Why is an IgG4 (Immunoglobulin G4) level above 135 mg/dL considered abnormal when the normal reference range is 3 to 201 mg/dL?

From the Guidelines

An IgG4 level above 135 mg/dL is considered abnormal in the context of IgG4-Related Disease (IgG4-RD) diagnosis, despite being within the normal reference range of 3 to 201 mg/dL, as it is a diagnostic criterion established through clinical research to help distinguish between those likely to have the disease and those who don't. This distinction is crucial because patients with IgG4-RD typically show elevated IgG4 levels, and using this threshold helps in identifying potential cases that require further investigation. The normal reference range for IgG4 levels is based on the distribution of values in healthy populations, whereas diagnostic cutoffs like 135 mg/dL are determined based on clinical significance in specific disease states, such as IgG4-RD, as noted in guidelines for the diagnosis and management of primary sclerosing cholangitis 1.

When evaluating for IgG4-RD, it's essential to interpret IgG4 levels alongside other clinical findings, imaging studies, and potentially tissue biopsies for a proper diagnosis. The British Society of Gastroenterology and UK-PSC guidelines recommend that elevated serum IgG4 levels support the diagnosis of clinically suspected IgG4-RD but cannot be relied on for making a definite diagnosis or distinguishing IgG4-SC from PSC, highlighting the need for a comprehensive diagnostic approach 1.

In the management of IgG4-SC, a common steroid regimen is used as first-line treatment, with the possibility of introducing an immunomodulator or considering biological therapy like rituximab for patients who fail to respond to initial treatments or have complex disease, as suggested by recent guidelines and studies 1. Therefore, while an IgG4 level of 135 mg/dL may not be abnormal in the general population, its clinical significance in the context of IgG4-RD diagnosis and management is substantial and should be considered in conjunction with other diagnostic and therapeutic strategies.

Key points to consider include:

• The distinction between normal reference ranges and diagnostic cutoffs in specific disease contexts
• The importance of interpreting IgG4 levels alongside other clinical and diagnostic findings
• The role of IgG4 levels in the diagnosis and management of IgG4-RD, as informed by recent clinical guidelines and research 1
• The need for a comprehensive and multidisciplinary approach to diagnosing and treating IgG4-RD, considering the complexity of the disease and the variety of treatment options available.

From the Research

IgG4-Related Disease Diagnosis and Treatment

• The diagnosis of IgG4-related disease (IgG4-RD) is based on a combination of clinical, radiological, and histopathological findings, as well as elevated serum IgG4 levels 2, 3.
• The normal reference range for IgG4 levels is 3 to 201 mg/dL, but levels above 135 mg/dL are often considered abnormal in the context of IgG4-RD diagnosis 2, 3.
• Elevated IgG4 levels are not exclusive to IgG4-RD and can be seen in other conditions, making it essential to consider the clinical scenario and other diagnostic criteria 3, 4.

Diagnostic Criteria and Challenges

• The diagnostic approach for IgG4-RD is complex and requires a combination of tests, including serum IgG4 levels, imaging studies, and histopathological examination 3, 5.
• Small biopsies can be challenging to interpret, and the absence of characteristic histological features does not necessarily rule out IgG4-RD 5.
• An elevated IgG4/total IgG ratio is a sensitive pathological feature and can be useful in diagnosing IgG4-RD, even in the absence of other characteristic features 5.

Treatment Options and Outcomes

• Glucocorticoids are the first-line treatment for IgG4-RD, but their use can be limited by toxic effects, particularly in elderly patients 2, 6, 4.
• Other treatment options, such as rituximab, immunosuppressants, and targeted immunomodulators, are being explored as potential alternatives or adjuncts to glucocorticoids 6, 4.
• Treatment outcomes for IgG4-RD can be favorable, with many patients achieving clinical remission, but recurrences are common, and long-term outcomes are less clear 2, 6.