Enteropathy with Epithelial Intracytoplasmic Microvillus Inclusions in a Goeldi’s Monkey (Callimico goeldii)
A captive, 701-g, 9-year-old, spayed female Goeldi’s monkey (Callimico goeldii) with a history of intermittent diarrhea beginning at 1 year of age, and a 3-month history of progressive weight loss, uremia, panleukopenia, anemia, and declining clinical condition was euthanatized and submitted for necropsy in good postmortem condition and fair nutritional status. Gross examination revealed bilateral chronic nephritis, multiple hepatic masses, and moderate diffuse glossitis.
Histologic examination revealed marked, multifocal villus atrophy with frequent crypt abscesses and crypt loss within the small intestine. Crypts within affected areas were often moderately to markedly ectatic with hyperplastic or dysplastic epithelium. The lamina propria had a moderate diffuse increase in the number of lymphocytes and plasma cells. Small numbers of epithelial cells within the apical mucosa, and rarely crypts, contained single, round, 10–30 µm diameter, intracytoplasmic inclusions which centrally contained basophilic material. Periodic acid-Schiff stains highlighted the intracytoplasmic inclusions, which exhibited a targetoid appearance. The colon also had rare intraepithelial vacuolated inclusions as well as marked, multifocal crypt abscesses and crypt loss. Small and large intestinal mucosa also contained few variably sized erosions with superficial accumulations of yeast organisms and pseudohyphae consistent with Candida sp.
Additional histologic lesions in this individual included marked, diffuse, membranoproliferative glomerulonephritis with moderate, multifocal chronic interstitial nephritis; marked, diffuse myeloid dysplasia and erythroid hypoplasia; multiple hepatic myelolipomas; moderate, diffuse glossal candidiasis; mild, multifocal myocardial fibrosis; and moderate, multifocal, thyroid cystic hyperplasia.
An area of the affected jejunum was evaluated by transmission electron microscopy, and surface epithelial cells occasionally exhibited shortened and disorganized microvilli. In other areas the integrity of the brush border was maintained. The most striking ultrastructural feature was the presence of large, intraepithelial, membrane-bound, vacuolated inclusions lined by either complete microvillus brush borders or intermittent disorganized tufts of microvilli.
Progressive weight loss and the progressive declining clinical condition in this animal were attributed to severe renal disease with likely some contribution from malabsorption due to enteric lesions. Chronic intermittent diarrhea may have been secondary to malabsorption, although this individual and other members of the colony also had several documented episodes of intestinal campylobacteriosis. Enteric and glossal candidiasis were consequences of debilitation subsequent to multiple disease processes.
Enteric changes observed in this monkey were similar to changes described in a severe, generalized enteropathy in human infants known as microvillus inclusion disease (MID), which causes intractable diarrhea, usually culminating in death.4,7 Familial cases occur, with a pattern consistent with autosomal recessive inheritance.4 The underlying etiology of MID has been localized to the cytoskeleton of the enterocyte.9 The constellation of biochemical and ultrastructural findings have led some to propose a defect of binding between actin and myosin in the terminal web as the cause.3 Others have postulated heterotopic formation of brush border proteins within the cell cytoplasm, rather than at the cell surface.4
Histopathologic hallmarks of MID are diffuse hypoplastic to normoplastic villus atrophy with normal to decreased numbers of lamina propria inflammatory cells.4,7 Enterocytes lack the normal linear brush border staining pattern with PAS, and often aggregates of PAS-positive material are noted in the apical cytoplasm.4,7 Ultrastructurally, epithelial cells often lack brush borders, or possess markedly shortened and disorganized microvilli.4,7 The apical cytoplasm frequently contains large membrane-bound vacuoles lined by microvilli, and smaller vesicular bodies containing small membrane fragments and sparsely lined by microvilli.4,7,9 Abundant secretory granules are also typically observed in the apical cytoplasm.4,7 Similar ultrastructural abnormalities are variably observed in mucosal epithelial cells of the colon, rectum, pyloric antrum, renal tubules, and gallbladder in patients with MID.4,8,9 Similar microvillus inclusions have been observed in animals or cell cultures treated with microtubule or microfilament inhibitors such as colchicine, vinblastine, and cytochalasin, and have been described in a human metastatic intestinal adenocarcinoma, and are sometimes observed in cultured Caco-2 cells, a human colonic carcinoma cell line.1,2,5-7
The histologic and ultrastructural appearance of enteric epithelial inclusions noted in this monkey were similar to microvillus inclusions and vesicular bodies of MID. Marked enteric villus atrophy was also similar, though in this case crypts were hyperplastic, not hypoplastic as in MID. Additionally, the moderate increase in lamina propria inflammatory cells was unlike MID, where normal or decreased inflammation is typical. Possibly lymphoplasmacytic inflammation in this case was a sequela of prior campylobacteriosis. The early age of onset and intractable diarrhea seen in MID were not observed, although intermittent diarrhea was noted clinically. The enteropathy in this monkey may have developed at a later age, or possibly was less severe. This monkey was not treated with any microtubule- or microfilament-inhibiting drugs, and the underlying etiology in this case remains unknown, but may be similar to MID. This is the first reported case of an enteropathy with epithelial microvillus inclusions in a nonhuman primate.
The authors acknowledge the excellent technical assistance of Jane Chladny and the Histopathology Laboratory, Laboratories of Veterinary Diagnostic Medicine, and the Ultrastructural Imaging Laboratory, Department of Veterinary Biosciences of the University of Illinois College of Veterinary Medicine.
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