RESUMO
Chronic hepatitis C infection is a major cause of liver cancer in the United States. Hawai'i's incidence of liver cancer consistently ranks among the highest in the US, due in part to the high prevalence of hepatitis B in the state. To better understand the factors associated with liver cancer among patients in Hawai'i with hepatitis C virus (HCV) infection, the patient database of Kaiser Permanente's Hawai'i region was used to identify a cohort of 3198 patients with a history of chronic HCV infection, of whom 159 (5%) were diagnosed with liver cancer between the years 2004-2020. Multiple logistic regression was used to identify factors independently associated with liver cancer. Male sex (AOR 2.02, 95% CI 1.34-3.06), Asian race (AOR 1.78, 1.16 - 2.74) and hepatitis B core antibody (HBCAB) positivity (AOR 1.76, 95% CI 1.25 - 2.49) emerged as independent predictors of liver cancer among patients with chronic HCV infection. A history of diabetes (AOR 1.56, 1.07 - 2.27) and older age at the time of HCV diagnosis (AOR 1.19, 1.09-1.29) also emerged as significant associations. HBCAB-positive individuals did not differ significantly from those who were HBCAB-negative in regards to demographics or 5-year survival rate. In this cohort of patients with chronic HCV, a positive HBCAB without evidence of active hepatitis B infection was associated with 1.76 increased odds of liver cancer compared to those with negative HBCAB. This finding may have important implications for screening algorithms among individuals with hepatitis C infection.
Assuntos
Hepatite B , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Havaí/epidemiologia , Hepacivirus , Hepatite B/complicações , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Hepatite C/complicações , Hepatite C/epidemiologia , Hepatite C/prevenção & controle , Hepatite C Crônica/complicações , Hepatite C Crônica/epidemiologia , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/epidemiologia , Masculino , Estados UnidosRESUMO
ABCC6 deficiency promotes ectopic calcification; however, circumstantial evidence suggested that ABCC6 may also influence atherosclerosis. The present study addressed the role of ABCC6 in atherosclerosis using Ldlr-/- mice and pseudoxanthoma elasticum (PXE) patients. Mice lacking the Abcc6 and Ldlr genes were fed an atherogenic diet for 16 weeks before intimal calcification, aortic plaque formation and lipoprotein profile were evaluated. Cholesterol efflux and the expression of several inflammation, atherosclerosis and cholesterol homeostasis-related genes were also determined in murine liver and bone marrow-derived macrophages. Furthermore, we examined plasma lipoproteins, vascular calcification, carotid intima-media thickness and atherosclerosis in a cohort of PXE patients with ABCC6 mutations and compared results to dysmetabolic subjects with increased cardiovascular risk. We found that ABCC6 deficiency causes changes in lipoproteins, with decreased HDL cholesterol in both mice and humans, and induces atherosclerosis. However, we found that the absence of ABCC6 does not influence overall vascular mineralization induced with atherosclerosis. Decreased cholesterol efflux from macrophage cells and other molecular changes such as increased pro-inflammation seen in both humans and mice are likely contributors for the phenotype. However, it is likely that other cellular and/or molecular mechanisms are involved. Our study showed a novel physiological role for ABCC6, influencing plasma lipoproteins and atherosclerosis in a haploinsufficient manner, with significant penetrance.
Assuntos
Aterosclerose/etiologia , Dislipidemias/etiologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/deficiência , Pseudoxantoma Elástico/complicações , Animais , Ácidos e Sais Biliares/sangue , Feminino , Humanos , Macrófagos/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Pseudoxantoma Elástico/sangue , Estudos RetrospectivosRESUMO
Because vascular or cardiac mineralization is inversely correlated with morbidity and long-term survival, we investigated the role of ABCC6 in the calcification response to cardiac injury in mice. By using two models of infarction, nonischemic cryoinjury and the pathologically relevant coronary artery ligation, we confirmed a large propensity to acute cardiac mineralization in Abcc6−/− mice. Furthermore, when the expression of ABCC6 was reduced to approximately 38% of wild-type levels in Abcc6+/− mice, no calcium deposits in injured cardiac tissue were observed. In addition, we used a gene therapy approach to deliver a functional human ABCC6 via hydrodynamic tail vein injection to approximately 13% of mouse hepatocytes, significantly reducing the calcification response to cardiac cryoinjury. We observed that the level and distribution of known regulators of mineralization, such as osteopontin and matrix Gla protein, but not osteocalcin, were concomitant to the level of hepatic expression of human and mouse ABCC6. We notably found that undercarboxylated matrix Gla protein precisely colocalized within areas of mineralization, whereas osteopontin was more diffusely distributed in the area of injury, suggesting a prominent association for matrix Gla protein and osteopontin in ABCC6-related dystrophic cardiac calcification. This study showed that the expression of ABCC6 in liver is an important determinant of calcification in cardiac tissues in response to injuries and is associated with changes in the expression patterns of regulators of mineralization.
Assuntos
Calcinose/metabolismo , Traumatismos Cardíacos/metabolismo , Fígado/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Western Blotting , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/metabolismo , Traumatismos Cardíacos/patologia , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Osteopontina/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteína de Matriz GlaRESUMO
Mutations in the ABCC6 gene cause soft-tissue calcification in pseudoxanthoma elasticum (PXE) and, in some patients, generalized arterial calcification of infancy (GACI). PXE is characterized by late onset and progressive mineralization of elastic fibers in dermal, ocular, and cardiovascular tissues. GACI patients present a more severe, often prenatal arterial calcification. We have tested 10 frequent disease-causing ABCC6 missense mutants for the transport activity by using Sf9 (Spodoptera frugiperda) cells, characterized the subcellular localization in MDCKII (Madin-Darby canine kidney (cell line)) cells and in mouse liver, and tested the phenotypic rescue in zebrafish. We aimed at identifying mutants with preserved transport activity but with improper plasma membrane localization for rescue by the chemical chaperone 4-phenylbutyrate (4-PBA). Seven of the mutants were transport-competent but mislocalized in mouse liver. The observed divergence in cellular localization of mutants in MDCKII cells versus mouse liver underlined the limitations of this 2D in vitro cell system. The functionality of ABCC6 mutants was tested in zebrafish, and minimal rescue of the morpholino-induced phenotype was found. However, 4-PBA, a drug approved for clinical use, restored the plasma membrane localization of four ABCC6 mutants (R1114P, S1121W, Q1347H, and R1314W), suggesting that allele-specific therapy may be useful for selected patients with PXE and GACI.
Assuntos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Mutação de Sentido Incorreto , Pseudoxantoma Elástico/genética , Transportadores de Cassetes de Ligação de ATP/genética , Alelos , Animais , Linhagem Celular , Membrana Celular/metabolismo , Cães , Humanos , Insetos , Fígado/metabolismo , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Fenótipo , Fenilbutiratos/química , Conformação Proteica , Dobramento de Proteína , Peixe-ZebraRESUMO
Pseudoxanthoma elasticum (PXE) is a heritable disease characterized by calcified elastic fibers in cutaneous, ocular, and vascular tissues. PXE is caused by mutations in ABCC6, which encodes a protein of the ATP-driven organic anion transporter family. The inability of this transporter to secrete its substrate into the circulation is the likely cause of PXE. Vitamin K plays a role in the regulation of mineralization processes as a co-factor in the carboxylation of calcification inhibitors such as Matrix Gla Protein (MGP). Vitamin K precursor or a conjugated form has been proposed as potential substrate(s) for ABCC6. We investigated whether an enriched diet of vitamin K1 or vitamin K2 (MK4) could stop or slow the disease progression in Abcc6 (-/-) mice. Abcc6 (-/-) mice were placed on a diet of either vitamin K1 or MK4 at 5 or 100 mg/kg at prenatal, 3 weeks or 3 months of age. Disease progression was quantified by measuring the calcium content of one side of the mouse muzzle skin and histological staining for calcium of the opposing side. Raising the vitamin K1 or MK4 content of the diet increased the concentration of circulating MK4 in the serum. However, this increase did not significantly affect the MGP carboxylation status or reduce its abnormal abundance, the total calcium content or the pathologic calcification in the whiskers of the 3 treatment groups compared to controls. Our findings showed that raising the dietary intake of vitamin K1 or MK4 was not beneficial in the treatment of PXE and suggested that the availability of vitamin K may not be a limiting factor in this pathology.