Version May 2024
INTRODUCTION — Alpha-1 antitrypsin (AAT) is a serine protease inhibitor (PI) that is produced in hepatocytes. AAT deficiency is characterized by autosomal co-dominant inheritance of mutations in the alpha-1 antitrypsin gene (MIM 107400) [1]. AAT deficiency is associated with lung, liver, skin disease, and possibly other organ diseases [2].
The extrapulmonary manifestations of AAT deficiency will be reviewed here. The pulmonary manifestations and treatment of AAT deficiency are discussed separately. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency" and "Treatment of alpha-1 antitrypsin deficiency".)
HEPATIC DISEASE — Some AAT-deficient genotypes are associated with increased risk for certain liver disorders, such as neonatal hepatitis, cirrhosis both in children and adults, and hepatocellular carcinoma [3-9]. Approximately 10 to 15 percent of newborns with these genotypes develop some form of hepatic disease, and approximately 10 to 15 percent of affected adults develop hepatic disease [10]. Among never smokers, the prevalence of liver disease at death is higher (28 percent) [11].
Genetics — The two alleles that are most commonly associated with liver disease, Z and M(malton), are associated with accumulation of AAT protein in the hepatocyte (table 1). Other rare alleles, M(duarte), M(nichinan), S, and S(iiyama), are also known to cause intrahepatocytic accumulation [10,12-14]. Liver disease has not yet been described in these latter disorders, but too few individuals have been identified to reach a conclusion [13,15]. The PI Null (Hong Kong) is a variant in which no serum AAT is detected, but truncated protein can be found in the endoplasmic reticulum in the hepatocyte in vitro. Whether clinical liver disease can accompany this variant is unclear based on sparse clinical experience [16].
Pathogenesis — The pathogenesis of the liver injury in AAT deficiency differs from that of the pulmonary disease.
Pulmonary disease is primarily due to a so-called "toxic loss of function" abnormality, ie, destruction of elastin by elastase and other proteases, the activity of which is increased because of deficiency of the elastase inhibitor AAT. Polymers of Z-type AAT protein have been shown to be chemotactic for neutrophils, which supports the hypothesis that polymers in the lung (either circulating or produced locally by alveolar macrophages) can contribute to emphysema through a so-called "toxic gain of function" abnormality. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".)
In contrast, liver disease is caused by pathologic polymerization of the variant AAT, resulting in intrahepatocyte accumulation of AAT molecules (also called a "toxic gain of function" abnormality), rather than a proteolytic mechanism [17-19]. Pathologically, the accumulated AAT appears as inclusions within hepatocytes that stain positively with periodic acid-Schiff (PAS) reagent but resist digestion by diastase (picture 1).
This mechanism of liver disease is supported by two main observations [15]:
●Liver disease has only been observed in individuals with alleles causing intrahepatocyte accumulation, eg, Z, M(malton).
●Liver disease has not been observed among PI*Null-Null individuals. These patients have no circulating AAT, which predicts the greatest proteolytic risk. However, the liver is not affected because there is no accumulation of AAT protein within the hepatocyte.
Intrahepatocyte accumulation of Z-type molecules occurs within the rough endoplasmic reticulum and results from abnormal folding and aggregation of variant AAT molecules in a mechanism called loop-sheet polymerization [7,20-22]. Factors promoting loop-sheet polymerization include increased temperature and increased concentration of Z-type protein [20]. Polypeptides that inhibit loop-sheet polymerization of variant Z-type molecules have been explored [23].
However, abnormal folding does not explain why only some PI*ZZ individuals develop liver disease. It appears that a second defect is also required: decreased degradation of the Z-type molecules within the endoplasmic reticulum, possibly through defects in the proteasomal or autophagic degradation pathways [24], which further promotes the intrahepatocyte accumulation of AAT [18].
It is unclear how the accumulation of Z-type protein within the rough endoplasmic reticulum causes liver cell injury. Possible mechanisms include simple cell engorgement related to mass build-up, and release of lysosomal enzymes caused by cell engorgement, with resultant cell damage. Some investigators have also suggested that the PI*ZZ genotype predisposes to hepatitis and that the liver damage is mediated by viral infection [25].
Risk and natural history
Childhood onset — Available data about the risk and natural history of liver disease in AAT-deficient individuals are based primarily on studies of PI*Z homozygotes identified by screening at birth. One study of 200,000 Swedish newborns, for example, found 127 PI*Z homozygotes (prevalence 1/1575) who were then followed into adolescence and adulthood [3,26].
●Liver damage occurred in 14 of these neonates (11 percent), most commonly presenting as neonatal hepatitis with cholestasis beginning between four days and four months after birth and persisting for up to 12 months.
●Other clinical presentations among newborns included hepatomegaly with elevated aminotransferase levels (but without hyperbilirubinemia), ascites, and bleeding (often umbilical, superficial, or intracranial [5 percent of affected newborns]). Early presentation of AAT-associated liver disease during the neonatal period is not necessarily associated with a worse prognosis compared with later presentation during childhood [3,27].
Follow-up of PI*Z homozygotes identified at birth shows a variable natural history of AAT deficiency-associated liver disease [28].
●Three of 14 children (21 percent) with neonatal hepatitis developed cirrhosis by age seven, two of whom died of complications of cirrhosis.
●By age eight, the remaining 11 children were clinically well but frequently had elevated aminotransferase levels. A few children (14 percent) developed newly elevated values of gamma glutamyl transferase without antecedent neonatal hepatitis.
●Later follow-up at age 12 showed elevated aminotransferase levels in 20 percent of those with icteric neonatal hepatitis and in 14 percent with anicteric hepatitis. However, none of these adolescents had clinically evident liver disease.
●By age 18, only 12 percent had elevations in serum alanine aminotransferase or gamma glutamyl transferase [6].
Others have summarized the natural history of liver dysfunction in children with the PI*ZZ genotype [29]. Of the 10 to 15 percent of newborns with neonatal hepatitis, 5 percent remained jaundiced and developed progressive cirrhosis with death from complications of cirrhosis within the first year of life. In the remaining children, four clinical patterns of liver evolution were apparent, each occurring in approximately 25 percent of cases:
●Resolution of hepatitis by ages 3 to 10 years without hepatomegaly or splenomegaly
●Development of cirrhosis between age six months and 17 years, often causing death from complications of end-stage liver disease
●Histologic evidence of cirrhosis but with survival through the first decade with few sequelae
●Persistent elevation of liver function tests without cirrhosis
Adult onset — Adults with at-risk alleles (eg, Z and M[malton]) may develop adult-onset chronic hepatitis, cirrhosis, or hepatocellular carcinoma, the former often occurring without antecedent childhood liver disease [9,11,30-33]. Approximately 40 percent of adults with PI*ZZ have histologically significant liver injury and cirrhosis [32]. Male sex, the metabolic syndrome, and obesity have been identified as risk factors for progression to advanced liver disease in adulthood among patients with severe AAT deficiency [34-36]. The exact effect of alcohol consumption is unclear, but alcohol misuse appears to hasten progression of AAT-associated liver fibrosis [36]. In contrast, viral hepatitis does not appear to increase the risk of progressive hepatic failure [34]. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)
Management
●Monitoring – The American Thoracic Society (ATS) guidelines suggest routine assessment of liver function tests in patients with known AAT deficiency and pulmonary symptoms [10]. However, in a cross sectional study of 647 adults with AAT deficiency, the prevalence of an elevated alanine aminotransferase level was 8 percent, which did not differ from normal controls [35]. In this study, the sensitivity of an elevated alanine aminotransferase (ALT) level for identifying self-reported liver disease was 12 percent. In a separate study of 49 PI*ZZ individuals, abnormal echogenicity on liver ultrasound demonstrated 100 percent sensitivity and 42 percent positive predictive value for detecting severe fibrosis or cirrhosis [37]. Also, an elevated ALT (>70 U/L) and a platelet count <174,000 demonstrated high sensitivity (70 and 50 percent, respectively), leading to a suggestion that conventional liver function tests, platelet count, and abdominal ultrasound represent an effective screening strategy for severe liver disease among at-risk individuals.
Pending greater clarity on the ideal testing protocol, our practice is to assess serum aminotransferases (eg, alanine aminotransferase, aspartate aminotransferase), alkaline phosphatase, and bilirubin annually [10]. Ultrasound-based elastography is increasingly used to monitor for fibrosis, although the optimal frequency of screening has not been determined [38-40]. (See "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography".)
●Hepatocellular carcinoma screening – Hepatocellular carcinoma can occur in patients with AAT deficiency in the absence of accompanying cirrhosis. In patients with AAT deficiency and established cirrhosis, targeted testing for hepatocellular carcinoma has been recommended with ultrasound examination of the liver every six months [36,41]. (See "Epidemiology and risk factors for hepatocellular carcinoma" and "Surveillance for hepatocellular carcinoma in adults", section on 'Our approach to surveillance'.)
A large longitudinal registry study found a highly increased risk of hepatocellular carcinoma over a median 17-year follow-up in both men (hazard ratio [HR] 47) and women (HR 6) with PI*ZZ, even after controlling for age, smoking status, and baseline liver disease [9,36,41].
●Treatment – Augmentation of AAT is ineffective in liver disease, as the mechanism of liver injury is the accumulation of mutant Z protein in hepatocytes rather than protease deficiency [32]. Management traditionally focuses on supportive measures to prevent or reduce the complications of chronic liver disease. For adults with end-stage liver disease due to AAT, liver transplantation has resulted in a five-year survival of 85 percent [42,43]. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis" and "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)
Fazirsiran, an investigational inhibitory RNA (RNAi) therapeutic that targets AAT and Z-AAT messenger RNA for degradation, has been evaluated in a small phase 2 study of 16 patients with PI*ZZ AAT deficiency [44]. Subcutaneous administration of fazirsiran led to an 83 percent decrease in total liver Z-AAT after 24 to 48 weeks (95% CI 76-90 percent). Improvements were also seen in histologic liver abnormalities, including a reduction in portal inflammation scoring in two-thirds of patients. In 15 patients who had biopsies at baseline and follow-up, histologic fibrosis regression occurred in seven patients and progression was observed in two. Pulmonary function remained stable, and there were no exacerbations among six patients with emphysema on AAT augmentation. Additional data are needed to establish the utility of this agent in clinical practice.
SKIN DISEASE — The major dermatologic manifestation of alpha-1 antitrypsin (AAT) deficiency, although rare, is necrotizing panniculitis. Other possible dermatologic associations with AAT deficiency include systemic vasculitis, psoriasis, urticaria, and angioedema [10]. (See 'ANCA-positive vasculitis' below.)
Clinical features — Necrotizing panniculitis is characterized by inflammatory lesions of the skin and subcutaneous tissue [45-48]. The mean age of onset is 40 years old [10]. Patients present with one or more hot, painful, red nodules or plaques on the thigh or buttocks [49]. These lesions can be difficult to distinguish from panniculitis due to other causes, but may be more inflammatory with an oily yellow discharge and more pronounced histologic evidence of acute inflammation (table 2). (See "Panniculitis: Recognition and diagnosis", section on 'Enzymatic destruction'.)
Panniculitis is the least common of the well-recognized complications of AAT deficiency, with relatively few cases reported in the English literature [45,48-52]. The prevalence among AAT-deficient subjects is probably less than one case per thousand. In rare instances, panniculitis may be accompanied by a polyserositis.
Pathogenesis — Panniculitis has been reported to occur in a variety of genotypes, including PI*ZZ, PI*MZ, PI*SS, and PI*MS [49]. Seventy percent of reported cases have occurred in patients with PI*ZZ genotype and severe AAT deficiency [49]. Similar to the pathophysiology of emphysema in such individuals, the panniculitis is thought to result from a "toxic loss of function" with unopposed proteolysis in the skin. In a case report, skin biopsy revealed Z type AAT polymers in affected areas, raising the possibility that AAT polymers in the skin contribute to the observed inflammation [53]. Further study is needed before this pathogenetic mechanism is established. (See 'Pathogenesis' above.)
Diagnosis and therapy — As necrotizing panniculitis is a rare manifestation of AAT deficiency, a deep excisional biopsy is usually obtained to establish the diagnosis. Characteristic histologic findings on skin biopsy include lobular fat necrosis of the lower reticular dermis and abundant neutrophil influx interspersed with normal-appearing fat and necrotic panniculus [10]. (See "Panniculitis: Recognition and diagnosis", section on 'Biopsy'.)
Based upon the presumed pathophysiologic mechanism of unopposed proteolysis, treatment of panniculitis in AAT-deficient subjects has focused on restoring antiprotease activity. Though off-label in this setting, intravenous infusion of purified AAT, sometimes with higher than the approved doses for emphysema management, has ameliorated the panniculitis in some patients [46,48,49,54].
Other treatments have included dapsone (100 mg/day for several weeks) and doxycycline (200 mg/day for as long as several months) [46,49,51,54,55]. However, evidence in support of these therapies is limited. Doxycycline is believed to act by scavenging reactive oxygen species produced by neutrophils and/or by slowing the breakdown of matrix proteins by elastase. Topical and systemic glucocorticoids have not been helpful [10].
OTHER ASSOCIATIONS — Associations between alpha-1 antitrypsin (AAT) deficiency and vascular disease, inflammatory bowel disease, glomerulonephritis, and vasculitis have been proposed but not definitively established.
Vascular disease — Vascular complications are a rare and less well-established consequence of the PI*ZZ genotype [56,57]. A number of vascular abnormalities have been suggested, including abdominal and intracranial aneurysms, arterial fibromuscular dysplasia, and venous thromboembolism (VTE), all based on the principle that unopposed proteolytic activity damages vessel walls in severely deficient individuals [10,49]. In one cohort study, VTE was increased by approximately 4.5-fold in patients with the PI*ZZ genotype [58]. Rare compound heterozygotes of the Z allele with non-benign missense or loss-of-function variants showed a similar VTE predisposition.
In addition, one allele (so-called AAT Pittsburgh) is characterized by substitution of an arginine for a methionine at position 358, causing the protein to mimic the hemorrhagic effects of antithrombin III [59]. Two individuals with AAT Pittsburgh have thus far been identified, one of whom died of massive bleeding when the acute phase reactant properties of the AAT protein caused levels of the Pittsburgh variant to rise after a viral infection [59].
Inflammatory bowel disease — Data are conflicting regarding an association between AAT and inflammatory bowel disease. It has been hypothesized that decreased antiprotease activity in the bowel may promote local injury and progression to inflammatory bowel disease [60]. One case-control study from Sweden found that significantly more patients with ulcerative colitis were PI*MZ than in the general population (8.5 versus 4.7 percent) and that PI*MZ individuals tended to have more severe colitis [61]. However, a second study from Germany comparing 135 patients with either Crohn's disease or ulcerative colitis with controls found no such associations [62].
Glomerulonephritis — Glomerular disease is an uncommon finding in AAT. Two different types have been described, one related to AAT and the other to the development of liver failure:
●A proliferative glomerulonephritis, most often of the membranoproliferative type, rarely occurs in association with the PI*ZZ genotype [63-66]. Why this might occur is not clear. Virtually all reported patients have had cirrhosis, suggesting that serious liver disease plays an important role in the development of this immune complex disorder. (See "Membranoproliferative glomerulonephritis: Classification, clinical features, and diagnosis".)
●IgA nephropathy is described in association with hepatic cirrhosis due to AAT deficiency [67-69]. Glomerular IgA deposition is a common finding in hepatic cirrhosis of any cause. Impaired removal of IgA-containing complexes (such as those directed against alimentary antigens) by the Kupffer cells in the liver is thought to predispose to IgA deposition in the kidney. One study evaluated 18 children with end-stage liver disease due mostly to AAT deficiency or biliary atresia in whom renal biopsy was performed at the time of hepatic transplantation [67]. Pathologic evidence of either a mesangial proliferative or membranoproliferative glomerulonephritis was seen in all; most patients had IgA nephropathy. (See "IgA nephropathy: Clinical features and diagnosis".)
ANCA-positive vasculitis — A putative association between vasculitis and AAT deficiency is based on reports from many countries that AAT variants, homozygous ZZ and SS, heterozygous Z, and SZ, occur in higher than expected frequency among individuals with multisystem vasculitides (table 3) [70-74]. In a series of 433 patients with granulomatosis and polyangiitis, the odds ratio for the PI*ZZ, PI*SZ, or PI*SS genotypes was markedly elevated (OR 14.58, 95% CI 2.33-infinity), compared with the normal MM genotype [72]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)
The association between AAT deficiency and cytoplasmic-antineutrophil cytoplasmic antibody (C-ANCA) positive vasculitis is strengthened by plausible pathogenetic mechanisms. For example, in the extravascular fluid, AAT plays an important role as an inhibitor of proteinase-3, a neutrophil elastase-like serine protease located in the primary granules of the neutrophil. Unchecked, proteinase-3 exerts potent tissue-destructive capacity, so a deficiency of AAT could conceivably trigger an auto-immune response by allowing increased extracellular exposure to proteinase-3 [75]. Alternatively, linkage disequilibrium might promote inheritance of important autoimmunity genes along with abnormal AAT genotypes [76]. Finally, though unproven, it is conceivable that circulating Z or S polymers could prompt a vasculitic response. (See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis".)
Systemic vasculitis with perinuclear-ANCA and specificity for myeloperoxidase has been described in patients with AAT deficiency [73,77]. Rare cases of ANCA-negative vasculitis (eg, eosinophilic granulomatosis with polyangiitis, Henoch Schönlein vasculitis) have also been reported in AAT deficient patients [78,79].
These findings have prompted a suggestion from the joint American Thoracic Society (ATS)/European Respiratory Society (ERS) in favor of genetic testing for AAT deficiency in individuals with C-ANCA positive vasculitis [10].
The ATS and ERS statement on the diagnosis and management of AAT deficiency, as well as other ATS guidelines, can be accessed through the ATS website at www.thoracic.org/statements.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease".)
SUMMARY AND RECOMMENDATIONS
●Depending on the specific variant of the alpha-1 antitrypsin (AAT) gene (OMIM 107400), a variety of extrapulmonary manifestations may occur in AAT deficient individuals (table 1). (See 'Introduction' above.)
●The types of liver disease associated with AAT deficiency include neonatal hepatitis, hepatomegaly with elevated aminotransferase levels, ascites, cirrhosis, and hepatocellular carcinoma. (See 'Hepatic disease' above.)
●The AAT variant that is most commonly associated with liver disease is Z. The pathogenesis of liver disease in AAT deficient individuals relates to accumulation of abnormal AAT protein within hepatocytes. The rare alleles, M(malton), M(duarte), M(nichinan), S, and S(iiyama), are also known to cause intrahepatocytic accumulation, but it is not known whether they cause clinically significant liver disease. (See 'Hepatic disease' above.)
●Among children with AAT deficiency and neonatal hepatitis, a quarter will have resolution of hepatitis by age 3 to 10 years without hepatomegaly or splenomegaly; a quarter will develop cirrhosis between age six months and 17 years, often causing end-stage liver disease; a quarter will have histologic evidence of cirrhosis but with few sequelae; and a quarter will have persistent elevation of liver function tests without cirrhosis. (See 'Risk and natural history' above.)
●Adults with the at-risk alleles (eg, Z, M[malton]) may develop cirrhosis or hepatocellular carcinoma without antecedent childhood liver disease. (See 'Adult onset' above and "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Determining the cause of cirrhosis' and "Clinical features and diagnosis of hepatocellular carcinoma", section on 'Imaging'.)
●Necrotizing panniculitis, which presents with one or more hot, painful, red nodules or plaques on the thigh or buttocks, is a rare manifestation of AAT deficiency. It occurs in patients with more severe AAT deficiency and those with the PI*ZZ, PI*MZ, PI*SS, and PI*MS genotypes. (See 'Clinical features' above.)
●Treatments for panniculitis include intravenous AAT augmentation therapy, dapsone, and doxycycline. (See 'Diagnosis and therapy' above and "Treatment of alpha-1 antitrypsin deficiency", section on 'Intravenous augmentation therapy'.)
●Associations between AAT and several other disease processes (eg, vascular disease, inflammatory bowel disease, glomerulonephritis, and systemic vasculitis) have been proposed, but not definitively established. (See 'Other associations' above.)
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