The mutant Z protein is transcribed and translated in the hepatocyte, then t ransported into the endoplasmic reticulum, where it undergoes folding into its final conformation in preparation for secretion. Unfortunately, the mutant protein folds inefficiently due to the amino acid substitution. Its abnormal configuration impairs its secretion from the ER, and these proteins are directed mostly into a variety of proteolytic pathways referred to as “ER-associated degradation (ERAD),” but some survive and take various conformations, including the linkage of large groups of Z protein “polymers” by noncovalent bonds that allow them to become visible on light microscopy as “globules” [12]. Although the actual degradation mechanism remains to be elucidated, calnexin, and ER manosidase have been identified to be possible points of control [13]. Pi^*ZZ homozygous patients with less efficient ERAD mechanisms are more susceptible to development of liver disease than those with more efficient mechanisms [14]. Autophagy is another important proteolytic pathway that is upregulated by the accumulation of Z protein polymers, leading to the degradation of abnormal proteins by specialized vacuoles. Increasing autophagy in animal models has led to a reduction in the accumulation of the Z protein polymers and consequent liver injury [15, 16]. Hepatocytes with large burden of polymerized Z proteins undergo apoptosis, initiating a chronic process of cell injury that leads to cell death, fibrosis, and eventually in some individuals, cirrhosis . However, it is well recognized that individuals with the same Pi^*ZZ genotype demonstrate variable extents of clinical liver injury, invoking the probable roles of environmental and genetic modifiers that alter the rate and severity of the clinical manifestation of the disease.

As is seen in other liver diseases that affect neonates, persistent jaundice is the most common presenting symptom at 4–8 weeks of age in those who manifest the disease. Accompanying symptoms may include poor feeding, poor weight gain, and pruritus. Some babies may have hepatomegaly, and the laboratory derangements may demonstrate either a hepatitis picture with elevated serum transaminases, or cholestasis with elevated alkaline phosphatase [17]. Occasionally, neonates present with bleeding from the gastrointestinal tract or from the umbilical stump, or easy bruising [18].

Liver disease from AATD may be diagnosed later in childhood, presenting with asymptomatic hepatomegaly or elevated transaminases, or with jaundice that may occur during the course of an unrelated illness. It can also remain further undetected until the adolescence or adulthood, where it can present with complications of cirrhosis and portal hypertension, such as splenomegaly and hypersplenism, gastrointestinal bleeding from varices, ascites, or hepatic encephalopathy [17]. The diagnosis should be considered in adults who present with chronic liver disease or cirrhosis of unknown etiology.

The natural history of liver disease due to AATD is remarkably variable. Most infants that manifested jaundice early in life recover and become asymptomatic by age 1 year, despite the few who would require liver transplantation. Majority of these children will remain without symptoms as they grow older. In the only prospective study of AATD diagnosed by screening 200,000 neonates in Sweden in the 1970s, 127 infants were diagnosed with the classic form of AATD. Eleven percent of these infants had prolonged jaundice, 6 % had hepatomegaly with or without elevated serum transaminases, and approximately 43 % had elevated serum transaminases alone. Five of the twenty neonates with clinical evidence of liver disease died of cirrhosis in early childhood. Follow-up of the remaining population at age 18 years showed that only 12 % of the ZZ phenotype had elevated serum transaminases, although there were no clinical signs of liver disease, while 10 % of the SZ phenotype had similar findings. Therefore, although 17 % of the population had clinical evidence of liver disease in the first 18 years of life, almost 90 % of those who reached adulthood had normal liver enzymes, although biopsies were not performed to confirm the absence of liver injury [11].

Lung destruction in the form of emphysema caused by AATD usually manifests later in the third decade. The incidence of liver disease in patients who were diagnosed with emphysema from AATD is not clearly defined, although one small series reported elevated liver chemistry tests in 50 % [19].

The diagnosis of AATD should be considered in an individual who presents with symptoms of chronic liver disease or demonstrates elevated liver chemistry tests, particularly those who do not have an obvious etiology. The disease is characterized by the presence of altered AAT proteins that accumulates in the liver, such that circulating serum AAT levels are expected to be low and the serum AAT phenotype determination by isoelectric-focusing electrophoresis would reveal the altered protein type. While screening for the disease is typically performed with the AAT level measurement, it is important to remember that these levels may be falsely elevated to normal or near-normal ranges in affected patients by a concomitant inflammatory host response. On the other hand, patients with advanced cirrhosis and compromised synthetic function of the liver may have low serum protein levels, including AAT levels. Therefore, both serum concentrations and phenotype determination should be obtained when the diagnosis is seriously considered.

Histologically, accumulation of the abnormal AAT molecules in the liver is represented by the presence of periodic acid-Schiff-positive, diastase-resistant globules in the endoplasmic reticulum of hepatocytes (Fig. 19.1). These inclusions are eosinophilic, round to oval, 1–40 μm in diameter located prominently in periportal hepatocytes, and less so in Kupffer cells and biliary epithelial cells [20]. However, it is important to note that the globules are not present in all hepatocytes, or can be small or “dust-like” in small infants, or totally absent in neonatal livers [21].

The lung manifestation of AATD is rarely seen in childhood or adolescence, but becomes more common when the individual reaches the mid to late 30 years of life. The development and severity of emphysema in AATD is significantly increased up to 1000-fold by cigarette smoking [22]. Alpha-1 antitrypsin deficiency has been associated with vasculitic diseases [23], and the c losest association has been demonstrated in a genome-wide sequence analysis that demonstrated the association of anti-proteinase 3 antineutrophil cytoplasmic antibody (ANCA) with the gene encoding AAT (SERPINA1) [24]. It also has been associated with panniculitis, which can respond to augmentation therapy [25, 26].

Whereas the management of lung disease from AATD focuses most ly on avoidance of smoking and pollution and augmentation therapy, these strategies do not have any impact on the liver. Referral to a pulmonologist to evaluate and manage any lung manifestation would be important, as regular monitoring of lung function would be essential as the risk of emphysema increases with age. Avoidance of first-hand or second-hand smoking as well as pollution must be stressed [27]. Augmentation therapy or exogenous AAT replacement, if indicated, can benefit lung disease.

Currently, the management of liver disease due to AATD consists mainly of supportive measures, as there is no available specific therapy targeted to the liver. The use of long-term ursodiol in children with milder liver disease from AAT has been associated with improvement in liver chemistry tests, but a true benefit on histologic disease or the natural history of the disease remains to be seen [28]. When cirrhosis of the liver is suspected or established, screening for hepatocellular carcinoma and for esophageal varices should be performed, and preventive measures against some complications such as variceal bleeding or malnutrition can be instituted. In the setting of advanced fibrosis or cirrhosis, abstinence from alcohol is necessary to avoid a more rapid decompensation. When hepatic decompensation or hepatocellular carcinoma has developed, liver transplantation may be necessary. Liver transplantation in children and adults is associated with excellent survival rates of 90 and 83 % in 5 years, respectively [29]. Animal models of AAT liver disease have demonstrated a unique toxicity of nonsteroidal anti-inflammatory drugs to the Pi^*ZZ liver by increasing the production of the mutant Z protein [30], so it would be prudent to avoid the use of NSAIDS in this patient population.