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Background and Aims: The course of adults with ZZ alpha‐1‐antitrypsin deficiency (AATD) liver disease is unpredictable. The utility of markers, including liver biopsy, is undefined. Methods: A prospective cohort, including protocol liver biopsies, was enrolled to address these questions. Results: We enrolled 96 homozygous ZZ AATD adults prospectively at three US sites with standardized clinical evaluations, and protocol liver biopsies. Fibrosis was scored using Ishak (stages 0–6). Also, 51% of the 96 subjects had Ishak score >1 fibrosis (49% Ishak 0–1, 36% Ishak 2–3 and 15% ≥4). Elevated aspartate aminotransferase (AST) more than alanine aminotransferase (ALT), high body mass index (BMI), obesity, AST platelet ratio index and elevated serum Z alpha 1 antitrypsin (AAT) polymer levels were associated with increased fibrosis. Steatosis did not correlate to fibrosis. Increased fibrosis was associated with increased mutant Z polymer globular inclusions (p =.002) and increased diffuse cytoplasmic Z polymer on biopsy (p =.0029) in a direct relationship. Increased globule Z polymer was associated with increased serum AST (p =.007) and increased periportal inflammation on histopathology (p =.004), but there was no relationship of Z polymer hepatocellular accumulation with ALT, gamma glutamine transferase, inflammation in other parts of the lobule, necrosis or steatosis. Serum Z polymer levels were directly correlated to hepatic Z protein polymer content. Lung function, smoking and alcohol consumption patterns were not associated with fibrosis. Conclusion: In AATD high BMI, obesity and elevated AST are associated with increased fibrosis. Liver biopsy features are correlated to some serum tests. Serum Z AAT polymer levels could be a future biomarker to detect fibrosis early and is directly correlated to liver Z content. [ABSTRACT FROM AUTHOR]

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease that results from mutations in the alpha-1 antitrypsin (AAT) gene. The mutant AAT protein aggregates and accumulates in the liver leading to AATD liver disease, which is only treatable by liver transplant. The PiZ transgenic mouse strain expresses a human AAT (hAAT) transgene that contains the AATD-associated Glu342Lys mutation. PiZ mice exhibit many AATD symptoms, including AAT protein aggregates, increased hepatocyte death, and liver fibrosis. In the present study, we systemically treated PiZ mice with an antisense oligonucleotide targeted against hAAT (AAT-ASO) and found reductions in circulating levels of AAT and both soluble and aggregated AAT protein in the liver. Furthermore, AAT-ASO administration in these animals stopped liver disease progression after short-term treatment, reversed liver disease after long-term treatment, and prevented liver disease in young animals. Addi-tionally, antisense oligonucleotide treatment markedly decreased liver fibrosis in this mouse model. Admin-istration of AAT-ASO in nonhuman primates led to an approximately 80% reduction in levels of circulating normal AAT, demonstrating potential for this approach in higher species. Antisense oligonucleotides thus represent a promising therapy for AATD liver disease., Introduction Alpha-1 antitrypsin (AAT) is a serum protease inhibitor mainly produced and secreted by hepatocytes. As a member of the serpin super family, AAT covalently binds to its protease target [...]

Homozygous, PIZZ [[alpha].sub.1]-antitrypsin ([[alpha].sub.1]-AT) deficiency is associated with chronic liver disease and hepatocellular carcinoma resulting from the toxic effects of mutant [[alpha].sub.1]-anti-trypsin Z ([[alpha].sub.1]-ATZ) protein retained in the endoplasmic reticulum (ER) of hepatocytes. However, the exact mechanism(s) by which retention of this aggregated mutant protein leads to cellular injury are still unknown. Previous studies have shown that retention of mutant [[alpha].sub.1]-ATZ in the ER induces an intense autophagic response in hepatocytes. In this study, we present evidence that the autophagic response induced by ER retention of [[alpha].sub.1]-ATZ also involves the mitochondria, with specific patterns of both mitochondrial autophagy and mitochondrial injury seen in cell culture models of [[alpha].sub.1]-AT deficiency, in PiZ transgenic mouse liver, and in liver from [[alpha].sub.1]-AT-deficient patients. Evidence for a unique pattern of caspase activation was also detected. Administration of cyclosporin A, an inhibitor of mitochondrial permeability transition, to PiZ mice was associated with a reduction in mitochondrial autophagy and injury and reduced mortality during experimental stress. These results provide evidence for the novel concept that mitochondrial damage and caspase activation play a role in the mechanism of liver cell injury in [[alpha].sub.1]-AT deficiency and suggest the possibility of mechanism-based therapeutic interventions. [[alpha].sub.1]-antitrypsin; autophagy; mitochondria; quality control; cyclosporin A

The bile acid nor-ursodeoxycholic acid (norUDCA) has many biological actions, including antiapoptotic effects. Homozygous PIZZ α-1-antitrypsin (A1AT)-deficient humans are known to be at risk for liver disease, cirrhosis, and liver cancer as a result of the accumulation of the toxic, A1AT mutant Z protein within hepatocytes. This accumulation triggers cell death in the hepatocytes with the largest mutant Z-protein burdens, followed by compensatory proliferation. Proteolysis pathways within the hepatocyte, including autophagy, act to reduce the intracellular burden of A1AT Z protein. We hypothesized that norUDCA would reduce liver cell death and injury in A1AT deficiency. We treated groups of PiZ transgenic mice and wild-type mice with norUDCA or vehicle, orally, and examined the effects on the liver. The PiZ mouse is the best model of A1AT liver injury and recapitulates many features of the human liver disease. Mice treated with norUDCA demonstrated reduced hepatocellular death by compensatory hepatocellular proliferation as determined by bromodeoxyuridine incorporation (3.8% control, 0.88% treated, P < 0.04). Ki-67 staining as a marker for hepatocellular senescence and death was also reduced (P < 0.02). Reduced apoptotic signaling was associated with norUDCA, including reduced cleavage of caspases-3, -7, and -8 (all P< 0.05). We determined that norUDCA was associated with a >70% reduction in intrahepatic mutant Z protein (P < 0.01). A 32% increase in hepatic autophagy associated with norUDCA was the likely mechanism. norUDCA administration is associated with increased autophagy, reduced A1AT protein accumulation, and reduced liver injury in a model of A1AT deficiency. [ABSTRACT FROM AUTHOR]

Homozygous, PIZZ α1-antitrypsin (oLd-AT) deficiency is associated with chronic liver disease and hepatocellular carcinoma resulting from the toxic effects of mutant α1 -anti-trypsin Z (α1-ATZ) protein retained in the endoplasmic reticulum (ER) of hepatocytes. However, the exact mechanism(s) by which retention of this aggregated mutant protein leads to cellular injury are still unknown. Previous studies have shown that retention of mutant α1-ATZ in the ER induces an intense autophagic response in hepatocytes. In this study, we present evidence that the autophagic response induced by ER retention of α1-ATZ also involves the mitochondria, with specific patterns of both mitochondrial autophagy and mitochondrial injury seen in cell culture models of αAT deficiency, in PiZ transgenic mouse liver, and in liver from α-Academy of deficiedeficient patients. Evidence for a unique pattern of caspase activation was also detected. Administration of cyclosporin A, an inhibitor of mitochondrial permeability transition, to PiZ mice was associated with a reduction in mitochondrial autophagy and injury and reduced mortality during experimental stress. These results provide evidence for the novel concept that mitochondrial damage and caspase activation play a role in the mechanism of liver cell injury in α1-AT deficiency and suggest the possibility of mechanism-based therapeutic interventions. [ABSTRACT FROM AUTHOR]