Pathogenesis of Chronic Liver Injury and Hepatocellular Carcinoma in Alpha-1-Antitrypsin Deficiency

Abstract

Alpha-1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children. In addition to chronic liver inflammation and injury, it has a predilection to cause hepatocellular carcinoma later in life. The deficiency is caused by a mutant protein, ATZ, which is retained in the endoplasmic reticulum (ER) in a polymerized form rather than secreted into the blood in its monomeric form. The histologic hallmark of the disease is ATZ-containing globules in some, but not all, hepatocytes. Liver injury results from a gain-of-toxic function mechanism in which mutant ATZ retained in the ER initiates a series of pathologic events, but little is known about the mechanism by which this leads to carcinogenesis. Several recent observations from my laboratory have led to a novel hypothetical paradigm for carcinogenesis in AT deficiency in which globulecontaining hepatocytes are "sick," relatively growth suppressed, but also elaborating trans-acting regenerative signals. These signals are received and transduced by globule-devoid hepatocytes, which, because they are younger and have a lesser load of accumulated ATZ, have a selective proliferative advantage. Chronic regeneration in the presence of tissue injury leads to adenomas and ultimately carcinomas. Aspects of this hypothetical paradigm may also explain the proclivity for hepatocarcinogenesis in other chronic liver diseases, including other genetic diseases, viral hepatitis, and nonalcoholic steatohepatitis. (Pediatr Res 60: 233-238, 2006)

Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells

“…Previous studies have shown that the Z allele (Glu342Lys) results in the formation of ordered polymers of α 1 -antitrypsin that are retained within the ER (17). These polymers accumulate within hepatocytes, predisposing the homozygote to neonatal hepatitis, cirrhosis, and hepatocellular carcinoma (18). This pathway of α 1 -antitrypsin polymerization is central to the clinical phenotype (17).…”

A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with α1-antitrypsin deficiency

“…2 These inclusions predispose the individual homozygous for the Z variant of the a 1 -antitrypsin protease inhibitor (PI*Z) to neonatal hepatitis, cirrhosis, and rarely, hepatocellular carcinoma. 3 Deficiency of circulating a 1 -antitrypsin results in early onset panlobular emphysema. 4 The Z mutation of a 1 -antitrypsin lies between the head of strand 5A and the base of the mobile reactive center loop 5 ( Fig.…”

Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in α-1-antitrypsin deficiency

“…2 It is predominantly synthesized by the liver and, as an acute phase reactant, its plasma concentrations increase significantly during the host response to inflammation and tissue injury. 3 In the classical form of AT deficiency, which affects 1 in 1800-2000 live births, a single nucleotide substitution results in abnormal folding early in the secretory pathway (reviewed in Perlmutter DH 4 ). The mutant protein, called ATZ, has an increased tendency to polymerize and aggregate, 5,6 with only 10-15% of newly synthesized molecules able to traverse the secretory pathway and reach the extracellular fluid.…”

“…We now know that AT deficiency is the most common genetic cause of liver disease in children. 3,4 It is also known to cause chronic liver disease and hepatocellular carcinoma first diagnosed in adults. 9 In contrast to what happens in the lung, liver disease is thought to be caused by a gain-of-toxic function mechanism in which the accumulation of the mutant AT molecule in the ER of liver cells initiates a series of events that are eventually hepatotoxic.…”