A stepwise approach to diagnosis (and treatment) is the cornerstone of modern medicine; no longer are patients beholden to the biases and hunches of any individual doctor. Rather, guidelines are in place to ensure that the most common causes for a set of symptoms are ruled out before rarer diseases are to be considered. 

Many diseases can in fact be diagnosed in a minimally invasive manner, and researchers are exploring further ways to make them even more pain- and hassle-free. In the future, physicians will hopefully have all the tools they need to definitively confirm the presence/absence of a disorder in as little time as possible. Of course, experience, medical intuition, and a fine grasp on diagnostic algorithms will aid these efforts.

In Diagnostics, Guillaud and colleagues conducted a review of the least invasive diagnostic tests in 2 rare disorders: Wilson disease and alpha-1 antitrypsin deficiency (AATD). Why the odd pairing? Guillard and colleagues point out that they are not as dissimilar as they initially appear: both are rare genetic diseases that greatly benefit from early diagnosis and treatment, especially before irreversible end-organ damage occurs. In addition, a diagnosis of either of the 2 conditions should prompt family screening to identify other family members at risk. 

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Wilson Disease 

Wilson disease is characterized by impaired biliary copper excretion. Diagnosing this disorder is challenging because symptoms can be vague/heterogenous. The accumulation of copper in the body can result in pathology in the cornea, liver, and the brain. Because there is no one symptom in this condition that is pathognomonic, clinicians tend to rely on a combination of diagnostic tests, thus delaying diagnosis. 

Read more about Wilson disease etiology 

Wilson disease is characterized by the classical triad of “low ceruloplasmin, low serum copper, and increased 24-h urinary copper levels.” Although this triad is not necessarily seen in all patients with Wilson disease, it offers a starting point for diagnostic investigations.

An extremely low ceruloplasmin level, defined as less than 0.10 g/dL, is ”highly suggestive of Wilson disease,” according to Guillard et al. There is some debate about the ideal cut-off point, but many scientists have proposed 0.20 g/dL as a threshold figure. 

Serum copper levels are typically measured alongside ceruloplasmin; however, there is a danger that it can be misleadingly high in the presence of acute liver failure. A 24-hour copper excretion test reveals the levels of circulating nonceruloplasmin-bound copper; aside from being a diagnostic test, this procedure can also be used to monitor the performance of Wilson disease therapeutics. 

Physicians are highly recommended to conduct a liver ultrasound in all patients with Wilson disease, regardless of their presentation. This is because the incidence of liver disease is high in patients with Wilson disease; for example, hepatic steatosis can be found in up to 88% of patients, while cholestasis is reported in up to 25% of patients. In addition, Wilson disease patients with neurological symptoms also have a higher rate of liver abnormalities. 

Alpha-1 Antitrypsin Deficiency 

In moderate-to-advanced AATD, the liver and the lungs are commonly damaged; hence, they should be examined on the occasion that a clinical suspicion of AATD is raised. However, the first investigative test typically conducted is the measurement of serum AAT, of which a cut-off point of 1.1 g/L is considered low. When serum AAT falls below these levels, phenotype/genotyping tests are typically carried out. 

Read more about AATD etiology 

When assessing the extent of liver damage, physicians should cover as many bases as possible, including physical examination, liver biochemistry, ultrasound, and noninvasive fibrosis assessment (although liver fibrosis may develop in the absence of liver enzyme derangement). The presence of significant liver disease is a sign of AATD progression, although there are few specific therapeutics potent enough to treat it. 

Lung disease is also a common characteristic of AATD, and its severity depends on a number of vulnerabilities and lifestyle choices, such as air pollution and smoking. Aside from typical lung assessments (chest auscultations and chest imaging, among others), clinicians should aim to conduct the 6-minute walk test and ask questions relating to a patient’s health-related quality of life. Pulmonary function tests should be performed routinely to assess lung disease progression. If lung disease is extensive, a lung transplantation may be required. 

In both Wilson disease and AATD, relatively noninvasive diagnostic tests are sufficient on their own to establish the presence of either disease. The point of prioritizing diagnostic tests that are less invasive in nature, besides the lower risk of complications, is that they are easier to perform and should theoretically lead to a quicker diagnosis; a quicker diagnosis should then allow for the early initiation of treatment, which may ultimately improve prognosis. 

“The early diagnosis of these diseases is important in order to initiate a specific treatment,” Guillaud and colleagues wrote. “These tests also play a pivotal role during the follow-up of patients by monitoring the effectiveness and tolerability of current treatments and new emerging therapies.” 


Guillaud O, Dumortier J, Couchonnal-Bedoya E, Ruiz M. Wilson disease and alpha1-antitrypsin deficiency: a review of non-invasive diagnostic testsDiagnostics. 2023;13(2):256. doi:10.3390/diagnostics13020256

Strnad P, McElvaney NG, Lomas DA. Alpha1-antitrypsin deficiencyN Engl J Med. 2020;382(15):1443-1455. doi:10.1056/NEJMra1910234