2,000 Portuguese Have a Hidden Genetic Lung Disease—And 95% Don't Know It

The Portuguese Society of Pneumology has issued a fresh warning about a genetic condition that may explain why thousands of residents develop severe respiratory disease—often without knowing the underlying cause. A deficiency in a liver-produced protein called alpha-1 antitrypsin leaves lungs vulnerable to progressive damage, even in non-smokers, and experts say the condition remains dramatically underdiagnosed across Portugal.

Why This Matters

• Around 2,000 Portuguese residents carry the most severe genetic variant (ZZ), yet fewer than 100 are currently receiving treatment—indicating a diagnostic gap exceeding 95%.

• Diagnosis takes an average of 8 years from symptom onset, a delay that can mean irreversible lung damage before therapy begins.

• Specific replacement therapy exists and is available through Portugal's public health system, but it works best when started early—making timely testing critical.

• Madeira has the world's highest prevalence of alpha-1 antitrypsin deficiency variants, with 41 cases per 1,000 residents.

The Invisible Genetic Threat

Alpha-1 antitrypsin is a protective protein manufactured primarily in the liver and released into the bloodstream to shield lung tissue from inflammation and enzymatic breakdown. When a genetic mutation reduces production or function of this protein, the lungs become exposed to gradual, cumulative injury. Over time, this leads to Chronic Obstructive Pulmonary Disease (COPD), emphysema, and chronic respiratory failure—conditions typically associated with heavy smoking, but which in this case strike patients with little or no tobacco exposure.

Dr. Teresa Martin, a pneumologist with the Portuguese Society of Pneumology, emphasized that the condition is "relatively simple to diagnose" yet remains "poorly tested" in clinical practice. The result is a significant diagnostic delay that robs patients of the chance to slow disease progression through preventive measures and targeted therapy.

The genetic alteration responsible for alpha-1 antitrypsin deficiency can also cause the misfolded protein to accumulate in liver cells, leading to progressive hepatic disease in some patients—a dual threat that underscores the importance of early identification.

Portugal's Hidden Epidemic

National and international estimates suggest that 1 in every 5,249 Portuguese residents carries the ZZ genotype—the most severe deficiency variant—translating to roughly 2,000 individuals nationwide. An additional 1 in 281 carry the SZ genotype, affecting approximately 37,400 people with moderate deficiency. On the island of Madeira, prevalence rates soar to 41 per 1,000, the highest documented globally, with the PIS mutation present in 18% of the population and the PIZ variant ranking third worldwide at 2.5%.

Despite these striking figures, the Portuguese health system has identified and is treating fewer than 100 patients. European physician surveys suggest that only 15% to 30% of cases are diagnosed, leaving the vast majority of affected individuals without knowledge of their condition or access to appropriate care.

A 2018 consensus document prepared by Portuguese pneumology specialists highlighted persistent gaps in awareness among both the general public and healthcare professionals. The lack of a national patient registry further obscures the true scale of the problem, making it difficult to track outcomes or allocate resources effectively.

Red Flags Every Resident Should Know

The Portuguese Society of Pneumology has identified key warning signs that should prompt testing for alpha-1 antitrypsin deficiency:

• Persistent shortness of breath or exercise intolerance

• Chronic cough without clear cause

• Frequent respiratory infections or pneumonia

• Difficult-to-control asthma despite optimal treatment

• COPD or emphysema diagnosis before age 45, especially in non-smokers or individuals without known risk factors

• Family history of early-onset lung or liver disease

Because these symptoms closely resemble more common respiratory conditions, physicians often do not consider genetic testing until the disease has progressed significantly. Dr. Martin stressed that early diagnosis can alter the disease trajectory, enabling patients to avoid tobacco and occupational exposures, initiate close monitoring, and—when criteria are met—begin replacement therapy with purified human alpha-1 antitrypsin.

What This Means for Residents

Who Should Get Tested

National and international guidelines recommend alpha-1 antitrypsin testing for:

• All patients diagnosed with COPD, regardless of age or smoking history

• Individuals with early-onset emphysema or emphysema without obvious risk factors

• Patients with difficult-to-control asthma and persistent airflow obstruction

• Adults with unexplained liver disease

• First-degree relatives of anyone diagnosed with the deficiency

• Residents of Madeira, given the island's exceptionally high prevalence

The test is straightforward: an initial blood test measures serum levels of alpha-1 antitrypsin. If levels are low (below 80 mg/dL), confirmatory phenotyping or genotyping identifies the specific genetic variant. For rare or novel mutations, full SERPINA1 gene sequencing is available.

Treatment and Public Health System Access

Portugal's National Health Service (SNS) provides access to augmentation therapy—intravenous infusions of concentrated, purified alpha-1 antitrypsin derived from healthy human donors. This treatment aims to maintain protective protein levels in the lungs, slow the decline in lung function, and improve quality of life.

Eligibility criteria include:

• Age 18 years or older

• Serum alpha-1 antitrypsin below 80 mg/dL

• Non-smoker or ex-smoker for at least 6 months

• Documented airflow obstruction or rapid lung function decline (FEV1 loss exceeding 120 mL per year)

The therapy is lifelong and high-cost, managed through specialized reference centers within the SNS. While exact prices per dose are not publicly disclosed, the Portuguese Central Administration of the Health System (ACSS) monitors monthly treatment costs per patient as part of transparency reporting. The Alpha-1 Association of Portugal continues to advocate for equitable access and treatment availability for all eligible patients.

Dr. Martin noted that the earlier therapy begins, the greater the benefit, though it is not indicated for all patients and does not reverse existing lung damage. The treatment does not appear effective for associated liver disease, which may require transplantation in severe cases.

How Portugal Compares to European Neighbors

Across Europe, alpha-1 antitrypsin deficiency remains vastly underdiagnosed. Most countries, including Portugal, rely on targeted screening of high-risk groups rather than population-wide programs. The American Thoracic Society (ATS) and European Respiratory Society (ERS), along with the World Health Organization, endorse this approach as cost-effective and clinically sound.

Ireland operates a national targeted detection program offering free testing to COPD patients, individuals with unresponsive asthma, those with unexplained liver disease, and relatives of diagnosed patients. Sweden conducted population-based neonatal screening in the 1970s, providing valuable natural history data, though such programs are now rare due to expense. Germany has demonstrated that public awareness campaigns paired with accessible testing significantly improve detection rates.

The European Alpha-1 Research Collaboration (EARCO) maintains an international patient registry and promotes early diagnosis, education, and timely care access across member states. Advocates urge all EU nations to integrate alpha-1 antitrypsin deficiency programs into national rare disease plans to ensure early identification and better outcomes.

Ongoing Awareness Efforts in 2026

On World Rare Disease Day this year, the Portuguese Society of Pneumology renewed its call for heightened vigilance and expanded testing. For the third consecutive year, a web-based knowledge platform for healthcare professionals interested in alpha-1 antitrypsin deficiency has been maintained with scientific support from the society, reflecting sustained commitment to medical education.

The Alpha-1 Association of Portugal continues to push for expanded awareness among patients and providers, emphasizing that timely identification transforms the disease from a silent, progressive killer into a manageable chronic condition.

No cure yet exists for alpha-1 antitrypsin deficiency. Management parallels standard COPD care—smoking cessation, pulmonary rehabilitation, inhaled bronchodilators, and vaccination against respiratory pathogens—supplemented by replacement therapy when appropriate. For advanced disease, lung or liver transplantation may be necessary.

Clinical trials exploring new therapeutic approaches are ongoing globally, and Portuguese patients are encouraged to discuss participation with their physicians. The Portuguese Liver Foundation notes that such trials test innovative strategies to prevent, screen, diagnose, or treat the condition, offering hope for future breakthroughs.

The Path Forward

Portugal faces a paradox: robust prevalence data and clear diagnostic guidelines exist, yet the overwhelming majority of affected residents remain unidentified. The solution lies in routine testing of at-risk populations, continued education of primary care and specialist physicians, and sustained public health messaging.

For individuals experiencing unexplained respiratory symptoms, early-onset lung disease, or difficult-to-manage asthma—especially those with no smoking history—requesting an alpha-1 antitrypsin test could be life-altering. For Madeira residents, where genetic risk is exceptionally high, proactive screening should be considered standard practice.

With augmentation therapy available through the SNS and growing clinical expertise in managing the condition, the primary barrier is no longer treatment access—it is awareness. Closing Portugal's diagnostic gap will require collaboration among patients, physicians, advocacy groups, and health authorities to ensure that a simple blood test reaches those who need it most.