How do you test for pernicious anemia (PA)?
If you suspect you have PA (a B12 deficiency due to a lack of intrinsic factor), it’s crucial to have a proper pernicious anemia diagnosis procedure as quickly as possible. This is because once neurological damage sets in, it often leads to irreversible changes.
In most countries, the current testing for pernicious anemia is inadequate. In the UK, a survey done by Pernicious Anemia Society found that 44% of patients were misdiagnosed with another condition; 22% waited for two years to get a correct diagnosis; 19% had to wait for five years; 4% waited for 10 years; and 14% waited for 10 years or more.
When you have PA and wait such a long time before starting treatment, you risk having permanent nerve damage. So, have a proper pernicious anemia test early on.
Reasons for Misdiagnosis
First of all, why is pernicious anemia so often misdiagnosed?
Doctors Don’t Test for B12
Doctors rarely test for B12 deficiency, unless you ask them to. In other words, in most countries you typically have to request a B12 level test. This leads to a high number of people, including those with PA, being totally unaware of their low B12 levels.
Before doctors do test for B12 levels, they often want to see macrocytosis (enlarged red blood cells). However, only about 60% of B12 deficiency patients show it. Even advanced B12 deficiencies – with neurological symptoms – may show normal red blood cells.
Also, supplementing with folic acid (as pregnant women do) will prevent the red blood cells from enlarging. Iron deficiency will also reduce their volume.
The “Normal” Blood Level Range Isn’t Optimal
In most countries, the blood level range for determining B12 deficiency is way too low. People show symptoms even at twice those levels. And the range is different depending on where you’re from. It makes no sense. Why would the difference of you being or not being diagnosed with B12 deficiency depend on your ZIP code?
The Blood Test Itself Isn’t Optimal
The total-B12 blood test doesn’t give you the full picture, because it tests for both active and inactive forms of B12. To illustrate, here’s a publication demonstrating how five different total-B12 assays gave normal B12 results in a patient with a proven pernicious anemia. This is why we strongly advocate for the use of the active-B12 test.
Additionally, the common B12 test uses a competitive binding luminescence assay, which can give false high results in 22-35% of patients, depending on the machine:
It is important to be aware that failure of CBLA assays to detect cobalamin deficiency can occur, especially in cases of pernicious anemia where IF‐blocking antibodies have been implicated in causing assay interference.
Laboratory testing for cobalamin deficiency in megaloblastic anemia
A Good Pernicious Anemia Diagnosis
How to test for pernicious anemia then? If you have been diagnosed with B12 deficiency and would like to determine if it’s due to pernicious anemia – a condition in which your body struggles to absorb B12 from the stomach – there are several useful tests.
Which Pernicious Anemia Test to Do?
Remember, the cause of PA is the body creating antibodies that make it very difficult to absorb the B12. So how do you diagnose pernicious anemia properly? There are two types of such antibodies, and you should go test for the presence of both:
Gastric Intrinsic Factor Antibodies (IFA)
Intrinsic factor is a protein created by the parietal cells that line the stomach wall. It binds to B12 to form a complex that is necessary for the absorption of the B12 in the small intestine. 40-60% of PA patients test positive for IFAs.
The guidelines indicate that all patients suspected of having PA should have a test for intrinsic factor antibodies, no matter what their serum B12 levels are. Even in the absence of anemia, patients with low B12 should be tested. This is particularly important for those who don’t have food-bound cobalamin malabsorption or other clear causes.
If you test positive for IFA, this confirms the diagnosis of pernicious anemia. Testing negative doesn’t exclude diagnosis, because the test is not robust enough to detect all cases. If it comes back negative, you may ask to do it again a few times, just in case.
Gastric Parietal Cells Antibodies (PCA)
PCAs attack those cells that line the stomach wall. The cells normally produce both the acids that release the B12 from food, and the intrinsic factor that binds to it. Without enough IF, vitamin B12 remains largely unabsorbed, and deficiency develops.
The majority of PA patients will have PCAs. However, not everyone with PCAs will have PA. This pernicious anemia diagnostic test isn’t as specific as the IFA test, since patients with other diseases such as gastritis, diabetes, and thyroiditis may also have these antibodies. However, if your B12 levels come in low, and you test positive for PCA, doctors will often diagnose you with PA. We advise to always test for IFA too.
Important: Before trying to establish an accurate pernicious anemia diagnosis, avoid supplementing with B12 for at least 72 hours. Otherwise, you could skew your test results. Some labs may prefer not to draw a blood sample within two weeks of a vitamin B12 injection.
PCA and IFA tests should be used in conjunction with each other after other tests have established that a patient has B12 deficiency and anemia or neuropathy.
However, since the treatment (B12 shots) has no side effects, the newer guidelines suggest to ignore negative test results and base diagnosis on signs and symptoms alone. And, most importantly – to begin injecting B12 right away. We recommend to inject daily at the beginning. If your doctor won’t prescribe enough B12, you can get it here:
Test Results: How to Diagnose Pernicious Anemia?
Got the results of your lab test for pernicious anemia? Here’s what to make of them:
Positive for both IFA and PCA? Immunological evidence of PA. Positive for both is the definitive test for pernicious anemia diagnosis.
Negative for both IFA and PCA? No immunological evidence of pernicious anemia.
Negative IFA but positive PCA? 90%+ to have autoimmune gastritis, which may or may not end up in pernicious anemia one day. Negative IFA does not exclude the possibility of PA, since only about half of PA patients test positive for this antibody.
Positive IFA but negative PCA? Immunological evidence of PA if the patient has low hemoglobin macrocytosis (enlarged red blood cells) and low B12 levels. If you’re older than 50, this test alone is usually enough to establish a diagnosis. A gastric biopsy may follow in order to confirm. In the absence of macrocytosis or anemia, you should repeat in six months with serum gastrin, a full blood count and fasting B12 to confirm.
Positive IFA but unknown PCA? Immunological evidence of pernicious anemia if the patient is older than 50. Test for PCA to confirm, and if negative, see above.
Negative IFA but unknown PCA? Test for PCA. Nearly half of all pernicious anemia patients test negative for IFA. In contrast, PCA is an excellent indicator of autoimmune gastritis, which often ends in pernicious anemia over the years.
Unknown IFA but positive PCA? Again, PCA is seen in more than 90% of patients with autoimmune gastritis, which may lead to PA. Of course, some people may test positive and never reach the stage of PA, so we suggest testing for IFA too.
Unknown IFA but negative PCA? Test for IFA just in case. At least 10% of those affected with pernicious anemia won’t have PCAs.
The Schilling Test For Pernicious Anemia Diagnosis
This test is no longer available. For 40 years it was used for PA diagnosis, but it involved radioactive substances that are no longer in use. Not relevant anymore.
How to Establish B12 Deficiency In The First Place?
The serum blood test for B12 is far from accurate, as it also accounts for your levels of inactive B12. The holotranscobalamin II (active B12) test, which measures only the active levels in the blood, is superior. We predict that it will replace the current test one day, since there are often big gaps between the serum B12 and active-B12 levels. Only a few hospitals offer this test.
Methylmalonic acid (MMA) test is useful as well:
Increased MMA may suggest a B12 deficiency (MMA is high in ~95% of B12 deficient patients). However, testing positive could also mean other things, like renal disease, small bowel bacterial overgrowth, or hemoconcentration. If plasma levels are higher than 0.75 µmol/l though, it’s almost surely a B12 deficiency. It’s a great B12 deficiency test, just not very popular, because it uses the expensive gas chromatography mass spectrometry (GC-MS).
Another useful test is plasma total homocysteine (tHcy). It’s a nice extra tool in the box, although low B6, low folate, hypothyroidism and renal failure can also elevate homocysteine levels. This test must be carried out within two hours of sampling the blood, which must be cooled during that time.
Other tests are the mean corpuscular hemoglobin (MCH) and the MCHC (mean corpuscular hemoglobin concentration), which check the amount of hemoglobin you have per red blood cell. MCHC also accounts for the volume of the cells. High levels in these tests may indicate a B12 deficiency.
All in all, you’re likely to have PA if you show low B12 or high MMA or homocysteine levels, as well as a positive pernicious anemia blood test result for IFA or PCA.
The Importance of Prompt Treatment
The new guidelines by the British Committee for Standards in Haematology show that the most important factor is the clinical picture. If you have clear pernicious anemia symptoms – even if your results look normal, or if you are yet to have a test – begin treatment right away. This is because B12 is a water-soluble vitamin. It means that any excess goes out through your urine. No risk at all, as you can’t overdose.
If you show any signs and symptoms, then ask your doctor for a therapeutic trial of methylcobalamin B12 shots. If your doctor refuses, or if you simply want to take control of your own health, you can order self-injectable B12 here. This will also ensure you’re getting the best form of B12. Inject daily for 3 months, and see how you feel.
Best of luck with your pernicious anemia diagnosis, and don’t panic if you test positive. We live in an age where cheap B12 shots can keep you alive and well. Just don’t wait! With PA, waiting could mean some very real and serious nerve damage.
All the best.