Quantitative Immunoglobulins (IgG, IgA, IgM): When to Order, What the Patterns Mean, and the Myeloma Connection

Quantitative Immunoglobulins (IgG, IgA, IgM): When to Order, What the Patterns Mean, and the Myeloma Connection

Recurrent infections, monoclonal spikes, and the difference between too much of one and not enough of everything else.

The Three Immunoglobulins

• IgG (700–1600 mg/dL): The workhorse—75% of serum immunoglobulins. Provides long-term immunity after infection or vaccination. Crosses the placenta (maternal IgG protects the newborn). Low IgG = increased risk of bacterial infections.
• IgA (70–400 mg/dL): Mucosal immunity—found in saliva, tears, respiratory and GI secretions. Selective IgA deficiency is the most common primary immunodeficiency (1 in 400–800). Connects to our celiac post (IgA deficiency causes false-negative tTG-IgA).
• IgM (40–230 mg/dL): The first responder—the initial antibody produced during acute infection. Elevated IgM on infection-specific testing = acute/recent infection. Also the antibody class in Waldenström's macroglobulinemia.

When to Order Quantitative Immunoglobulins

Order When You See

• Recurrent sinopulmonary infections (2+ pneumonias in a year, 4+ ear infections, chronic sinusitis requiring antibiotics) — evaluate for humoral immunodeficiency
• Suspected primary immunodeficiency: CVID (common variable immunodeficiency), selective IgA deficiency, X-linked agammaglobulinemia in boys
• Monoclonal gammopathy workup: SPEP shows an M-spike — quantitative Igs help characterize suppression of uninvolved immunoglobulins (immune paresis)
• Multiple myeloma monitoring: Suppressed uninvolved Igs (immune paresis) = worse prognosis and higher infection risk
• Autoimmune hepatitis evaluation: Elevated IgG is part of the diagnostic criteria (with ANA/SMA/anti-LKM)
• Suspected Waldenström's macroglobulinemia: Markedly elevated IgM with lymphoplasmacytic infiltration
• Before starting rituximab or other B-cell depleting therapy: Baseline Ig levels for monitoring secondary hypogammaglobulinemia
• Celiac workup with negative tTG-IgA: Check total IgA to rule out IgA deficiency

The Patterns

Pattern	IgG	IgA	IgM	Think About
All low (panhypogamma)	↓	↓	↓	CVID, X-linked agammaglobulinemia (boys), secondary causes (rituximab, myeloma treatment, nephrotic syndrome protein loss, chronic lymphocytic leukemia)
Selective IgA deficiency	Normal	↓↓ (<7 mg/dL)	Normal	Most common primary immunodeficiency. Usually asymptomatic. Associated with celiac disease, autoimmune conditions, and anaphylaxis to blood products containing IgA.
One Ig markedly elevated, others suppressed	One ↑↑↑, others ↓			Monoclonal gammopathy / myeloma. The elevated Ig is monoclonal (M-protein). Confirm with SPEP + immunofixation. Suppression of uninvolved Igs = "immune paresis."
All elevated (polyclonal)	↑	↑	↑	Chronic infections (HIV, HCV, TB), autoimmune diseases (SLE, RA, Sjögren's), chronic liver disease (cirrhosis), sarcoidosis
IgG elevated, others normal	↑↑	Normal	Normal	Autoimmune hepatitis (type 1), chronic infections, connective tissue diseases
IgM markedly elevated	Normal/↓	Normal/↓	↑↑↑	Waldenström's macroglobulinemia, primary biliary cholangitis (moderate IgM elevation), acute infection (transient)
IgA elevated	Normal	↑↑	Normal	IgA nephropathy, alcoholic liver disease, celiac disease (paradoxically, some celiac patients have elevated IgA), mucosal infections

The Myeloma Connection: Immune Paresis

Critical Pattern

In multiple myeloma, the malignant plasma cells produce massive amounts of one monoclonal immunoglobulin while suppressing normal immunoglobulin production. This means: IgG myeloma = very high IgG (monoclonal) with very low IgA and IgM. IgA myeloma = very high IgA (monoclonal) with very low IgG and IgM. Light chain myeloma = all immunoglobulins may be low (the paraprotein is free light chains only, not measurable as intact Ig). Immune paresis (suppressed uninvolved Igs) is a hallmark of myeloma and is the reason these patients have severe infection susceptibility. IgG <500 mg/dL in a myeloma patient indicates high infection risk and may warrant immunoglobulin replacement therapy.

CVID: The Primary Immunodeficiency to Know

Common Variable Immunodeficiency is the most clinically significant primary immunodeficiency in adults. Diagnostic criteria: markedly reduced IgG (usually <500) with low IgA and/or IgM, impaired vaccine responses, and exclusion of other causes. Patients present with recurrent sinopulmonary infections, bronchiectasis, autoimmune cytopenias, granulomatous disease, and increased lymphoma risk. Mean age of diagnosis: 20–30s. Many patients are misdiagnosed for years before the Ig levels are checked.

Pediatric Note

Neonates have high IgG (transplacental maternal IgG) that wanes by 3–6 months, creating a physiologic nadir. Transient hypogammaglobulinemia of infancy is a delayed maturation of IgG production that self-resolves by 2–4 years—distinguish from true primary immunodeficiency by the child's ability to make specific antibodies to vaccines. X-linked agammaglobulinemia (Bruton's) presents in boys at 6–12 months when maternal IgG wanes, with all Ig classes virtually absent and no circulating B cells.

Selective IgA Deficiency: The Autoimmune Crossover

IgA deficiency (<7 mg/dL with normal IgG and IgM) connects to multiple posts in this series:

• Celiac disease: IgA deficiency causes false-negative tTG-IgA; always check total IgA with celiac screening
• Autoimmune associations: Higher prevalence of SLE, RA, thyroiditis, and type 1 diabetes
• Transfusion risk: Rare patients develop anti-IgA antibodies, causing anaphylaxis to blood products containing IgA. Use IgA-deficient or washed blood products if anti-IgA antibodies are documented.
• Most IgA-deficient patients are completely asymptomatic and require no treatment.

The Pitfalls

• Don't confuse quantitative Igs with SPEP: Quantitative Igs measure total amounts. SPEP separates proteins by electrophoretic pattern and detects monoclonal spikes. Both are needed for myeloma workup—they answer different questions.
• A "normal" IgG in myeloma patients is misleading: The total IgG may appear normal because the monoclonal IgG is included in the total. Subtract the M-spike from the total IgG to get the uninvolved (polyclonal) IgG, which is often severely depleted.
• Secondary hypogammaglobulinemia is increasingly common: Rituximab, anti-CD38 antibodies (daratumumab), CAR-T therapy, and chronic corticosteroids all cause IgG suppression. Monitor Ig levels in these patients and consider replacement when IgG <400–500 with recurrent infections.
• Age-dependent norms in children: Pediatric Ig levels change dramatically with age. Use age-specific reference ranges. Neonatal IgG is high (maternal); IgM is low (produced by the infant, not transplacental).

Bottom Line

Quantitative immunoglobulins are essential for evaluating recurrent infections, characterizing monoclonal gammopathies, monitoring immunosuppressive therapy, and diagnosing primary immunodeficiencies. One Ig massively elevated with others suppressed = think myeloma. All Igs low = think CVID or secondary immunodeficiency. Selective IgA deficiency = check for celiac and autoimmune associations. And always use age-appropriate norms in children.

Stay sharp out there.

The Celiac Serologic Panel: Getting It Right the First Time

 

The Celiac Serologic Panel: Getting It Right the First Time

Two tests, one massive pitfall, and the number-one mistake that makes the whole workup useless.

Celiac disease affects roughly 1 in 100 people, but up to 80% of cases remain undiagnosed. It masquerades as IBS, iron deficiency anemia, unexplained osteoporosis, chronic fatigue, infertility, and even "normal" GI symptoms that patients have lived with for years. The serologic panel is straightforward—but there are pitfalls that will make you miss the diagnosis entirely if you don't know them.

Let's get this one right.

The Tests: What to Order and Why

The First-Line Screen: tTG-IgA + Total IgA

That's it. For most patients over age 2, you need exactly two tests:

1

tTG-IgA (Tissue Transglutaminase IgA Antibody)
The preferred screening test per ACG, AGA, and ESPGHAN guidelines. Sensitivity of 93–98%, specificity of 96–98%. This is the workhorse of celiac diagnosis. If it's positive, you're on the right track. If it's strongly positive (>10× upper limit of normal), that alone may be sufficient for diagnosis in children without biopsy (per ESPGHAN criteria).

2

Total Serum IgA
This is the test that gets forgotten—and it's the one that saves you from a false negative. Selective IgA deficiency occurs in 2–3% of celiac patients (compared to 1 in 400–800 in the general population). If your patient is IgA-deficient, every IgA-based celiac test will be falsely negative. You need this result to know whether you can trust the tTG-IgA.

The #1 Mistake

Ordering tTG-IgA without a total IgA level. If your patient happens to be IgA-deficient, a negative tTG-IgA means nothing. You've just given them a false all-clear for celiac disease. Always order both together.

When IgA Is Deficient: The IgG Backup Panel

If total IgA is low or undetectable, switch to IgG-based tests:

• DGP-IgG (Deamidated Gliadin Peptide IgG) — the preferred IgG test in the setting of IgA deficiency. Slightly better sensitivity than tTG-IgG.
• tTG-IgG — less specific than tTG-IgA; should only be used if IgA deficiency is confirmed. In IgA-sufficient patients, tTG-IgG has an unacceptably high false-positive rate.
• EMA-IgG (Endomysial Antibody IgG) — highly specific but expensive and observer-dependent. Available at some centers.

Key Rule

Never order tTG-IgG in an IgA-sufficient patient. Per AGA best practice advice, IgG isotype testing for tTG is not specific in the absence of IgA deficiency. It will generate false positives and unnecessary endoscopies.

The Other Tests You'll See on Panels

Test	Role	When to Use
tTG-IgA	First-line screening	All patients ≥2 years with suspected celiac disease
Total IgA	Rule out IgA deficiency	Always order alongside tTG-IgA
DGP-IgG	Best IgG alternative	When IgA deficiency is confirmed; also useful in children <2
tTG-IgG	IgG backup	Only in confirmed IgA deficiency (high false-positive rate otherwise)
EMA-IgA	Confirmatory test (~100% specificity)	To confirm a positive tTG-IgA, especially if tTG is >10× ULN (biopsy-free pathway in children)
DGP-IgA	Secondary test	No advantage over tTG-IgA for initial screening; higher false-positive rate
HLA-DQ2/DQ8	Rule-out test (excellent negative predictive value)	If negative, celiac is virtually excluded. Does NOT confirm celiac if positive (30–40% of the general population carries these alleles)

The Pitfalls: Where Clinicians Go Wrong

1. Testing While the Patient Is Already Gluten-Free

This is the single most destructive mistake in celiac testing. If the patient has already eliminated or significantly reduced gluten, both serology and biopsy may be falsely negative. Antibody levels decline within weeks to months on a gluten-free diet (GFD), and villous atrophy can begin healing.

Critical Rule

Do NOT allow the patient to start a GFD before completing the diagnostic workup. If they've already started one, they need a gluten challenge (consuming gluten daily for at least 2–6 weeks, ideally 6–12 weeks) before testing. Many patients are unwilling to do this after they've felt better gluten-free—which is why getting the testing done first is so important.

2. Forgetting Total IgA

Worth repeating: 2–3% of celiac patients are selectively IgA-deficient. Without checking total IgA, you may reassure an IgA-deficient celiac patient that they don't have the disease. This is a preventable miss.

3. Ordering the Full Panel Instead of the Right Tests

Many labs offer "celiac panels" that include tTG-IgA, tTG-IgG, DGP-IgA, DGP-IgG, and sometimes EMA. Per the AAFP Choosing Wisely recommendation, don't order tTG-IgG or DGP antibodies as initial screening tests. They have higher false-positive rates and add cost without improving diagnostic accuracy in IgA-sufficient patients. Start with tTG-IgA + total IgA. Add IgG tests only if IgA deficiency is confirmed.

4. Low-Positive tTG-IgA Results

False-positive tTG-IgA results occur, typically at low titers (1–2× the upper limit of normal). These can be seen in type 1 diabetes, autoimmune thyroid disease, autoimmune liver disease, heart failure, and other inflammatory conditions. A low-positive tTG-IgA should be confirmed with EMA or repeated before committing the patient to endoscopy. Strongly positive results (>10× ULN) are much more reliable.

5. Assuming a Positive Serology = Celiac Disease

In adults, a positive tTG-IgA should lead to referral for endoscopic duodenal biopsy to confirm the diagnosis before starting a GFD. Serology alone is not diagnostic in adults per current ACG guidelines. In children and adolescents, the ESPGHAN guidelines do allow a biopsy-free diagnosis if tTG-IgA is >10× ULN AND EMA-IgA is positive on a second, separate blood draw—but this decision should be made by a pediatric gastroenterologist.

6. Children Under 2: Use DGP Too

In very young children, tTG-IgA may be less sensitive. ACG guidelines recommend adding DGP-IgA and DGP-IgG to the workup in children under 2 years of age. The immune response to gluten takes time to develop, and these children need to have been eating gluten-containing foods for a sufficient period before testing will be accurate.

7. HLA Testing: Great for Ruling OUT, Not for Ruling IN

HLA-DQ2 and HLA-DQ8 are present in virtually all celiac patients. But they're also carried by 30–40% of the general population, most of whom will never develop celiac disease. The value of HLA testing is its negative predictive value: if a patient is DQ2/DQ8-negative, celiac disease is essentially excluded. This is particularly useful for first-degree relatives being considered for lifelong screening, or for patients already on a GFD where serology is unreliable.

Who Should Be Tested?

Test When You See

• Chronic or recurrent diarrhea, bloating, abdominal pain (especially if labeled "IBS")
• Unexplained iron deficiency anemia (especially if refractory to supplementation)
• Unexplained weight loss or failure to thrive in children
• Unexplained osteoporosis or osteopenia, particularly in premenopausal women or men
• Dermatitis herpetiformis (intensely pruritic blistering rash on elbows, knees, buttocks—this IS celiac disease of the skin)
• Recurrent aphthous stomatitis (canker sores)
• Unexplained elevated transaminases
• Peripheral neuropathy without other explanation
• Dental enamel defects
• Unexplained infertility or recurrent miscarriage
• First-degree relatives of celiac patients
• Type 1 diabetes (associated autoimmune condition—screen if symptomatic)
• Autoimmune thyroid disease, Down syndrome, Turner syndrome, Williams syndrome

Do NOT Test

• As population screening in asymptomatic, low-risk individuals
• While the patient is already on a GFD (results will be unreliable)
• With tTG-IgG or DGP as first-line tests in IgA-sufficient patients

The Autoimmune Connection

This is where celiac testing intersects with the rest of this blog series. Celiac disease clusters with other autoimmune conditions:

• Type 1 diabetes — 3–8% of T1D patients have celiac disease
• Hashimoto's thyroiditis and Graves' disease — increased prevalence
• Autoimmune liver disease — celiac can cause cryptogenic transaminitis
• Sjögren's syndrome, SLE, RA — shared autoimmune susceptibility
• Selective IgA deficiency — both associated with celiac AND causes false-negative testing
• Dermatitis herpetiformis — the skin manifestation of celiac disease; always biopsy the uninvolved skin adjacent to the lesion (direct immunofluorescence shows granular IgA deposits at the dermal papillae)

If you're working up one autoimmune condition, keep celiac in the differential—especially if the patient has unexplained anemia, GI symptoms, or weight changes.

Monitoring After Diagnosis

Once celiac disease is confirmed and a GFD is started:

• Recheck tTG-IgA (or DGP-IgG if IgA-deficient) at 3–6 months after diagnosis
• Continue checking every 6 months until levels normalize
• Then annually to monitor GFD adherence
• Persistent or rising antibodies suggest ongoing gluten exposure (intentional or inadvertent)
• Screen for nutritional deficiencies at diagnosis: iron, B12, folate, vitamin D, calcium, zinc
• Repeat DEXA scan if osteopenia/osteoporosis was present at diagnosis

Quick-Reference: The Celiac Testing Algorithm

Scenario	What to Order	Next Step
Standard screen (age ≥2)	tTG-IgA + total IgA	If tTG-IgA positive → refer GI for biopsy
IgA deficient	DGP-IgG (± tTG-IgG)	If positive → refer GI for biopsy
Children <2 years	tTG-IgA + DGP-IgA + DGP-IgG + total IgA	Refer pediatric GI for interpretation
Low-positive tTG-IgA (1–2× ULN)	Confirm with EMA-IgA or repeat tTG-IgA	If confirmed → refer for biopsy. If negative on repeat → likely false positive
Already on GFD	HLA-DQ2/DQ8 (to rule out), or gluten challenge then serology	If HLA negative → celiac excluded. If HLA positive → need gluten challenge for definitive testing
Monitoring on GFD	tTG-IgA (or DGP-IgG if IgA-deficient)	Every 6 months until normal, then annually

Bottom Line

Celiac testing is deceptively simple: two tests will get you there in most cases. But the pitfalls are real—forgetting total IgA, testing on a GFD, ordering the wrong IgG tests in IgA-sufficient patients, and accepting low-positive results without confirmation. Get the order right, make sure the patient is still eating gluten, and always check that total IgA.

For your autoimmune patients especially, celiac disease should live permanently on your differential diagnosis list. It's common, it's underdiagnosed, and it's one of the few autoimmune conditions where the treatment—a gluten-free diet—can fully control the disease.

Stay sharp out there.