A 47-Year-Old With Progressive Dyspnea and Weepy Nodules

Dora E. Izaguirre, MD; Jesus Lanza, MD


November 19, 2021

AATD was first described by Laurell and Eriksson in 1963.[1,4] The condition often goes undiagnosed, even though it is a relatively common genetic condition. COPD and liver disease are common in persons with AATD. Approximately 1%-5% of patients diagnosed with COPD are believed to have AATD.[5] The incidence of liver disease increases over time.

AATD is one of the most common genetic diseases that causes death in adult white persons. Severe AATD is found in approximately 70,000-100,000 people. At least one deficient gene is present in an estimated 25 million individuals, although fewer than 10% are identified.[1,2,4,6]

Specific morbidity and mortality rates are unclear. Not all individuals with homozygous deficiency display emphysema or cirrhosis, and the condition commonly goes undetected. Patients describe having symptoms for several years that were examined by multiple physicians before diagnosis. The median time between symptom presentation and diagnosis is estimated to be 8 years. Symptomatic patients have a high mortality rate.

Early symptoms of AATD include wheezing, intermittent cough, and sputum production. Dyspnea in AATD is initially evident only with high exertion. Eventually, the condition limits even milder exertion.

Dyspnea develops 20-30 years earlier in individuals with AATD than in individuals who smoke. Smoking accelerates emphysema progression in AATD; symptoms are evident 10 years earlier in individuals with AATD who smoke regularly. Infections and exposure to dust or fumes can also increase the onset of symptoms or worsen disease progression.

AATD emphysema cannot be confirmed by a single physical sign, and most signs associated with emphysema from any cause are easily missed. Individuals with unexplained liver disease should be investigated for AATD, regardless of whether respiratory symptoms are present. Chronic liver disease and panniculitis must be investigated. Hepatomegaly is not specific for AATD but may also be present.

Elevated levels of bilirubin, aspartate transaminase, and alanine aminotransferase may be observed but are nonspecific and nonsensitive for AATD. Serum levels of AAT below 11 µmol/L suggest AATD; however, this finding alone lacks the sensitivity and specificity to confirm the diagnosis.

Pulmonary function tests are also not sensitive or specific for AATD; however, they are important in diagnosing obstructive lung disease and determining severity of emphysema. These results typically include increased total lung capacity, reduced FEV1, reduced FVC, and reduced FEV1/FVC ratio.

DNA tests are used to determine specific mutations.[3] Isoelectric focusing (IEF) phenotyping is the criterion standard in the diagnosis of AATD; however, it requires complex interpretation.

Findings on liver histopathology have been shown to vary, depending on the classification and staging of disease. The presence of periodic acid-Schiff-positive globules may suggest AATD, but further investigation is recommended.

Bibasilar hyperlucent fields and flattened diaphragms are seen on chest radiography. Mild forms may be missed on HRCT; when the disease is moderate, determining the panlobular nature of the process and the characteristic lower zone predominance is possible. Severe forms can be indistinguishable from severe centrilobular emphysema. Unspecific changes related with cirrhosis or hepatocellular carcinoma may be observed on CT of the abdomen.[3]


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