Q:

Thank you for this service. An 11-year-old otherwise healthy but somewhat obese boy was referred to me for an elevated IgA of 280 (normal for lab 53-204). It is unclear to me why this was checked in the first place. He has no significant past medical history. Review of systems shows that he has a history of symptoms suggesting lactose intolerance (loose stools and flatulence with "a lot" of milk only). He has some periodic nasal symptoms. He's not on any medications.

 

Patient's father is a patient of mine. He has stable asymptomatic low IgM, and a somewhat low IgG subclass. The father does not have a history of infections.

 

Work-up thus far includes:
-negative percutaneous scratch test.
-IgG 1673 (698-1560), IgG subcalss 2 647 (147-493)
-IgA rechecked 283 (53-204)
-AST slightly elevated 43(0-40)
-ALT slightly elevated 93 (0-55)
-IgM and IgE normal
-negative serum protein electrophoresis
-ANA negative
-CBC normal
-Anti-gliadin IgA and IgG negative
-tTG IgA and IgG negative
-endomysial IgA negative
-Chemistry panel otherwise negative.
-Urinalysis negative
-Hemoglobin A1c 5.8
-TSH, Rheumatoid factor, ESR, CRP negative

 

My questions are:
1. What is the cause of the patient's elevated IgA (and IgG)?
2. Did I miss any work-up/Is there anything else I need to do?
3. Are the elevated transaminases related to the first issue?

 

Thank you for your time and assistance.
 Thank you for your recent inquiry.

 

First of all, I am copying below an answer to a previous question submitted regarding an unexplained elevation of IgA. Although this case is not the same as your, since your patient is asymptomatic, it will give you some insight as to the potential causes of an elevated IgA.

 

As you can see from my answer to that question, this is a frustrating problem in that to identify a cause of elevated IgA is difficult, and the attempt is usually futile. I am also copying below two abstracts that have looked at this issue. These abstracts are of interest, but again they are not very helpful, as in the case of most such studies I have seen, in eliciting the cause of an elevated IgA.

 

Therefore, unfortunately, I cannot give you any evidence-based data to solve your problem. My summary would be based on clinical experience and a review of the available information which, as previously noted, is not terribly helpful. But, in my opinion, in answer to your specific questions:

 

We are not going to be able to identify the cause of your patient's elevated IgA and G. Presumably they are a response to infection. I might add parenthetically that these levels are not markedly elevated and would not concern me to any great extent.

 

I do not think that you have missed anything, and in my opinion, I do not feel further workup is indicated.
There is no reason of which I am aware to suspect that the elevated transaminase levels are in any way related to the elevated IgG and IgA.

 

We often see such patients in practice, and in the past, I have simply chosen, as long as they are asymptomatic, to follow them and be available.

 

Thank you again for your inquiry and we hope this response is helpful to you.

 

Previous inquiry submitted to Ask the Expert 12/21/10:
Causes of Elevated IgA
12/21/2010
Question:
A referring PCP asked me today what could cause increase in IgA?

 

Her pt is 54 female with recurrent sinusitis and had Immune w/u with IgA 530 and normal IgG, IgM. the PCP then worked pt up further due to increase IgA and the following were all normal: SEP, Urine electrophoresis, metabolic panel, ANA, tissue transglut IgA, neutrophil cytoplasmic AB, and CBC. Pt is not an alcoholic.

 

I wonder if IgA could be elevated in chronic sinusitis or could this be just a normal varient for this pt or something more forebouding in the future?

 

Are further labs needed? A Dx? Yes the IgA was repeated 6 months later and still elevated thus the above w/u.

 

Thanks as always.

A:

Thank you for your recent inquiry.

Unfortunately I am not sure that I can be of any practical help to you in this regard. If one looks up a list of causes of elevated IgA, you see a total of 48 different diagnoses. They are divided into infections, neoplastic disorders, autoimmune disorders, neoplasms, congenital disorders, immune deficiencies (e.g., Wiskott-Aldrich, et cetera), poisonings (acute alcoholic hepatitis), and gastrointestinal diseases such as gluten enteropathy. However, none of these seem to fit your patient, and I doubt that any further evaluation would be fruitful in determining the underlying cause.

The most important thing that one can do is rule out monoclonality. The family physician seeing your patient has effectively done this with a serum protein electrophoresis, but if you wanted to add a more definitive touch, you could order an immunoelectrophoresis or an immunofixation. This would of course conclusively rule out any monoclonal elevation of IgA such as would occur in a malignancy. However, this of course is highly unlikely in the presence of a normal serum protein electrophoresis.

I can only add some anecdotal comments in that it is not terribly unusual to see elevations of IgA of this magnitude without known cause. In the course of working up individuals, we have seen several instances of nonspecific polyclonal elevation of IgA, and since these workups have been done to rule out immunodeficiency because of recurrent sinusitis, I have always attributed the elevated IgA levels to a response to recurrent bacterial sinusitis. You have alluded to this in your inquiry, and I certainly think this is a likely possibility. However, I could find no confirmation of this etiology in the literature. I have not been able to find any reference that has looked at this issue and documented repeated sinusitis as a cause for an elevated polyclonal serum IgA. Thus although the possibility seems rational, a role for recurrent bacterial sinusitis in producing an elevated IgA has not been conclusively documented in the literature.

Once again, returning to anecdotal experience, none of the patients that we have seen with polyclonal elevations of IgA, to my knowledge, have developed any complications, and have not experienced a clinical course any different from those patients with recurrent bacterial sinusitis and normal IgA levels. It may be reassuring for you to note that an elevated IgA in a woman is not a bad prognostic sign as evidenced by the abstract copied below. In a man, however, it evidently has been associated with an increase in mortality.

In summary, I think the most likely explanation for the elevated IgA, since it appears to be polyclonal, is a response to bacterial sinusitis. If you wanted to work it up further, the only thing that you might do would be to further document the polyclonal nature of the elevation by doing an immunoelectrophoresis or immunofixation. Finally, I doubt that this finding indicates a bad prognosis.

Thank you again for your inquiry and we hope this response is helpful to you.

Gerontology. 2009;55(2):179-85. Epub 2008 Oct 7.
IgA level is associated with risk for mortality in an eighty-year-old population.
Torisu T, Takata Y, Ansai T, Soh I, Awano S, Sonoki K, Kagiyama S, Nakamichi I, Yoshida A, Hamasaki T, Matsumoto T, Iida M, Takehara T.
Division of General Internal Medicine, Department of Health Promotion, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Japan. r07torisu@fa.kyu-dent.ac.jp
Abstract
BACKGROUND: Immunoglobulin levels are elevated in the older people. However, it is unknown whether these levels are related to mortality.
OBJECT: To evaluate the association between immunoglobulin levels and mortality.
METHODS: The study population included 697 individuals (277 males and 420 females) of 1,282 eighty-year-old individuals residing in the Fukuoka prefecture, Japan. The participants were followed for 4 years after the baseline examination.
RESULTS: The hyper-IgA group, defined as a serum IgA level >400 mg/dl, had high mortality using Kaplan-Meier analysis (log rank, p=0.037). Multivariate Cox regression analyses revealed a high risk of mortality (hazard rate=1.233, 95% confidence interval 1.109-1.491, p=0.031) after adjusting for covariates. The high risk of mortality in the hyper-IgA group was significant in males, but not in females. Moreover, Kaplan-Meier analysis revealed that IgA was related to cancer mortality in males (log rank, p=0.031), but not to pneumonia or cardiovascular disease. IgM and IgG levels were not related to high risk of mortality.
CONCLUSION: Serum IgA levels appear to be a predictor of mortality, especially cancer mortality in males.

Two abstracts:
Significance of high levels of serum IgA and IgA-class circulating immune complexes (IgA-CIC) in patients with non-insulin-dependent diabetes mellitus
Journal of Diabetes and its Complications, Volume 9, Issue 1, January-March 1995, Pages 42-48
Abstract
Significance of serum IgA and IgA-class circulating immune complexes (IgA-CIC) elevation in patients with non-insulin-dependent diabetes mellitus (NIDDM) was described. Seventeen patients with NIDDM and 17 patients with diffuse mesangial proliferative glomerulonephritis without deposition of IgA (DPGN) as controls were examined. The levels of serum IgA in patients with NIDDM were significantly higher than those in patients with DPGN (p 0.01). The levels of IgA-CIC in patients with NIDDM were also significantly higher than those in patients with DPGN (p 0.01). Production of IgA derived from B cells and the proportion of IgA bearing B cells in patients with NIDDM were not significantly higher than those in patients with DPGN. Furthermore, the levels of IgA in pharyngeal washings from diabetic patients were not significantly higher than those for DPGN patients. Duration of diabetes, the level of HbA1c, and the presence of hypertension, microalbuminuria, or retinopathy showed no significant correlations with the levels of serum IgA or IgA-CIC in patients with NIDDM. It was postulated that the elevations of serum IgA and IgA-CIC were based on subclinical infection of the mucosa and/or deterioration of IgA clearance in patiente with NIDDM.

Mary Ellen Conley Serum IgA1 and IgA2 in normal adults and patients with systemic lupus erythematosus and hepatic disease.Clinical Immunology and Immunopathology
Volume 26, Issue 3, March 1983, Pages 390-397

Abstract

As an early step in examining the factors that regulate synthesis of the IgA subclasses, IgA1 and IgA2, we determined the serum levels of IgA1, IgA2and total IgA in 50 normal adults, 20 patients with systemic lupus erythematosus (SLE), and 11 patients with liver disease. A quantitative solid phase radioimmunoassay using subclass specific monoclonal hybridoma antibodies was used. Within the normal population there were large variations in the concentrations of IgA1 and IgA2. The levels of IgA1 and IgA2 in samples from males were not significantly different from those from females. However, the mean concentration of IgA1 in samples from Blacks was significantly lower than that from Caucasians, P < 0.005. In the control population IgA2 constituted from 6 to 35% of the total serum IgA and the levels of IgA1 did not correlate with the levels of IgA2. The mean IgA1 and total IgA in samples obtained from patients with SLE were significantly higher than those from the normal population (P < 0.0001) although there was no significant difference in the levels of IgA2 in the two groups. In the samples obtained from patients with liver disease both IgA1 and IgA2 were markedly elevated and the levels of IgA1 did correlate with the levels of IgA2. These results indicate that the serum levels of IgA1 and IgA2 are controlled by factors that influence each subclass independently as well as factors that affect each subclass equivalently.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology