# Gastrointestinal and hepatic manifestations of primary immune deficiency diseases



## Malgrave (Nov 15, 2012)

Abstract

Primary immune deficiency diseases (PIDs) are a heterogeneous group of inherited diseases characterized by variable genetic immune defects, conferring susceptibility to recurrent infections. They have a vast array of manifestations some of which involve the gastrointestinal and hepatobiliary systems. These complications can be the consequence of five different factors, namely, infection, autoimmune process, unregulated inflammation, malignancies and complications of therapeutic intervention. They may precede the PID diagnosis and, once developed, they pose high risk of morbidity. Untrained clinicians may treat these manifestations only at the level of their presentation, leaving the PIDs dangerously undiagnosed. In fact, early diagnosis of PIDs and accompanied gastrointestinal and hepatic complications clearly require appropriate treatment, and in-turn lead to an improved quality of life for the patient. To improve the awareness of gastroenterologists and related health care providers about these diseases, we have reviewed herein the complications of different PIDs focusing on gastrointestinal and hepatic manifestation.


http://www.saudijgastro.com/article...16;issue=2;spage=66;epage=74;aulast=Al-Muhsen


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## Tenacity (Nov 15, 2012)

Wow that is so interesting.  So there could be some of us walking around thinking we have IBD, when in fact we have a Primary Immune Deficiency Disease.  I read the entire article and also found the following exert very note worthy:

Inflammatory Bowel Disease as a Primary Immunodeficiency Disease	

The examples discussed above represent a group of PIDs that may present with GI manifestations. Colitis resembling IBD is an evident example. On the other hand, there is a new concept postulating that IBD, particularly CD, is not considered solely an inflammatory disease but is also a bonafide genetic trait, resulting in an immune defect in the macrophage. It may result from impaired recruitment of granulocytes to the GI wall, causing impaired clearance of the microorganism, and hence contributing to granuloma formation. [79],[80],[81] Over the last 2 decades, the genetic cause of CD remains elusive despite the identification of up to 32 candidate loci in wide genome association studies, among which there is robust association with NOD2/CARD15 gene, encoding the cytosolic receptor that recognizes bacterial peptidoglycans, particularly mycobacterial N-glycolyl muramyl dipeptide. [82],[83] The new hypothesis focuses on impaired macrophage function, caused by a single gene Mendelian defect, rather than polygenic disease. If this is proven to be correct, it will cause a paradigm shift in our understanding of IBD and shall pave the way for major discoveries to delineate genetic causes of CD. [79] 

This to me says that anyone considering doing a donor allogeniec stem cell transplant, should have the donor stem cells checked to make sure it is not at the very least carrying the NOD2 gene.

With gastroenterologists not trained to be looking out for any PID's, do you think the specialist we should see to rule this out is an Immunologist then?  Or which speciality do you think would be best to see about this?


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## Malgrave (Nov 15, 2012)

I agree Tenacity, this was very interesting article indeed 

And like highlighted in the article, I am convinced that most of the gastroenterologists don't have a slightest clue about the immunodeficiencies and their potential GI manifestations.

I think that we would definitely need immunological expertise combined with the gastroenterological espertise, but I don't know, how often that kind of combined expertise is available.

And like you said, there may be people at this very moment thinking that they or their children have IBD but in fact they may have immunodeficiency with GI manifestation. And when we know that for example in the case of Common Variable Immune Deficiency (CVID, also mentioned in the article) the majority of patients are diagnosed in the 3rd or 4th decade of life (see below), this may not concern only little children, but also adolescence and adults.

Definition of Common Variable Immune Deficiency
(see http://primaryimmune.org/about-prim...pes-of-pidd/common-variable-immune-deficiency)

Common Variable Immune Deficiency (CVID) is a disorder characterized by low levels of serum immunoglobulins (antibodies) and an increased susceptibility to infections. The exact cause of the low levels of serum immunoglobulins is usually not known. It is a relatively common form of immunodeficiency, hence, the word “common.” The degree and type of deficiency of serum immunoglobulins, and the clinical course, varies from patient to patient, hence, the word “variable.” In some patients, there is a decrease in both IgG and IgA; in others, all three major types (IgG, IgA and IgM) of immunoglobulins may be decreased. The clinical signs and symptoms also vary from severe to mild. Frequent and unusual infections may first occur during early childhood, adolescence or adult life. In the majority of patients, the diagnosis is not made until the 3rd or 4th decade of life. However, about 20% of patients have symptoms of disease or are found to be immunodeficient under the age of 16.


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## Tenacity (Nov 15, 2012)

Very interesting!  I had an appointment with our gastroenterologist this morning and spoke to him about this topic.  He agreed that there could indeed be an underlying PID or CVID which caused the IBD.  He said if this was the case then it has been there from the start.  He agreed to refer us to an immunologist and said he would call me with the name of someone who would be experienced in this area.  I will let you know what happens when we get in to see the immunologist.  You would think they would test all patients with IBD for this!


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## my little penguin (Nov 15, 2012)

Thanks for the post.
Ds actually had the allergy area tested first prior to learning of his IBD.
 His second opinion GI did ask specifically how many times he got sick etc... to help rule immune deficiency In/out.
 I could see how this could easily get over looked when the child only has a GI specialist.


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## Malgrave (Nov 16, 2012)

I found this interesting article on how vaccines can be used to diagnose antibody deficiencies which is often the case in PID:

http://www.touchbriefings.com/pdf/3211/vries.pdf

My son's immunoglobulin levels are normal/very high, he has very seldom flu or respitary problems and he has had fever (always mild) less than five times in his life (his only problem is severe very early onset CD), yet the doctors think that he may have some sort of PID (the first tests have shown that he has not developed antibodies to measles vaccination, which they think is a sign of immunodeficiency).


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## Tenacity (Nov 18, 2012)

Thank you Malgrave - I printed out that article and will take it with me to the appointment!


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## kimmidwife (Dec 11, 2012)

Thanks for reporting this link. This is very interesting. I am going to ask about our GI about it.one question though. Which you guys may or may not know the answer to. Would a child who has this be getting a lot more colds and flu type illnesses throughout their lives? I am wondering because other then crohns the only other thing caitlyn has had was mono at age five which we never figure out where it came from. Other then that she has been pretty healthy not even frequent colds or anything.


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## Malgrave (Dec 11, 2012)

I guess that many people with PID have problems with recurrent respitary infections but this is not necessarily the case.

My son (who may have a very rare PID, still to be conformed) had flu like diseases only very rarely before he started Remicade. With Remicade he started to have some respitary problems and then he had one pneumonia. He has very seldom fever and if he has, it is very mild, maybe for one day only.

In the broad tests performed so far, a chronic EBV infection was also found. This seemed to be quite an important finding for the doctors. If I have understood it right, immunodeficient people may have inefficient reaction to EBV and that is why they may get chronic EBV infection. Some people also think that after an EBV, an immunocompromised person may easily develop a chronic autoimmunity disease. There seems to be a lot of articles for example on the suspected link between EBV and CFS...


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## Malgrave (Feb 12, 2013)

Below some more interesting links to the articles on the connection between PIDs and gastrointestinal problems. I wonder why this connection is not discussed more? Already in 1997 (the first article) the authors said that _In patients with unusual inflammatory GI disorders, measurement of serum immunoglobulins should be obtained._

http://www.ncbi.nlm.nih.gov/pubmed/9000499

http://www.ncbi.nlm.nih.gov/pubmed/20871412

http://www.ncbi.nlm.nih.gov/pubmed/21489888

http://jem.rupress.org/content/206/9/1839.full

http://www.aaaai.org/conditions-and-treatments/primary-immunodeficiency-disease.aspx

http://www.cisociety.com/files/what-is-PID.html

http://www.info4pi.org/aboutPI/index.cfm?section=aboutPI&content=faq

http://scdlifestyle.com/2012/04/how...gnosed-primary-immunodeficiency-disease-pidd/

...


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## Zinnia (Mar 1, 2013)

Hi.  My child is diagnosed with CD and also had the EBV a few years ago.  He even had a skin reaction associated with EBV.  I've wondered how or if EBV factors in anywhere.  We were a little surprised he got it.


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## Malgrave (Mar 8, 2013)

Here are interesting pages on the PIDs and IBD:


http://www.immunodeficiencysearch.com/algorithm#!__algorithm

(see Clinical features/Gastrointestinal abnormalities and Autoimmune/IBD)


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## countyourblessings (Jul 24, 2013)

I'm a new member - thanks malgrave for all the articles.  I wish I would have started here when I was looking for info.  I'm a CVID'er and also diagnosed with Crohns.  To some points above, I'm lucky that I have a great GI doctor that partners with my immunologist to coordinate care and treatment.  Although I don't have all the answers I want yet, they definitely need to talk to coordinate care.

Agree with Tenacity - I think I'm one of those people walking around thinking I have IBD and I really have a PID (CVID).  
Also have a great GI - he's the one that finally had my Iga/Igg/Igm levels tested when I was initially diagnosed with Crohns.  I've suffered from sinusitis/respiratory issues for a long time and my ENT never made the connection with PID.  Thankfully, my wonderful GI did.


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## Malgrave (Oct 1, 2013)

Diagnosis and Treatment of Gastrointestinal Disorders in Patients With Primary Immunodeficiency

http://www.cghjournal.org/article/S1542-3565(13)00313-3/fulltext


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## Malgrave (Dec 2, 2013)

Unravelling the association of partial T‐cell immunodeficiency and immune dysregulation

http://physio.ucsf.edu/gems/courses..._and_siggs_nature_reviews_immunology_2008.pdf


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## Malgrave (Feb 13, 2014)

Crohn's-like disease in a patient with common variable immunodeficiency treated with azathioprine and adalimumab

http://scielo.isciii.es/scielo.php?pid=S1130-01082013000500010&script=sci_arttext


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## kikig (Mar 3, 2015)

Just speculation on my part but I wonder if there is a specialisation issue here. My former immunologist is emphatic that I am primary immunodeficient. My current GI is emphatic that my immunodeficiency is just a symptom of my malabsorption issue. 
I am going to present some of these articles to my GI next week, just to see how he reacts (and to provide me with some giggles)


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## Malgrave (Mar 3, 2015)

Kikig, you may find also this article interesting, especially the authors from LMU München...

http://www.sciencedirect.com/science/article/pii/S0016508514009196


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## kimmidwife (Mar 3, 2015)

This is such an important post. I wonder if we can tag it to stay at the top of the page?
I think all newly diagnosed kids should see an immunologist.


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## kikig (Mar 4, 2015)

@kimmidwife

I totally agree. The body is a collection of cooperating systems or a team, as I like to think, but clinical treatment seems to be a singular effort. (This is 30 odd years of personal frustration with multiple countries medical systems talking)

Immunological workups should be done in most gastro problem cases in my opinion. 

Gastrointestinal issues are multifaceted, and when a GI doc waves away the idea of a dietician like you suggested a hairdresser, what hope is there of an immunologist being called in?

I mean, I am still struggling to get clarity :ybatty:


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## Malgrave (Apr 13, 2015)

Chronic Granulomatous Disease and Crohn's Disease Histopathological Distinctive Features: A Pediatric Study

http://www.ghrnet.org/index.php/joghr/article/view/529/571


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## Pilgrim (Apr 21, 2015)

What is the significance of never getting a fever? My daughter who was diagnosed about a year ago with Crohn's (multiple granulomas on biopsy) at age 3 almost never gets any sort of fever. It has caused a problem along the line when she had a drug reaction which was ignored for days because she had no fever. I didn't read all of the articles yet. I'm just wondering if someone can synopsize where this fits in?


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## Malgrave (Apr 22, 2015)

My son is the same! Now 7 yo, has experienced a mild fever only once during chicken pox! We think it has something to do with his possible PID and CD like disease and try to raise that to doctors. They always say "Interesting" and that's it!


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## Crohn2357 (Apr 22, 2015)

Fever is a mechanism of the immune system so it could be PID but I'm not an expert.


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## kimmidwife (Apr 27, 2015)

Our doctor wants my daughter to see the immunologist again to see if we can figure out if there is something immune also going on. She keeps getting flushed in the face when ever she eats. It is so strange.


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## Malgrave (Dec 2, 2015)

http://www.wjgnet.com/1007-9327/pdf/v21/i43/12296.pdf


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## Malgrave (Dec 4, 2015)

CGD behind Crohn's like IBD:

http://ecco-jcc.oxfordjournals.org/content/eccojc/early/2015/10/13/ecco-jcc.jjv186.full.pdf


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## Malgrave (Dec 7, 2015)

For this study, the authors performed genetic analysis of 209 patients with very early onset IBD and identified five patients with rare loss-of-function missense mutations in NOX1 or DUOX2. Importantly, these mutations were associated with reduced production of reactive oxygen species (ROS) and defective host resistance to the bacterial pathogen Campylobacter jejuni.

http://www.gastro.org/news_items/20...that-cause-rare-cases-of-very-early-onset-ibd


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