Gastrointestinal Complications of Hypogammaglobulinemia · associated with graft-versus-host disease. Clinically, CVID IBD causes diarrhea, rectal bleeding, and abdominal pain. Treatment

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


Yel. J Clin Immunol. 2010;30: 10–16.


CVID


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. Clin Gastroenterol Hepatol 2013;11:1050–1063.

CVID


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%.


Resnick et al. Blood 2012;119:1650-7.

CVID


CVID


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).

Documents

Gastrointestinal Complications of Hypogammaglobulinemia · associated with graft-versus-host disease. Clinically, CVID IBD causes diarrhea, rectal bleeding, and abdominal pain. Treatment