Patient experience of alpha-1 antitrypsin deficiency-associated liver disease: a qualitative study

Alpha-1 antitrypsin deficiency (AATD) is an inherited condition that can cause liver and/or lung disease. A change in a single gene creates an abnormal protein in the liver. Individuals who have two copies of the abnormal gene are protease inhibitor (Pi) ZZ and those with one copy can be Pi*MZ or Pi*SZ. Researchers wanted to know more about how liver disease in AATD (AATD-LD) affects people’s lives. They did this by gathering information on the experiences of patients with AATD-LD from peer-reviewed articles, patient blog posts, and interviews with doctors, and then interviews with 15 US adults with AATD-LD aged 28–78 years. Overall, 41 signs/symptoms were identified and grouped based on their frequency and how much bother they cause. The most frequent and bothersome signs/symptoms were fatigue, respiratory infections, shortness of breath, confusion/difficulty concentrating, and swelling. Other notable signs/symptoms were abdominal swelling, acid reflux, sleep disturbance, vomiting, abdominal pain/tenderness, itchiness, and back pain. The study also identified 16 areas of life affected by AATD-LD; the most affected areas were work/employment, leisure activities, and personal relationships. Mobility was also notably affected. This study focused on a small number of patients and many signs/symptoms were noted in earlier stages of liver disease. These findings highlight the need for additional research in a larger and more diverse group of patients to better understand the experiences of patients with AATD-LD. The development of tools that can accurately measure the experiences of patients with AATD-LD is crucial for improving care.

Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant genetic condition that manifests clinically as liver and/or lung disease in children and adults [1‐4]. AATD is caused by genetic mutations in SERPINA1, which encodes alpha-1 antitrypsin (AAT), a serine protease inhibitor (Pi) synthesized mainly in hepatocytes that functions primarily to maintain the protease–antiprotease balance in the lungs [5‐8]. Many SERPINA1 variants exist with variable effects, with Pi*Z and Pi*S being most commonly associated with clinical cases [9, 10]. The homozygous Pi*ZZ genotype carries the greatest risk of AATD-associated liver disease (AATD-LD), followed by the Pi*SZ genotype [11, 12]. The Pi*MZ genotype increases susceptibility to liver injury and promotes the progression of other chronic liver diseases, while the Pi*SS genotype is not associated with hepatic abnormalities [11, 12]. In a large systematic assessment of liver disease burden in a multinational cohort of 403 patients with the Pi*ZZ genotype, the prevalence of significant and advanced liver fibrosis was 20–36% and 5–26%, respectively [13].

Severe AATD manifests clinically as pulmonary dysfunction (asthma, bronchiectasis, chronic bronchitis, chronic obstructive pulmonary disease [COPD], or emphysema) and/or hepatic dysfunction (fibrosis, cirrhosis, hepatitis, hepatocarcinoma, or liver failure) in affected individuals from infancy to adulthood [2, 14]. While previous studies of the quality-of-life (QoL) burden of AATD have focused on AATD-associated lung disease [15], there is limited real-world evidence on the experience of patients with AATD-LD, which remains underdiagnosed owing to its variable and nonspecific clinical presentation and often asymptomatic course until decompensated cirrhosis occurs [16‐18]. Individuals with AATD-LD may experience lengthy delays and visit several physicians before receiving a definitive diagnosis; the average delay between the onset of symptoms and diagnosis of AATD-LD exceeds 5 years [19‐23]. There are currently no specific treatments for AATD-LD, and liver transplantation is the only way to resolve advanced liver cirrhosis [9, 24]. There are validated patient-reported tools for the assessment of QoL in patients with liver disease, including disease-specific tools such as Liver Disease Quality of Life (LDQOL) and Chronic Liver Disease Questionnaire (CLDQ), and generic tools such as Short-form Survey (SF-36), Sickness Impact Profile (SIP), and Nottingham Health Profile (NHP) [25]. However, these tools have not been used to assess the burden of liver disease in patients with AATD. Therefore, to address this clear unmet need to better understand the experiences of patients with AATD-LD, this qualitative study aimed to evaluate the experiences of patients with AATD-LD and a Pi*ZZ or Pi*MZ genotype in terms of the signs and/or symptoms they experience and their impacts, as well as to understand other issues such as barriers to diagnosis and care and available treatments.

This small sample of adults with AATD-LD and primarily a Pi*ZZ genotype were highly symptomatic. Several symptom categories—including fatigue/tiredness, respiratory, gastrointestinal, and dermatological—were the most frequently reported and were often characterized by patients as being very bothersome. In addition, the experience of patients with AATD-LD varied, with fatigue/tiredness being the only sign/symptom reported by more than two-thirds of the patient sample. This broadly aligns with the literature on patients with chronic liver disease, for whom fatigue is the most commonly reported symptom, with a prevalence of 35–85% [26]. Moreover, in this patient sample, impacts on many aspects of daily living were noted, particularly physical, social, and emotional categories, all of which have the potential to have a profound toll on patients’ health-related QoL.

A number of signs and/or symptoms, and impacts that were not identified via the TLR, search of patient blog posts, or clinician interviews were newly elicited via the patient CE interviews. These signs and/or symptoms were back pain, changes in weight, constipation, diarrhea, fever, gassiness, headaches/migraines, muscle loss, pain, rash, respiratory infections, respiratory allergies/sensitivities, shakiness, skin infections, skin nodules/lesions, and uncontrollable bleeding. The additional impacts identified in the CE interviews were avoiding medications, embarrassment, financial difficulties, frustration, missing/avoiding social events, and regret/shame/guilt. The additional signs and/or symptoms, and impacts elicited via the patient CE interviews show that the literature and other sources may not fully capture the experiences of patients with AATD-LD. The open-ended, conversational format of the patient CE interviews may have facilitated the sharing of additional experiences than what was reported in blog posts, in the literature, or by clinicians, further highlighting the value of patient interviews.

AATD-LD is considered an asymptomatic, silent, progressive disease, particularly in its early stages, with symptoms appearing gradually as fibrosis progresses, potentially leading to end-stage liver disease [3, 24, 27]. However, patients in this study reported signs and/or symptoms at earlier fibrosis stages, such as shortness of breath, sleep disturbance, and itchiness. These observations may suggest that, unlike other chronic liver diseases, patients with AATD-LD may experience early signs and/or symptoms prior to progressing to advanced fibrosis, although some of these can be perceived as nonspecific to the disease. Although these observations are derived from a small patient sample, given the lack of available data on the experience of patients with AATD-LD, we firmly believe that this qualitative study contributes to an improved understanding in this area, which should be built upon in future quantitative studies to support the clinical management of these patients.

Delayed AATD-LD diagnosis is a major source of frustration among patients owing to the nonspecific signs and/or symptoms, or limited knowledge of the disease or perceived beliefs among clinicians. In our study, some patients believed that their clinicians were unwilling to listen to their concerns because of a belief that their liver disease may have been caused by alcohol misuse. This may highlight a need for improved patient–clinician communication. In addition, many patients reported that they believed that delayed diagnoses and barriers to care which they experienced could be attributed to their clinician’s perceived lack of knowledge about AATD-LD or unwillingness to take the symptoms seriously. This may highlight a need for additional clinician education. The lack of treatment options was also a cause of frustration among our CE patient sample. Currently, there are no specific therapies for preventing liver disease progression in AATD-LD, and liver transplantation is the only available curative treatment [18, 24]. Treatment is limited to lifestyle modifications, such as nutritional management, prevention of obesity, and limiting alcohol intake [18, 28].

This study has several limitations. First, a relatively small number of patients were interviewed who were enrolled from a recruitment/patient engagement agency (n = 5 patients) and an academic medical center (n = 10 patients) in the USA, which may have been a source of bias. Although patients may have been enrolled from various locations within the USA, the generalizability of our findings to the wider population of individuals with AATD-LD is limited, and the small sample size limits our ability to draw definitive conclusions. Second, patients were not always able to indicate their fibrosis stage or provide detailed information about when signs and/or symptoms, and impacts emerged, thus affecting the precision of their reporting on their own experience. Third, patients were asked during their CE interviews whether they had received a diagnosis of lung disease, but the diagnosis was not confirmed by a physician. Therefore, some patients may have inaccurately reported the presence or absence of lung disease. Fourth, owing to patient recruitment challenges, the study deviated from the original plan of exclusively recruiting patients with a Pi*ZZ genotype by also including patients with a Pi*MZ genotype, whose experience with AATD-LD may differ. Further research with a larger, more geographically representative sample across all verified fibrosis stages is warranted. Fifth, saturation was not fully achieved because several less salient concepts arose for the first time in the last wave of interviews. This is not unexpected in a small population of patients with a rare disease associated with a heterogenous symptom set. Finally, it was not possible to isolate the burden attributed specifically to AATD-LD from the burden associated with comorbidities and environmental factors; nevertheless, this study sought to gain preliminary insights into the burden of AATD-LD and identify the patient population of interest for future quantitative studies.

Further research is needed to determine which signs and/or symptoms, and impacts remain salient in a broader patient population, how the signs, symptoms, and impacts change over time and with disease progression, and which signs and/or symptoms are specific to AATD-LD. Moreover, the heterogeneity of the patient experience observed in our study may also have implications for endpoint selection and measurement in clinical trials. Consideration of clinical outcome assessments that are broad enough to capture the “most salient” and “highly salient” concepts defined in this study is warranted to appropriately assess the nuances of each patient’s experience.

To the best of our knowledge, this is the first qualitative study to evaluate the experience of patients living with AATD-LD, including an assessment of signs and/or symptoms of the disease and their impacts. The study revealed a heterogeneous sample of patients living with a range of bothersome signs and/or symptoms, and disturbing impacts on daily life.