GASTROINTESTINAL COMPLICATIONS OF HYPOGAMMAGLOBULINEMIA John F. Valentine, MD University of Utah February 23, 2016 IBD ECHO
GASTROINTESTINAL COMPLICATIONS OF HYPOGAMMAGLOBULINEMIA
John F. Valentine, MD
University of Utah
February 23, 2016
IBD ECHO
Hypogammaglobulinemia may be caused by:
1. Primary immune deficiencies
2. Protein loss from the kidney, gastrointestinal tract,
lymphatic circulation, peritoneal dialysis, and skin
3. Immunosuppressive medications
• Corticosteroids
• Azathioprine
• Rituximab
4. Chemotherapy
5. Anticonvulsants
• Phenytoin
• Carbamazepine
Primary antibody deficiencies are the most common form of primary
immunodeficiency diseases.
Wide spectrum of immune deficiency ranging from a complete lack of
B cells and absent serum immunoglobulins in X-linked
agammaglobulinemia (XLA) to a reduction in only specific
immunoglobulin isotypes, such as in selective IgA deficiency.
Despite this broad difference in immunity, the antibody deficiency
syndromes share clinical manifestations, such as recurrent
sinopulmonary infections, autoimmunity, and gastrointestinal disease.
Furthermore, IgA is a key mechanism that directly influences the
function and structure of the microbiota and maintain intestinal
health1. Human gut microbiota that are IgA targets exacerbate murine
colitis while non-IgA targeted bacteria did not2.
1Stephens and Round. Cell Host Microbe. 2014;16:265-72Palm et al. Cell 2014;158:1000–1010.
Agarwal and Mayer. J Allergy Clin Immunol 2009;124:658-64
There are 4 major types of gastrointestinal manifestations
associated with humoral immunodeficiencies. The incidence:
20% to 60%
Agarwal and Mayer. J Allergy Clin Immunol 2009;124:658-64;
Clin Gastroenterol Hepatol 2013;11:1050–1063
May mimic classic forms of disease (such as celiac sprue, inflammatory
bowel disease (IBD), and pernicious anemia but differ in pathogenesis
and are often unresponsive to conventional therapies.
Selective IgA deficiency
The most common primary immunodeficiency:
~ 1 in 300 to 700 in Caucasians
Serum IgA level of less than 7 mg/dL (0.07 g/L) is considered
as selective IgA deficiency .
Serum IgA level is higher than 7 mg/dL but two standard deviations
below normal for age, the condition may be referred to as partial IgA
deficiency
The majority of IgA deficient patients are asymptomatic.
Some with IgA deficiency also have very low levels of certain IgG
subclasses (usually IgG2 and/or IgG4) which may increase
susceptibility to sinopulmonary infections, gastrointestinal infections,
allergies, autoimmune conditions, and malignancies.
Agarwal and Mayer. J Allergy Clin Immunol 2009;124:658-64.
Yel. J Clin Immunol. 2010;30: 10–16.
Agarwal and Mayer. Clin Gastroenterol Hepatol 2013;11:1050–1063
Selective IgA deficiency
There is a 10- to 20-fold increased risk for celiac disease
Nodular Lymphoid Hyperplasia (NLH) can occur with or without
giardiasis and leads to diarrhea and further malabsorption, which
might be difficult to treat, although the nodules are exquisitely
sensitive to corticosteroids.
Other associations with gastrointestinal diseases (not well defined
in the literature) include:
• Lymphomas,
• Pernicious anemia,
• Crohn’s disease,
• Ulcerative colitis,
• Chronic hepatitis,
• Biliary cirrhosis
Agarwal and Mayer. J Allergy Clin Immunol 2009;124:658-64.
Yel. J Clin Immunol. 2010;30: 10–16.
Agarwal and Mayer. Clin Gastroenterol Hepatol 2013;11:1050–1063
CVID
Agarwal and Mayer. J Allergy Clin Immunol 2009;124:658-64.
Agarwal and Mayer. Clin Gastroenterol Hepatol 2013;11:1050–1063.
Heterogeneous disorder involving defects in both humoral and cell-
mediated immunity.
Prevalence: ~ 1 in 25,000 to 50,000.
GI disease is more common in patients with CVID and XLA and IgA def
GI manifestations range from 20% to 60%.
Infections with Giardia lamblia is common as are Cryptosporidium
parvum, cytomegalovirus, Salmonella sp, C difficile, and Campylobacter
jejuni.
H pylori infection is common and might account for the incidence of
chronic gastritis (in ~1/3) and possibly gastric adenocarcinoma.
Villous flattening in the small intestine is observed in 24% to 50% of
duodenal samples from patients and does not respond to gluten
withdrawal.
CVID
Crohn-like and ulcerative colitis–like diseases is observed in 4%1.
The IBD is distinct from classic IBD and shares histologic features
consistent with lymphocytic colitis, collagenous colitis, and colitis
associated with graft-versus-host disease.
Clinically, CVID IBD causes diarrhea, rectal bleeding, and abdominal
pain. Treatment with immunoglobulin does not reverse the colitis
suggesting that inflammation is driven by T cells or other
immunoregulatory defects.
Treatment of colitis is the same as for patients with classic IBD,
including thiopurines (6MP/Azathioprine). Corticosteroids at any dose
can lead to a significant risk of infections. Anti-TNF has been used
with some benefit; however, patients should be monitored for fungal
infections
Agarwal and Mayer. J Allergy Clin Immunol 2009;124:658-64.
Agarwal and Mayer. Clin Gastroenterol Hepatol 2013;11:1050–1063.
CVID
Agarwal and Mayer. Clin Gastroenterol Hepatol 2013;11:1050–1063
NLH, especially in the small intestine, has been observed in 8%
Small bowel bacterial overgrowth: can cause diarrhea, bloating,
malabsorption. Diagnosed with breath test or response to antibiotics
when infectious causes have been eliminated.
Many patients have concurrent achlorhydria and atrophic gastritis with
B12 deficiency. B12 deficiency should be evaluated in patients with
CVID.
Liver disease, including primary biliary cirrhosis and what appears to
be autoimmune hepatitis, has been observed in patients with CVID
The cause of this ‘‘CVID hepatitis’’ is not clear, but the investigators
speculate that it is a consequence of chronic inflammation
of the gastrointestinal tract with excessive translocation of luminal
antigens into the liver.
CVID
GI malignancy is also more common in CVID patients, in
comparison with patients with IgA deficiency or XLA
Cohort of 473 CVID patients (208 male; 265 female) at Memorial
Sloan-Kettering Cancer Center (1974-1986) or Mount Sinai Medical
Center (1986-2010).
• hematologic or organ specific autoimmunity, 28.6%;
• Chronic lung disease, 28.5%;
• Bronchiectasis 11.2%;
• gastrointestinal inflammatory disease, 15.4%;
• malabsorption, 5.9%;
• Granulomatous disease, 9.7%;
• liver diseases and hepatitis, 9.1%;
• lymphoma, 8.2%;
• other cancers, 7.0%.
Agarwal and Mayer. Clin Gastroenterol Hepatol 2013;11:1050–1063
Resnick et al. Blood 2012;119:1650-7.
CVID
Resnick et al. Blood 2012;119:1650-7.
CVID
Resnick et al. Blood 2012;119:1650-7.
In this group, the risk of death in this interval was nearly 11 times
higher for CVID patients with 1 or more of the noninfectious
complications than for subjects who had infections only (hazard
ratio [HR] = 10.96; P < .0001).