Case 2 -
Malabsorption and Dysmotility Secondary to Autoimmune Polyglandular Syndrome Type 1 (APS1)
David Geffen School of Medicine, UCLA
Los Angeles, CA
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This is a case of a Persian-American female (Iranian Jewish origin) who first came to our attention at
age 6 years. She had complaints of constipation and abdominal distention for over three years. She
occasionally needed mineral oil and enemas to relieve the constipation. The abdominal distention
significantly affected her ability to eat and drink. She began to fall off her growth curve. Physical
examination showed a non tender distended soft abdomen, positive bowel sounds, no palpable mass, and no
Barium enema failed to demonstrate a stricture. The upper GI radiographic study showed marked delay
in the small bowel transit time and questionable stricture at the terminal ileum.
The girl's condition proved mysterious, but it was surmised that the questionable stricture might be
contributing to her distention and resultant reduced caloric intake. It was decided for her to undergo
surgery to examine her distal small bowel and adjacent right colon and to possibly resect it. Diagnostic
laparoscopy revealed hypermotility throughout the bowel. Exploratory laparotomy revealed a segment of
bowel with thick inspissated luminal contents in the distal ileum but no mechanical obstruction. After
consulting a pediatric gastroenterologist, it was decided to proceed with the resection of the terminal
ileum and right colon in hopes of alleviating this 'partial obstruction'.
- Negative testing for cystic fibrosis (including a DNA analysis)
- Nutritional status: albumin 3.9 gm/dL [3.7-4.8], vitamin A level 0.3 mg/L [0.3-0.9], vitamin E level
4.8 mg/L [5.6-22]
- Normal electrolytes.
The resection specimen was submitted to surgical pathology with clinical diagnosis of
'pseudo-obstruction' (despite the lack of supporting data). The specimen had a smooth and shiny serosal
surface and no obvious stricture. Upon opening, the specimen was found to contain thick stool in the
distal small bowel, but did not demonstrate a mechanical obstruction. The mucosa appeared normal. At
the ileocecal valve, the mucosal and mural folds were exaggerated. No gross photos were taken.
Photomicrographs are shown in figures 1-4.
After the surgery the patient's abdominal distention was no longer recognizable. The patient had one
to two loose stools a day but no diarrhea. One year after surgery, she had gained weight but had not
shown any catch-up in weight (5th to 10th percentile) or height (3rd percentile). She started growth
hormone therapy at 9 years.
When she was 15-years old, she was evaluated for hypocalcemia of unknown cause (ionized calcium 0.71
mmol/L [1.09-1.29], phosphorus 7.8 mg/dL [2.2-4.7]) with a history of low levels of fat soluble vitamins
despite vitamin supplements (vitamin A 0.4 mg/L [0.3-0.9], vitamin D- 25 hydroxy <7 ng/mL [30-80],
vitamin E 7.59 mg/L [5.6-22]); and zinc 60 ug/dL [60-120]). EGD with biopsy was done to 'rule out
malabsorption'. Photomicrographs are show in figures 5-10. Colonoscopy revealed retained stool, no
lesions, and no biopsies were taken.
In light of the immunohistochemical findings, immunostains were also performed in the resection
specimen from nine years prior. A photomicrograph is shown in figure 11.
Case 2 - Figure 1
Full thickness small bowel from resection specimen at age 6
Case 2 - Figure 2
Colonic mucosa and submucosa from resection specimen at age 6
Case 2 - Figure 3
Small bowel muscularis propria and myenteric plexus from resection specimen at age 6
The key microscopic finding is the marked paucity of endocrine cells in the small intestinal, gastric
and colonic mucosa (figures 2, 5, 6- 8, 11). Stains for chromogranin A confirmed a marked reduction in
endocrine cells. Normally, a large fraction of enteroendocrine cells may be seen on H&E stained
slides by examining the epithelium for cells with subnuclear red granules. In the stomach, antral G
cells can be identified in epithelium by examining for clear cytoplasm that gives the cell a perinuclear
halo. The best way to confirm an absence of gut endocrine cells is with immunohistochemistry for
chromogranin A. Two to five chromogranin A positive endocrine cells are seen per gland. In this case,
pertinent negative microscopic findings include a lack of enterocolonic inflammation. Also, no
abnormalities of the enteric musculature or nerve plexuses were seen.
Esophageal candidiasis is seen with PAS (figure 10). There is a mild lymphoplasmacytic infiltrate see
in the antral and oxyntic mucosa (figures 7 and 9). The oxyntic mucosa shows neutrophilic inflammation
including microabscesses in the foveolar pits. No atrophy is present. No metaplastic changes are
Malabsorption and dysmotility secondary to autoimmune
polyglandular syndrome type 1 (APS1)
The key histological hallmarks are the paucity of endocrine
cells in the stomach, small bowel and colon. The esophageal candidiasis can be counted as strongly
supporting the clinical diagnosis but only in the correct context. The chronic active oxyntic gastritis
is compatible with the disease, but is otherwise the least of the positive findings. Sequencing of the
autoimmune regulator gene (AIRE), and finding homozygous mutations of both
alleles confirmed the diagnosis. The disease is also known by the abbreviation APECED (autoimmune
polyendocrinopathy candidiasis ectodermal dystrophy). Recently, the patient has developed autoimmune
adrenal insufficiency. She has not developed hypoparathyroidism.
Autoimmune polyglandular syndromes (APS) were initially defined as a multiple endocrine gland
insufficiency associated with an autoimmune disease. APS1 is characterized by presence of chronic mucocutaneous candidiasis, hypoparathyroidism,
and adrenal insufficiency. Classically, two of the three are required for the
clinical diagnosis of APS1. The disease is usually diagnosed by age 10y. Patients routinely exhibit a
variable number of other autoimmune manifestations including thyroiditis, type 1diabetes, gonadal
failure, hepatitis and other manifestations summarized in table 1. These secondary features differ widely
from patient to patient, even between siblings with exactly the same genetic lesion and similar
environmental exposures. APS2 shares adrenal insufficiency with APS1, it primarily affects adults.
Table 1. APS1 Manifestations
|CLASSIC ||GASTROINTESTINAL/LIVER/PANCREAS ||OTHER|
|Mucocutaneous candidiasis ||Chronic hepatitis ||Hypogonadism|
|Hypoparathyroidism ||Chronic atrophic gastritis ||Alopecia|
|Adrenal insufficiency ||Esophageal candidiasis ||Vitiligo|
| ||Pernicious anemia ||Sjogren syndrome|
| ||Malabsorption ||Autoimmune thyroid disease|
| ||IDDM ||Keratoconjunctivitis|
| ||Chronic diarrhea ||Hypophysitis|
| ||Severe constipation (obstipation) ||Turner syndrome|
| || ||Hemolytic anemia|
| || ||Vasculitis|
| || ||Growth hormone deficiency|
By far the most pronounced gastrointestinal manifestation is malabsorption. The malabsorption is
believed to be due to the loss of endocrine cells, particularly the small intestine. The loss of
endocrine cells is due to autoimmune destruction. The role of enteroendocrine cells include regulation
of all aspects of gut function such as motility, secretion, absorption, sensing, and even metabolism
. For example, fat malabsorption in an APS1 patient was tied to loss of CCK expressing cells, loss of
serum CCK, and decreased bile secretion . However, with the loss of nearly all endocrine cells the
mechanism of gut dysfunction is likely more complex. A list of GI-pancreatic endocrine cells and their
products is given in table 2. A loss of all enteroendocrine cells is known to cause generalized
malabsorption, not just fat malabsorption, more consistent with the extensive role of enteroendocrine
cells . It is important to stress that no histologically identifiable inflammation of the small
intestine or colon accompanies the loss of enteroendocrine cells in APS1.
Table 2. GI-Pancreatic Endocrine Cells 
|CELL TYPE ||PRODUCT|
|PP ||Pancreatic polypeptide|
The gastric manifestations of APS1 are distinct from the small bowel and colonic disease. The gastric
mucosa may be visibly inflamed in a manner nearly identical to adult type atrophic gastritis.
Lymphoplasmacytic inflammation and neutrophils are seen. There is a loss of parietal cells, but
metaplastic changes are not typical . The atrophy may be due to the autoimmune destruction of
parietal cells, but may also be due to chronic hypogastrinemia. The hypogastrinemia is due to G cell
Finally, the list of GI, hepatic, and pancreatic involvement continues with varying penetrance .
Despite the problem of malabsorption, some patients have protracted constipation via an unknown
mechanism. Esophageal candidiasis is common, and chronic esophageal candidiasis has resulted in squamous
carcinoma in some. Systemic sepsis from Candida does not occur due to adequate B cell function.
Occasionally, chronic hepatitis can be seen, and rare cases of fatal fulminant hepatitis have been
reported. Type 1 diabetes secondary to beta cell destruction in the pancreas is part of the spectrum of
The disease is due to inherited defects in the AIRE (autoimmune
regulator} gene, the p attern of inheritance is autosomal recessive
Over 60 mutations have been
localized in the AIRE gene of different patients with APS1. This disease is
uncommon, the Johns Hopkins Autoimmune Disease Research Center puts the incidence at 1 in 100,000 (by
comparison, Peutz Jeghers incidence is 1 in 120,000). The most highly affected populations are Finns,
Sardinians, and Iranian Jews. The discovery of the specific gene mutation has expanded the diagnostic
repertoire beyond the classical triad. Now a patient with some combination of APS1 manifestations (table
1) can be referred for gene sequencing and have the diagnosis confirmed.
The pathophysiology of APS1 is three fold. The first is the loss of AIRE
function, leading to autoimmunity. The loss of function affects self tolerance to antigens mediated in
the thymus . AIRE has a role in the expression of tissue restricted
antigens in the thymus and therefore thymic selection. AIRE also has a role
in selecting T regulatory cells (Tregs) for the maintenance of peripheral tolerance. The second aspect
of APS1 is related to the organ(s) damaged by autoimmunity. Endocrine deficiencies predominate.
Parathyroid and adrenal glands are injured, leading to hypocalcemia and adrenocortical insufficiency.
For instance, a patient may present with tetany secondary to hypocalcemia (typically due to PTH
deficiency, but malabsorption may play a role here). Of note, malabsorption secondary to loss of gut
endocrine cells may be the earliest endocrine manifestation of APS1 . In addition to endocrine
organs, other tissues such as nail, enamel, liver and gastric mucosa are injured by autoimmunity. The
third pathology is immune dysfunction leading to mucocutaneous candidiasis. This appears to be a risk
factor for oral and esophageal squamous cell carcinoma in APS1 patients.
The differential diagnosis in this case is variable depending on which clinical problem or
pathological finding is considered dominant. The clinical problem list includes: growth retardation,
malabsorption, growth hormone deficiency, constipation, and hypocalcemia. The differential diagnosis for
each problem is beyond this forum, but a disease involving the gastrointestinal tract
is likely based on the problems- growth retardation, malabsorption, constipation, and even
hypocalcemia; however, growth hormone deficiency does not directly
relate to GI disease. The value of the gastrointestinal biopsies and the earlier resection is high, and
ultimately lead to the diagnosis of APS1. The histopathological problem list was remarkable for nearly
absent gastroenteric endocrine cells, gastritis, and esophageal candidiasis
1. Clinical problem: Malabsorption. Malabsorption can contribute to growth retardation and
hypocalcemia. Causes of malabsorption include celiac sprue, infection, Crohn disease, short gut,
abetalipoproteinemia, microvillus inclusion disease, tufting enteropathy, pseudo-obstruction, autoimmune
enteropathy, enteroendocrine cell dysgenesis, and APS1.
- Infection/inflammation: The lack of intestinal inflammation or identification of any pathogenic
organisms rules out much of the differential including infection, celiac sprue, Crohn disease, autoimmune
-Short gut: She did not have short gut (defined as length less than 200cm or 50% reduction in gut
-Congenital: Her disease did not present congenitally and she did not show the lipid laden
enterocytes of abetalipoproteinemia or the villus blunting and epithelial alterations of tufting
enteropathy or microvillus inclusion disease. Enteroendocrine cell dysgenesis presents congenitally and
can be excluded, but it shares some histopathology with APS1 in the gut, namely a severe paucity of
enteroendocrine cells (see below).
2. Clinical Problem: Pseudoobstruction (PO). This patient had symptomatic constipation. No
mechanical obstruction was identified. A request to rule out PO was made. For completeness sake the
major morphologically identifiable causes of pseudoobstruction were excluded, these include neuropathies,
myopathies, Cajal cell abnormalities.
- Neuropathy: The presence of ganglion cells excluded Hirschprung disease. No megamitochondria or
peripheral neuropathy excluded mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). No
inflammatory neuropathy was found thus ruling out paraneoplastic and granulomatous visceral neuropathy.
The criteria for neuronal intestinal dysplasia remain controversial, and thus a search for a neuropathy
-Myopathy: No atrophy of any layer of muscle to suggest visceral myopathy was present. No
inflammation to suggest leiomyositis was seen.
-Cajal cell loss. Cajal cells were appropriately identified immunohistochemically by CD117
immunohistochemistry in the original resection (not shown), thus their absence was ruled out.
- Endocrinopathy: various endocrine disorders can result in PO but few are identifiable by GI
histopathology. Diabetes and hypoparathyroidism have clinical overlap with APS1, and therefore
technically are viable elements to the differential diagnosis (table 1). Some APS1 patients are known to
have chronic constipation.
3. Histopathological finding: Paucity of endocrine cells. There are three conditions where a marked
paucity of gut endocrine cells occurs. They are APS1, autoimmune enteropathy, and enteroendocrine cell
-Autoimmune enteropathy: In some cases, autoimmune enteropathy loses secretory cells including
goblet, Paneth and endocrine cells . Autoimmune enteropathy can be excluded since it demonstrates
inflammation, a feature absent from the small intestine and colon in this case. In addition, no loss of
goblet or Paneth cells was seen. Subsets of autoimmune enteropathy patients have mutations in the FOXP3
gene, but not AIRE.
- Eenteroendocrine cell dysgenesis (ECD). ECD presents congenitally with generalized malabsorption
and may later develop diabetes, has no inflammation, and nearly no endocrine cells in the small intestine
ECD stomachs remain populated with endocrine cells, unlike the current case. ECD
patients have mutations in the neurogenin 3 gene, but not AIRE.
Only APS1 appears in the above breakdown of various approaches to the differential
diagnosis. Classically APS1 should be diagnosed based on 2 of the following: adrenal insufficiency,
hypoparathyroidism, and mucocutaneous candidiasis. However, a patient presenting with a number of
findings from table 1
many of which are in the realm of gastrointestinal pathology, should be
genetically tested for APS1 to make the diagnosis.
Acknowledgements: Dr. Ananya Manuyakorn assisted in researching this topic.
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