Advanced laboratory services

HLA-DQ2 & HLA-DQ8 

The haplotypes HLA-DQ2 (encoded by DQB1*02 and DQA1*05) or DQ8 (encoded by DQB1*0302 and DQA1*03) are present in almost all patients with celiac disease. Testing for these haplotypes has a negative predictive value of greater than 99 percent, but positive predictive value is only around 12 percent because these haplotypes are common in the general population. Hence, HLA testing is useful only in ruling out celiac disease:

● Patients with discordant celiac-specific serology and histology: 

1) Positive serology and non-diagnostic small bowel biopsies – tTG-IgA serology may occasionally be positive but the small intestinal biopsy may be normal or equivocal (Marsh 0 or 1, respectively). In patients with celiac disease, discordant serology and biopsy results may be due to the following:

• False positive tTG – False positive tTG results are rare but do occur and are usually low titer (typically less than twice the upper limit of normal). Case reports suggest that tTG-IgA antibodies may be falsely elevated during or after a febrile illness. There are also concerns about the quantitative variability and lack of standardization between commercially- available serologic tests for celiac disease.

• False negative biopsy results – Celiac disease may have a patchy distribution or initially be confined to the duodenal bulb.

If HLADQ2/DQ8 is negative, celiac disease is excluded.

If HLADQ2/DQ8 is positive, the patient can be placed on a high-gluten diet (>10 grams per day, equivalent of at least four slices of gluten containing bread per day) and, after 6 to 12 weeks, additional biopsies obtained from multiple sites in the mid and distal duodenum since celiac disease enteropathy can be patchy and missed due to sampling error.

2) Negative serology and abnormal small bowel biopsy - For patients with histologic findings suggestive of celiac disease (eg, villous atrophy) but negative serologies, we perform HLA-DQ2, DQ8 genotyping. If haplotypes HLA-DQ2 or DQ8 are present, we recommend a gluten-free diet for 12 to 24 months and monitor the clinical response. We also perform a repeat upper endoscopy with biopsies after 12 to 24 months of a gluten-free diet to confirm mucosal healing. Patients with a histologic response are likely to have celiac disease. Individuals without a histologic response likely have non-celiac villous atrophy.

● Patients who refuse upper endoscopy

● Evaluation of patients on a gluten-free diet with negative baseline serologies.

● Patients with suspicion of refractory celiac disease where the original diagnosis of celiac disease remains in question.

● HLA typing is sometimes performed in patients at high risk for celiac disease (eg, family history of celiac disease). A negative result will exclude celiac disease risk. This approach is most commonly used in at-risk children to obviate the need for periodic serology testing. 

Source: Ciarán P Kelly, MD; Diagnosis of celiac disease; Uptodate; Oct 2021

HLA-B51

The pooled estimates of a meta-analysis of 4,800 cases and 16,289 controls indicate that the risk (“odds”) of HLA–B51/B5 carriers developing Behcet Syndrome is increased by a factor of 5.78, and by a factor of 5.90 when considering only the split antigen HLA–B51. In agreement with previous observations the pooled rates of HLA–B51/B5–positive BD cases varied across geographic locations, but the relative risk increases associated with this allele is fairly even for different ethnic populations. (PMID: 19790126)

HLA-B27

In most studies, HLA-B27 is present in 85 to 95 percent of White patients with AS but in only approximately 8 percent of the general population. Thus, a positive test for HLA-B27 alone is not diagnostic for axial spondyloarthritis (axSpA), and a negative test for HLA-B27 does not exclude the diagnosis of axSpA.

HLA-B27 can be useful to increase the confidence of a diagnosis of axSpA in patients in whom plain radiographs or magnetic resonance imaging (MRI) also exhibit abnormalities consistent with axSpA. In patients in whom plain radiographs or MRI are equivocal for axSpA, positive testing for HLA-B27 would only be useful if there are additional parameters present that also suggest the presence of axSpA (eg, heel enthesitis). The presence of three parameters identified as characteristic features of axSpA brings the probability to about 50 percent. In such a scenario, being HLA-B27-positive increases the probability of having axSpA to 80 to 90 percent. More importantly, a negative test for HLA-B27 in these borderline cases reduces the probability of axSpA to a very low level. 

HLA-B27 can also be used as a screening tool in primary care in patients presenting with chronic back pain or Inflammatory Back Pain (IBP) suspected by the primary clinician as having a significant probability for axSpA. The probability of axSpA goes up from 5 to about 30 percent in chronic back pain patients and from 14 to about 60 percent in patients with IBP if HLA-B27 is positive. 

Source: David T Yu, MD; Diagnosis of axial spondyloarthritis; Uptodate; Oct 2021