Whipple's Disease - Causes

In 1992, the bacterial nature of the disease was established (Relman, Schmidt, MacDermott, 1992). Gram-positive actinomycetes Tropheryna whippelii were identified as the infectious agent. These small gram-positive bacilli are found in large quantities in the mucous membrane of the small intestine and other organs during the active phase of the disease and disappear after intensive antibacterial therapy. A predisposing factor to the development of the disease is a dysfunction of the immune system of various origins.

Whipple's disease occurs sporadically and is so rare that no epidemic features have been established. There are no recorded cases of direct transmission from one person to another, and the entry point for infection is unknown.

Microorganisms are probably the main, but only partial, etiologic factor. Additional predisposing factors are necessary for the development of the disease, possibly defects in the immune system, but the results of relevant studies are contradictory. Humoral immunity disorders in Whipple's disease have been excluded, while cellular immunity disorders, especially the interaction of lymphocytes and macrophages, have not yet been sufficiently studied.

In response to invasion by microorganisms, reactive changes develop in the affected organs. Infiltration of tissues by large macrophages contributes to the appearance of clinical manifestations. For example, infiltration of the proper layer of the small intestinal mucosa cannot but affect absorption. Absorption occurs through slightly changed enterocytes. However, further transport of nutrients through the affected proper layer into the vessels of the mucosa and the lymphatic space is hampered, and it is even more impaired with infiltration and enlargement of the lymph nodes, since this affects the lymphatic drainage of the small intestine, which prevents the normal release of absorbed substances. However, the exact mechanism of development of the disorders detected in the organs has not yet been established. As a rule, maximum changes are found in the small intestine and mesenteric lymph nodes. In Whipple's disease, the small intestine is compacted, the folds of the mucous membrane are rough and edematous. Small yellowish nodules are sometimes visible on the serous membrane. The lymph nodes of the mesentery are sharply enlarged, an increase in the periportal, retroperitoneal and other groups of lymph nodes is possible, as well as peritonitis.

Histological examination clearly reveals damage to the structure of the intestinal mucosa. The villi of the small intestine are shortened, thickened, and deformed in places. The crypts are flattened. The proper layer of the mucosa is diffusely infiltrated with large polygonal macrophages. Their cytoplasm is filled with a large number of glycoprotein PAS-positive granules, which gives the cells a foamy appearance. These macrophages in the intestinal mucosa are pathognomonic for Whipple's disease. The proper layer may contain clusters of polymorphonuclear leukocytes. The usual cellular elements of the proper layer of the mucosa - plasma cells, lymphocytes, eosinophils - have a normal appearance. However, their content is noticeably reduced because they are replaced by a large number of macrophages. In all layers of the intestinal wall, individual dilated lymphatic vessels with fat vacuoles are found. In the extracellular space of the proper layer there are fat accumulations of various sizes. Some of them look like cavities lined with endothelium. The capillaries are dilated. Although the architecture of the villi is noticeably disrupted, the superficial epithelium is preserved. There are only focal non-specific changes. The height of the enterocytes is reduced. The brush border is sparse. There is a moderate accumulation of lipids in the cytoplasm.

Electron microscopic examination of the stratum propria of the intestinal mucosa in untreated patients reveals a large number of bacilli-like bodies 1-2.5 μm long and 0.25 μm wide. The bacilli are localized in various areas, but are found in greatest numbers in the subepithelial zone and around the vessels in the upper half of the mucosa. They are also found in PAS-positive macrophages, by which they are phagocytosed and in which they undergo degeneration and disintegration. "Whipple's bacilli" and their products are responsible for the PAS-positive granules of macrophages. In some cases, bacilli may be seen in and between epithelial cells, as well as in polymorphonuclear leukocytes, plasma cells, and endothelial cells of the stratum propria.

Under the influence of treatment, the structure of the mucous membrane gradually normalizes. Bacilli disappear from the intercellular space and after 4-6 weeks only degenerative organisms can be identified in the cytoplasm of macrophages. The number of specific macrophages in the proper layer gradually decreases, and the number of normally present cells is restored. The structure of the villi and enterocytes is normalized. However, in some cases, despite the absence of clinical manifestations, the structure of the intestinal mucous membrane may not be completely restored. Persistent foci of PAS-positive macrophages around intestinal crypts and dilated lymphatic vessels, as well as fat accumulations, may remain.

In Whipple's disease, the colon is often involved in the pathological process. In the affected areas, its mucous membrane is infiltrated with characteristic macrophages and bacilli. Detection of only PAS-positive macrophages in the colon without bacilli is insufficient for diagnosis. Similar macrophages can be found in the mucous membrane of the rectum and colon in healthy individuals and are constantly detected in histiocytosis and melanosis of the colon.

In Whipple's disease, systemic involvement has been demonstrated. PAS-positive macrophages and bacilli can be found in many organs of patients: in the peripheral lymph nodes, heart, adrenal glands, central nervous system, etc.

In many body systems, nonspecific pathological changes develop in Whipple's disease, secondary to impaired nutrient absorption: muscle atrophy, hyperplasia of the parathyroid glands, atrophy of the adrenal cortex, follicular hyperkeratosis of the skin, bone marrow hyperplasia, etc.