Review
Diagnosis and Management of Patients With α1-Antitrypsin (A1AT) Deficiency

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Alpha1-antitrypsin (A1AT) deficiency is an autosomal codominant disease that can cause chronic liver disease, cirrhosis, and hepatocellular carcinoma in children and adults and increases risk for emphysema in adults. The development of symptomatic disease varies; some patients have life-threatening symptoms in childhood, whereas others remain asymptomatic and healthy into old age. As a result of this variability, patients present across multiple disciplines, including pediatrics, adult medicine, hepatology, genetics, and pulmonology. This can give physicians the mistaken impression that the condition is less common than it actually is and can lead to fragmented care that omits critical interventions commonly performed by other specialists. We sought to present a rational approach for hepatologists to manage adult patients with A1AT deficiency.

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Liver Disease in Pediatric Patients

Although most cases of A1AT deficiency are associated with a single variant (such as ZZ), the clinical presentation of liver disease varies greatly.1 Some children develop cholestatic jaundice and hepatitis shortly after birth, called neonatal hepatitis syndrome; it is indistinguishable from the early phases of extrahepatic biliary atresia, cystic fibrosis, congenital infection, and many other conditions. Because A1AT deficiency is relatively more common than the other disorders, serum testing

Liver Disease in Adult Patients

Most adult patients with A1AT deficiency have fairly normal results from liver tests and minimal or no symptoms of liver disease. They can present with asymptomatic, abnormal levels of liver enzymes, clinical manifestations of advanced cirrhosis, or hepatocellular carcinoma (HCC)2; liver disease appears to be the next most common manifestation of A1AT deficiency after lung disease.3 The best information for the effects of A1AT deficiency on liver disease comes from an analysis of autopsy data

Pathophysiology

Strategies to degrade the aggregates of A1AT in hepatocytes might be used to reduce or prevent liver disease. Soluble monomers of A1AT in the endoplasmic reticulum could be degraded by proteasomes, or polymerized aggregates could be degraded by autophagosomes (Figure 1).

The genetic and environmental factors that predispose some patients with A1AT deficiency to liver disease are unknown. A postmortem study in Sweden reported that adults with ZZ-associated A1AT deficiency who died of causes

Heterozygous Variants of Alpha1-Antitrypsin

The effects of heterozygous variants of A1AT on risk for liver disease are controversial. Several studies have reported that there is a higher prevalence of the MZ genotype among patients with cirrhosis, compared with control populations or patients with noncirrhotic liver diseases,19, 20, 21, 22, 23 and also among patients with cryptogenic cirrhosis.19, 20, 21, 22 However, a more recent study did not associate the MZ genotype with chronic liver disease overall, although a significantly greater

Rationale and Options for Alpha1-Antitrypsin Testing

Despite its relatively high prevalence, A1AT deficiency is under-recognized and underdiagnosed.25 Although it is considered to be a rare condition, there are approximately 20 million individuals in the United States who carry at least 1 allele of A1AT associated with the disease, and the prevalence of homozygosity for variants associated with A1AT deficiency is at least 100,000 in the United States.26 An estimated less than 10% of people with this disorder have been properly diagnosed, with an

Management

Because A1AT deficiency is an inherited disease, family members are at risk and should be considered for testing. Siblings of individuals with A1AT deficiency are the only family members for whom genetic testing is recommended, because they have 25% or greater risk of also having the condition.33 Although the risk of A1AT deficiency in parents, offspring, and second-degree relatives of patients is low but greater than that of the general population, it is common practice to recommend that they

Recommendations for Screening

The American Association for the Study of Liver Disease recommends that patients with cirrhosis from A1AT deficiency be screened for HCC. This practice guideline bases its recommendations for surveillance on estimates of the risk for HCC. For groups of patients in whom the threshold incidence for efficacy of screening is estimated to be >1.5% per year, surveillance is recommended. For patients with A1AT deficiency, it is acknowledged that the exact incidence of HCC is unknown, but it is thought

Patient Education

A range of advocacy and research activities are available to patients with this disease and to their families. The National Institutes of Health–sponsored Children's Liver Disease Research and Education Network is a study enrolling patients who are up to 25 years old in a prospective cohort study to gather data on natural history and to investigate genetic and environmental modifiers of disease. Patients can also be offered contact with the Alpha-1 Registry, a self-report database for all ages

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      Citation Excerpt :

      Therefore, there is likely a significant role for genetic and environmental disease modifiers, or second hits, which determine whether a given individual will develop liver injury and at what age this might occur. Liver disease associated with AAT deficiency is highly variable and may have a variety of clinical presentations, including chronic hepatitis, cirrhosis, hepatocellular carcinoma (HCC), or the rare occurrence of fulminant hepatic failure4–6 The pathogenesis of liver and lung disease seems to be independent and, therefore, it is likely that they are neither protective of each other nor a risk factor for each other. The peak incidence of diagnosis of liver and lung disease occurs at different ages in ZZ patients, which gives the impression to caretakers that one does not occur in the presence of the other.

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by grants from the National Institutes of Health (NIH RO1 DK090962-01, NIH RO1 DK072237-06, NIH RO1 GM041804-24, NIH P50 AA011999-13) to David A. Brenner.

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