Page 1051 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1014 Part seven Organ-Specific Inflammatory Disease

most frequent and significant gut manifestations, and these are agammaglobulinemia infrequently develop overt GI disease (they
discussed in detail below. However, a variety of inherited condi- lack B cells but have functionally intact T-cell populations). Even
tions of broad lymphocyte or innate immune cell dysfunction persons with selective IgA deficiency have little in the way of GI
can also lead to gut disease. The study of monogenic diseases disease, including infections. In fact, the T-cell dysfunction that
that are associated with inflammatory diseases of the gut have often accompanies CVID may contribute substantially to sus-
come to the attention of investigators, as they may be models ceptibility to GI disease.
for the mechanisms that could contribute to the pathophysiology In terms of an increased GI infection risk, autoimmune
of more genetically complex conditions, such as Crohn disease gastritis-induced achlorhydria could increase small-bowel
and UC. 68 exposure to swallowed commensals and pathogens escaping this
innate gastric barrier to infection. In addition, although the loss
Common Variable Immunodeficiency of secreted IgA alone is not enough to meaningfully increase
CVID is a syndrome of hypogammaglobulinemia (low levels of susceptibility to intestinal infections, perhaps the additional loss
IgG and IgA and/or IgM) accompanied by recurrent sinopul- of IgG and IgM and presence of T-cell dysfunction is more
monary infections (Chapter 34). Patients have no isohemag- permissive, but no mechanism for this has been established.
glutinins and cannot mount an adequate antibody response to Mucosal nodular lymphoid hyperplasia, characterized by disor-
many vaccine antigens. In general, Ig replacement therapy ganized secondary lymphoid nodules with poorly formed germinal
improves the sinopulmonary infection rate but does not affect centers, is likely related to the inability of B cells to undergo
other complications, such as autoimmune disease and GI class switching when presented with antigen in situ. Last, CVID
symptoms, including intestinal infections. Case series of patients enteropathy is characterized clinically by severe malabsorption
with CVID have shown that up to 60% of patients experience and histologically by blunted villi and increased intraepithelial
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GI symptoms and that endoscopic and histological abnormalities lymphocytes, and epithelial apoptosis is associated with excess
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can occur in the majority of patients with CVID. When consider- Th1 cytokine secretion (IL-12 and IFN-γ). It remains unknown
ing the differential diagnostic possibilities for the GI complications why this inflammatory lesion occurs in the first place.
of CVID, it is helpful to separate them into infectious, immune-
mediated, and neoplastic processes. Among the infectious agents, Diagnosis
Giardia lamblia, nontyphoidal Salmonella, and Campylobacter The workup of GI complications of CVID often takes place as
jejuni are frequently seen, but Cryptosporidium may also be found, symptoms are usually first episodic but may eventually turn into
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and C. difficile and viral agents (CMV) may be encountered. In chronic, progressive complaints. The key to successful diagnosis
addition to the higher rate of gastric H. pylori infection, small- is the initial search for treatable infectious causes. This requires
intestinal bacterial overgrowth (SIBO) is present in up to 30% stool assay and culture for bacterial (especially Campylobacter)
of patients with CVID. The immune-mediated GI complications and protozoal pathogens. In addition, hydrogen breath testing
of CVID include idiopathic enteropathy (villous atrophy, increased can help detect SIBO to provide another antibiotic-responsive
intraepithelial lymphocytes/microscopic colitis, nodular lymphoid etiology of the symptoms.
hyperplasia) (Fig. 75.1F) manifesting as severe malabsorption Negative results for infectious causes require endoscopy for
(see below) and, much less frequently, macroscopic ulcerating biopsy of the proximal small intestine and colon. Routine histology
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disease resembling UC or Crohn disease. CVID-associated will detect the features of enteropathy, including blunted villi
autoimmune disease involving the GI tract also includes type II and increased IELs, which are often interpreted as celiac disease.
gastritis that can lead to achlorhydria and vitamin B 12 deficiency Unlike celiac disease, there usually is a lack of plasma cell infiltrate
(“pernicious anemia”) and even autoimmune hepatitis and and crypt hyperplasia, as well as a preserved brush border and
primary biliary cirrhosis. Last, neoplastic complications of Goblet cells, and there is often an increase in epithelial cell
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intestinal lymphoma and gastric adenocarcinoma (related to apoptosis, particularly in the colon. In fact, some of the villus
achlorhydric autoimmune gastritis) have been reported. changes in CVID enteropathy can be mimicked by SIBO, which
should be investigated as described above. If the diagnosis of
Presentation celiac disease must be considered, then genetic testing for celiac
The most common symptom of GI complications of CVID is susceptibility HLA alleles should be performed; the absence of
episodic diarrhea that can progress to chronic diarrhea, regardless combinations of A and B alleles for HLA-DQ2 or -DQ8 that
of the etiology. Weight loss and evidence of vitamin or mineral confer risk will rule this out. However, even if celiac disease gene
deficiencies may occur, with underlying maldigestion or mal- alleles are detected, it still does not indicate that this is a gluten-
absorption. In addition, patients may present with abdominal driven celiac disease lesion but will require a trial of GFD
pain related to splenomegaly (with or without portal hyperten- nonetheless. The functional significance of any histological lesion
sion) or ascites (portal hypertension secondary to hepatic nodular in the small intestine can be evaluated by a measure of steatorrhea
regenerative hyperplasia [NRH] as a known complication of (fecal fat excretion) and small-bowel absorption (d-xylose
CVID). Fever, together with intestinal obstruction and GI bleeding, absorption test), values that can be used to track improvement
may indicate the development of small-bowel lymphoma. Patients following treatments.
with CVID may report increased frequency of GERD symptoms
as well as dyspepsia, but these complaints are nonspecific and Treatment
have been difficult to link with immune defects or autoimmune None of the GI complications of CVID is treated by
complications. intravenous or subcutaneous immunoglobulin (IV/SCIG) (initial
treatment might alleviate GI symptoms, it does not treat overt
Immune Pathophysiology gut inflammation and ulcers), and in fact, these complications
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It is not clear if lack of Igs alone causes susceptibility to gut typically occur in patients who have adequate trough levels of
infections and inflammation because patients with X-linked IgG. Patients with any bacterial or protozoal pathogens should be