (SIRPalpha1) in autoimmune hepatitis (AIH) and approach the relationship between SIRPalpha1 and the extent of inflammation.

METHODSImmunohistochemistry is used to detect the expression of SIRPalpha1 in the paraffin section preparations of 33 AIH and 10 normal hepatic tissue.

RESULTSSIRPalpha1 is positive or weakly positive expressed in AIH. The staining is localized in the cytoplasm of Kupffer cells in the hepatic sinusoid with focal distribution. It is negative in normal hepatic tissue. In light AIH, it is negative or weakly positive expressed with a 36.4 percent of the positive rate (4/11). The positive or strong positive expression is found in the moderate AIH with an 84.2 percent of the positive rate(16/19). There is statistical significance between both light AIH, moderate AIH and severe AIH (P less than 0.001) and moderate AIH and light AIH (P less than 0.001). There is no statistical significance between both light AIH and severe AIH (P = 0.145 ) and moderate AIH and severe AIH (P = 0.084).

CONCLUSIONSAs a negative regulatory factor, the expression of SIRPalpha1 in hepatic sinusoid Kupffer cells is some associated with the extent of AIH.

Adolescent ; Adult ; Aged ; Antigens, Differentiation ; metabolism ; Cell Communication ; Child ; Female ; Hepatitis, Autoimmune ; metabolism ; pathology ; Hepatocytes ; metabolism ; pathology ; Humans ; Kupffer Cells ; metabolism ; pathology ; Male ; Middle Aged ; Receptors, Immunologic ; metabolism ; Young Adult

OBJECTIVETo evaluate whether the D-3-phosphoglycerate dehydrogenase (Phgdh) correlative antibodies is crucial for AIH, we cloned Phgdh cDNA and constructed plasmid, then purified and identified the immunoreactivity of the recombinant protein, and established the enzyme linked immunosorbent assay (ELISA) to detect Phgdh autoantigen correlative antibodies in diagnosis of autoimmune hepatitis.

METHODSThe constructed plasmid was transformed into E. coli. BL21(D3). This fusion protein was purified by Ni-NTA chromatography and its immunoreactivity was identified by SDS-PAGE and Western blot. The ELISA with the fusion protein was established first, then, the Phgdh autoantigen correlative antibodies in serum of patients with AIH (65) and patients with PBC (122) as well as chronic hepatitis B (CHB) (56), chronic hepatitis C (CHC) (117), and normal controls (60) were detected.

RESULTSThe sequence of Phgdh autoantigen gene was the same as the sequence reported on the genebank. The fusion protein was found about 60kD strip on SDS-PAGE. Western blot analysis showed that the fusion protein had immunoreactivity. When analyzing the serum by ELISA, the immune reactivity to Phgdh was detected in 66.15% of patients with AIH, 21.42% of patients with PBC, 12.50% of patients with CHB, 6.83% of patients with CHC, and 3.30% of normal individuals. The differences of prevalence between AIH patients and healthy controls as well as other diseases were of statistical significance (P less than 0.01).

CONCLUSIONThe Phgdh cDNA is successfully cloned into E. coli BL21 (D3). The frequency of antibodies to Phgdh is much higher in patients with AIH than in patients with PBC, CHB, CHC and normal control. The antibodies to Phgdh may have utility in improved diagnosis of AIH.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Autoantibodies ; analysis ; genetics ; Autoantigens ; immunology ; Cloning, Molecular ; Enzyme-Linked Immunosorbent Assay ; methods ; Escherichia coli ; genetics ; metabolism ; Female ; Gene Expression ; Genetic Vectors ; Hepatitis B, Chronic ; blood ; diagnosis ; Hepatitis, Autoimmune ; blood ; diagnosis ; Humans ; Liver Cirrhosis, Biliary ; blood ; diagnosis ; Male ; Middle Aged ; Phosphoglycerate Dehydrogenase ; genetics ; immunology ; Plasmids ; Recombinant Proteins ; genetics ; metabolism ; Young Adult

Animals ; Disease Models, Animal ; Fibrinogen ; metabolism ; Hepatitis, Autoimmune ; immunology ; metabolism ; Male ; Mice ; Mice, Inbred C57BL

Acute-Phase Proteins ; metabolism ; Animals ; Female ; Hepatitis, Autoimmune ; immunology ; metabolism ; pathology ; Interleukin-17 ; metabolism ; Lipocalin-2 ; Lipocalins ; metabolism ; Liver ; pathology ; Mice ; Mice, Inbred BALB C ; Oncogene Proteins ; metabolism

Adrenal Cortex Hormones ; therapeutic use ; Autoantigens ; immunology ; Child ; Cytokines ; metabolism ; HLA Antigens ; genetics ; Hepatitis, Autoimmune ; diagnosis ; immunology ; therapy ; Humans ; Immunosuppressive Agents ; therapeutic use ; Liver ; drug effects ; metabolism ; pathology ; Liver Transplantation

OBJECTIVETo express and identify soluble liver antigen (SLA) and cytochrome P-450 (CYP 2D6).

METHODSSLA cDNA and CYP 2D6 cDNA were obtained from human liver tissue poly (A)+RNA by RT-PCR. The cDNAs were inserted into fusion expression vector PQE-30 site of BamH I and Hind III. SLA and CYP 2D6 were identified by the SDS-PAGE and Western blot.

RESULTSSDS-PAGE analysis showed that there was a very strong stained band at about 47 kd and 50 kd, respectively. The products could specifically band to anti-SLA or anti-CYP 2D6 autoantibodies.

CONCLUSIONSThe clone and expression of SLA and CYP 2D6 provide useful substances for the diagnosis and research of pathogenesis on autoimmune hepatitis.

Autoantigens ; genetics ; Cytochrome P-450 Enzyme System ; genetics ; DNA, Complementary ; genetics ; Electrophoresis, Polyacrylamide Gel ; Escherichia coli ; genetics ; Gene Expression ; Hepatitis, Autoimmune ; genetics ; Humans ; Liver ; metabolism ; Recombinant Fusion Proteins ; genetics ; metabolism