Alpha-1-antitrypsin deficiency: A new paradigm for hepatocellular carcinoma in genetic liver disease

Abstract

Liver disease in alpha-1-antitrypsin (␣1AT) deficiency is caused by a gain-of-toxic function mechanism engendered by the accumulation of a mutant glycoprotein in the endoplasmic reticulum (ER). The extraordinary degree of variation in phenotypical expression of this liver disease is believed to be determined by genetic modifiers and/or environmental factors that influence the intracellular disposal of the mutant glycoprotein or the signal transduction pathways that are activated. Recent investigations suggest that a specific repertoire of signaling pathways are involved, including the autophagic response, mitochondrial-and ER-caspase activation, and nuclear factor kappaB (NF B) activation. Whether activation of these signaling pathways, presumably to protect the cell, inadvertently contributes to liver injury or perhaps protects the cell from one injury and, in so doing, predisposes it to another type of injury, such as hepatocarcinogenesis, is not yet known. Recent studies also suggest that hepatocytes with marked accumulation of ␣1ATZ, globule-containing hepatocytes, engender a cancer-prone state by surviving with intrinsic damage and by chronically stimulating in 'trans' adjacent relatively undamaged hepatocytes that have a selective T he classic form of alpha-1-antitrypsin (␣1AT) deficiency, associated with homozygosity for the ␣1ATZ allele, is the most common genetic cause of liver disease in children. It also causes chronic liver injury and hepatocellular carcinoma in adults. 1 Moreover, the predilection for hepatocellular carcinoma in homozygotes for the Z allele is significantly greater than that attributable to cirrhosis alone. 1 The histopathological hallmark of the disease is intracellular globules in hepatocytes that stain positively with periodic acid-Schiff (PAS) after treatment with diastase, the so-called PAS-positive/ diastase-resistant globules. Early studies showed that these globules represent the mutant glycoprotein, ␣1ATZ, retained in the rough endoplasmic reticulum (ER) of liver cells (reviewed in Perlmutter 2 ). Although considerable discussion of these globules is found in the literature as well as investigation of their origin, relatively limited discussion, or investigation, has taken place, regarding the curious fact that many hepatocytes in these patients do not have globules (Fig. 1). Studies of the Z#2 mouse model, generated by using a human ␣1ATZ genomic fragment as transgene, 3 have shown that these globuledevoid cells occupy an increasing proportion of the liver as the animal ages and ultimately become the site of adenomas and carcinomas. 4 In more recent studies using the PiZ mouse model, another transgenic mouse created with a human ␣1ATZ genomic fragment, 5 we have shown that there is increased proliferation of these globule-devoid hepatocytes at a rate that is directly proportional to the number of globule-containing hepatocytes. 6

Hepatocellular carcinoma in a 12-year-old child with PiZZ α1-antitrypsin deficiency

“…Whether the abdominal trauma suffered 8 months earlier played a role in the development of HCC in our patient remains speculative. The minimal atypia, very low proliferative rate, slow clinical progression, and incipient accumulation of the dPAS-positive material in the lesional hepatocytes indicate that hepatocarcinogenesis in metabolic conditions, as recently postulated, 1 …”

Intracellular Inclusions Containing Mutant α1-Antitrypsin Z Are Propagated in the Absence of Autophagic Activity

“…Previous studies have suggested that globule-devoid hepatocytes do express ␣ 1 -ATZ but to apparently lesser levels than globule-containing hepatocytes, presumably because they are progenitor or younger cells (27,33,34). Thus, the most likely explanation for the presence of autophagosomes in both of these cell populations is that the threshold for induction of autophagy is reached at the lower level of ␣ 1 -ATZ in the globule-devoid hepatocytes.…”

“…It is also well known that mutant ␣ 1 -ATZ forms large globules in the ER of some, but not all, hepatocytes (27). The globule-devoid hepatocytes are thought to be progenitor, or at least relatively immature, hepatocytes that express ␣ 1 -ATZ but not to the extent that there is enough accumulation to form intracellular globules (27,34). In Fig.…”

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

“…39 Consistent with this, almost all of the adenomas and carcinomas that occur in the human disease and in the mouse model arise in the globule-devoid hepatocytic population. 40 These results have led us to hypothesize (Figure 4) that the pathogenesis of hepatic carcinoma involves the interplay of globule-containing cells that are 'sick but not yet dead' and chronically stimulating the globule-devoid cells 'in trans' in the presence of inflammation. 40 We know that the globule-devoid cells have accumulated aggregated mutant ATZ 41 and activated a number of cellular 'alarm' pathways, including ER-and mitochondrial caspases, NF-kB and autophagy.…”

“…40 These results have led us to hypothesize (Figure 4) that the pathogenesis of hepatic carcinoma involves the interplay of globule-containing cells that are 'sick but not yet dead' and chronically stimulating the globule-devoid cells 'in trans' in the presence of inflammation. 40 We know that the globule-devoid cells have accumulated aggregated mutant ATZ 41 and activated a number of cellular 'alarm' pathways, including ER-and mitochondrial caspases, NF-kB and autophagy. 27 Furthermore, we know that the globule-containing cells are relatively impaired in cell proliferation.…”