Whipple’s disease with aortic regurgitation requiring aortic valve replacement

Summary Cardiac involvement in Whipple’s disease is well established. However, clinical consequences beside antibiotic therapy have rarely been reported. Our observation of a middle-aged man with increasing dyspnea, fatigue, chest pain, and dizziness leading to admission to a cardiology department demonstrates that cardiac symptoms may represent the main symptoms in patients with Whipple’s disease. The diagnosis was not made prior to upper endoscopy, performed because of diarrhea, and revealed Whipple’s agent now classified asTropheryma whippelii, which is a PAS-positive rod-shaped bacterium in the macrophages of the intestinal lamina propria. The aortic valve was replaced after the intestinal symptoms were resolved by antibiotic treatment reducing the number of infectious agents in the duodenal mucosa. Histological analysis of the aortic valve demonstrated the presence of PAS-positive rod shaped material as the most likely cause of aortic insufficiency. Five months after valve replacement, the patient had completely recovered from intestinal and cardiac symptoms. Still under antibiotic treatment 16 months later, no more PAS-positive macrophages were detectable in the intestinal mucosa.     

Zinc plasma levels after oral zinc tolerance test in nonalcoholic cirrhosis

Zinc absorption was examined in 25 nonalcoholic cirrhotic patients using the oral zinc tolerance test and comparing results to a healthy control group. With 22.5 mg elementary zinc, the increase in plasma zinc was significantly lower in the cirrhotic patients than in the control group with P less than 0.01 in the first and second hours and P less than 0.05 in the fourth hour. The zinc malabsorption may result from an abnormal small intestinal mucosa. Indeed small intestinal biopsies in all patients showed partial shortening and prominent distension of villi and intense stromal edema with inflammatory cell infiltration of the lamina propria. However, it is not clear whether these intestinal changes are due to zinc deficiency or to portal hypertension. Thus zinc malabsorption appears to contribute to zinc deficiency in nonalcoholic cirrhotics and seems to result, in part, from pathological changes in the mucosa.     

The cell population of the upper jejunal mucosa in tropical sprue and postinfective malabsorption

The cell population of the upper jejunal mucosa has been studied in cases of tropical sprue from the Far East and Middle East, and in similar cases arising in western Europe (`post-infective malabsorption'), and compared with cases of untreated coeliac disease and patients without small bowel disease.

Infiltration of the epithelial layer of the upper jejunal mucosa by lymphocytes was found in tropical sprue to the same extent as in coeliac disease, and, to a lesser extent, in `postinfective malabsorption'.

In the lamina propria, in all forms of acute sprue there was an increased density of lymphocytes. With increasing duration and with increasing mucosal atrophy, the lymphocytes were progressively replaced by plasma cells, and the cellular infiltration in chronic sprue was indistinguishable from that of coeliac disease.

The findings suggest that a humoral antibody response is a feature of sprue, and becomes more prominent as the condition becomes chronic.

     

Intestinal pseudoobstruction caused by diffuse lymphoid infiltration of the small intestine

Four young women presented with diarrhea, malabsorption, and intestinal pseudoobstruction. Intestinal biopsy specimens (both peroral and full-thickness) showed flat small intestinal mucosa, sparsity of crypts, and a widespread lymphoid infiltrate in the lamina propria, muscularis propria, and myenteric plexus. There was no neuron or nerve fiber loss or damage in the plexus; muscle cell absence in the vicinity of lymphoid cell infiltration in the muscularis propria probably accounted for the pathogenesis of pseudoobstruction. Immunochemical stains showed that the infiltrate was polyclonal, and none of the patients has developed lymphoma on clinical follow-up of 4-16 yr. Transient improvement in symptoms occurred after antibiotic therapy in 3 patients, and 1 patient had improvement after treatment with cyclophosphamide and prednisone; however, symptoms of pseudoobstruction persist in all. These cases illustrate yet another cause of intestinal pseudoobstruction which is histologically distinct from visceral myopathies and neuropathies. The pathogenesis of this illness may be related to that of diffuse immunoproliferative diseases seen in Third World countries.     

Lymphocytic gastritis in patients with celiac sprue or spruelike intestinal disease

A distinctive form of gastritis, characterized by lymphocytic infiltration of pit epithelium, has recently been described in association with evidence of Campylobacter pylori infection. We have evaluated simultaneous small bowel and gastric biopsies from 22 patients with diarrhea or malabsorption, all of which showed small bowel changes characteristic of sprue or spruelike disease. In 10 of 22 patients, striking lymphocytic gastritis was identified. Cases positive for lymphocytic gastritis had a mean of 46.5 lymphocytes per 100 epithelial cells, compared with a mean of 3.5 in normal gastric controls and 5.1 in abnormal controls, including cases with Campylobacter gastritis. Concurrent small bowel biopsies had a mean of 47.2 lymphocytes per 100 epithelial cells. Cases without lymphocytic gastritis had means of 10.8 and 39.9 lymphocytes per 100 gastric and intestinal epithelial cells, respectively. Campylobacter organisms were identified in only 1 of the 10 patients with lymphocytic gastritis and in 3 of the 12 patients without lymphocytic gastritis. Intraepithelial lymphocytes in small bowel and stomach were positive for the antibody MT-1, indicating a T-cell infiltrate at both sites. These findings suggest that lymphocytic gastritis may occur as a manifestation of celiac sprue or spruelike disease and that the lymphocytic infiltration of celiac sprue may affect gastric epithelial mucous cells.     

Hypersensitivity reactions in the small intestine. 2. Effects of allograft rejection on mucosal architecture and lymphoid cell infiltrate.

Small intestinal mucosa contains both thymus dependent and thymus independent lymphoid cells and thus has the capacity to act via humoral and cellular mechanisms as a site of local immunity and local hypersensitivity. Allograft rejection of mouse small intestine is a model of a local cell mediated reaction. The effects of this clearly defined, immunologically mediated damage villi, crypts, enterocytes, and lymphoid cell infiltrate have been assessed by comparing the morphology of rejecting allografts with that of isografts and normal small intestine of the same age. In rejection there is infiltration of the lamina propria with lymphocytes, hyperplasia of the crypts of Lieberkuhn, and an eventual sloughing off of the mucosa. Usually, but not always, there is villous atrophy and increased numbers of intraepithelial lymphocytes. However, the morphology of individual enterocytes remains normal throughout rejection and neither plasma cells nor polymorphonuclear leucocytes infiltrate the lamina propria before mucosal ulceration. These results show unequivocally that a local T cell mediated immune response causes villous atrophy and crypt hyperplasia in this animal model, and since there is no evidence of local enterocyte cytotoxicity, a lymphokine may be the link between the activated T cell and the effects on mucosal architecture. We suggest that a local CMI reaction may be the cause of villous atrophy, crypt hyperplasia, and malabsorption in many clinical and experimental conditions, including coeliac disease, food allergy, and intestinal infections.     

Update on collagenous sprue

Collagenous sprue has traditionally been defined as a small intestinal mucosal disorder characterized by persistent diarrhea, severe malabsorption with multiple nutrient def iciencies and progressive weight loss. Pathologically, a severe to variably severe “flattened“ mucosal biopsy lesion with distinctive sub-epithelial deposits in the lamina propria region is detected. Histochemical stains and ultrastructural studies have conf irmed that these deposits contain collagens. Often, an initial diagnosis of cel...     

Refractory celiac disease

Celiac disease is a gluten-sensitive enteropathy, characterized by villous atrophy, which is reversed by gluten withdrawal. A minority of patients with celiac-like enteropathy are resistant to gluten-free diet, so-called refractory sprue, or unclassified sprue. Refractory sprue is a diagnosis of exclusion; all other causes of a celiac-like enteropathy must be eliminated before a diagnosis of refractory sprue can be made. Recent evidence suggests that refractory sprue comprises a heterogenous group of patients with diverse underlying causes. A small proportion of these patients seem to have an adult form of autoimmune enteropathy, characterized by the presence of antienterocyte antibodies. However, a larger group of patients with refractory sprue now seem to have a cryptic intestinal T-cell lymphoma, characterized by the presence of phenotypically abnormal, monoclonal intraepithelial lymphocytes, despite benign cytology. Current therapeutic options include nutritional support and immunosuppressive therapy, but response is variable. The prognosis of refractory sprue may be poor; patients may die of severe malabsorption, or through synchronous or metachronous development of an enteropathy-associated T-cell lymphoma. Based on this recent evidence, patients with refractory sprue should be screened for antienterocyte antibodies and have T-cell receptor and monoclonal antibody studies performed; this could facilitate identification of cases of adult-onset autoimmune enteropathy and those of cryptic T-cell lymphoma. Moreover, early recognition of the malignant nature of the intestinal infiltrate in some cases of refractory sprue could permit the development of novel chemotherapeutic regimens for this condition.     

Whipple’s Disease: A Rare Disease Revisited

Since the original postmortem diagnosis of “intestinal lipodystrophy” by Dr. George H. Whipple in 1907, the complexities of Whipple’s disease have been elucidated through case reports. Universally fatal prior to the advent of antibiotics, Tropheryma whipplei is increasingly recognized as an organism that can be treated only if the clinician seeks to identify it. Whipple’s disease is primarily a gastrointestinal disease manifesting as a malabsorption syndrome, and is detected through endoscopy and intestinal biopsy. Nongastrointestinal manifestations of the disease, although less common, are reported and have aided in its recognition as a multiorgan disease entity. Because of its rarity, treatment recommendations are currently based on observational studies and on one recent prospective study, which outlined induction therapy followed by several months of suppressive maintenance therapy to prevent relapse, which is often characterized by neurologic symptoms.     

Autoimmune Enteropathy with Severe Atrophic Gastritis and Colitis in an Adult: Proposal of a Generalized Autoimmune Disorder of the Alimentary Tract

Background: We describe the case of an adult with autoimmune enteropathy consistent with both severe atrophic gastritis accompanying antral stenosis and colitis. Methods and Results: The patient, positive for anti-intrinsic factor antibody, had intractable diarrhea and protein-losing enteropathy. In the ileum inflammatory cells were observed infiltrating the lamina propria along with villus atrophy, and similar inflammation was also found in the lamina propria of the colon and stomach, with complete loss of specialized glands. The myenteric ganglion cells of the hypertrophied muscularis propria in the stenosed antrum showed degeneration with surrounding T-lymphocyte infiltration. There were more CD8⁺ than CD4⁺ lymphocytes in the lamina propria of the stomach and colon. Conclusions: The CD8⁺ (suppressor-cytotoxic) T lymphocytes may have played an important role in the production of lesions in the stomach, small intestine, and colon, so we propose this case as an example of a generalized autoimmune disorder of the alimentary tract.     

Clinical features and diagnosis of celiac disease

Celiac disease is a life-long enteropathy caused by an intolerance to gluten. The pathologic lesion of the small intestinal mucosa is characterized by the loss of absorptive villi, crypt cell hyperplasia, and infiltration of the lamina propria with inflammatory cells. The clinical presentation of celiac disease varies greatly depending on patient's age, duration and extent of the disease, and the presence of extraintestinal manifestations. The classical symptoms like diarrhea, weight loss and abdominal pain are seen less common. Unfortunately, most patients with celiac disease have either silent or atypical presentations, thus escaping diagnosis for several years. The pathologic changes and symptoms resolve when gluten is excluded from the diet for a sustained period. Untreated celiac disease is associated with significant risk of the development of enteropathy-associated intestinal lymphoma.     

Einheimische Sprue (Zöliakie)

Celiac disease is a life-long enteropathy caused by an intolerance to gluten. The pathologic lesion of the small intestinal mucosa is characterized by the loss of absorptive villi, crypt cell hyperplasia, and infiltration of the lamina propria with inflammatory cells. The clinical presentation of celiac disease varies greatly depending on patient’s age, duration and extent of the disease, and the presence of extraintestinal manifestations. The classical symptoms like diarrhea, weight loss and abdominal pain are seen less common. Unfortunately, most patients with celiac disease have either silent or atypical presentations, thus escaping diagnosis for several years. The pathologic changes and symptoms resolve when gluten is excluded from the diet for a sustained period. Untreated celiac disease is associated with significant risk of the development of enteropathy-associated intestinal lymphoma.     

Collagenous enterocolitis: a manifestation of gluten-sensitive enteropathy.

We report coexistent collagenous colitis and collagenous sprue in a 62-year-old woman with diarrhea. Investigations suggested malabsorption, and small intestinal biopsies demonstrated a flattened mucosa with subepithelial collagen deposition. Colonic biopsies also showed a thickened subepithelial collagen band as well as a striking lamina propria inflammatory cell infiltrate. Symptomatic remission was induced with a gluten/lactose-free diet, oral prednisone, and sulfasalazine and has been maintained with gluten restriction alone. Repeat biopsies after 2 months demonstrated restoration of normal small intestinal and colonic collagen bands; only a chronic inflammatory cell infiltrate (consistent with microscopic/lymphocytic colitis) persisted in colonic biopsies. We propose that, in this instance, collagenous enterocolitis represented a diffuse manifestation of gluten sensitivity.     

Tropical sprue

Opinion statement Tropical sprue is a disease that causes progressive villus atrophy in the small intestine, similar to nontropical (celiac) sprue. The loss of intestinal villi profoundly affects intestinal absorptive function, and patients with tropical or nontropical sprue present with malabsorption. Whereas the etiology of celiac sprue has been elucidated in considerable detail, the etiology of tropical sprue remains obscure. The favored hypothesis is that the disease is either initiated or sustained by a still-undefined infection. Patients with tropical sprue typically present with macrocytic anemia due to malabsorption of folate and/or vitamin B₁₂.Treatment of tropical sprue with folic acid replacement was introduced more than 50 years ago and has become standard medical treatment. Vitamin B₁₂Replacement is usually added if there is evidence of B₁₂deficiency or malabsorption. Treatment of tropical sprue with folate and B₁₂cures the macrocytic anemia and the accompanying glossitis, and often results in increased appetite and weight gain. However, even prolonged treatment with these vitamins fails to restore villus atrophy, and malabsorption usually persists. The benefit of antibiotic treatment of tropical sprue was first documented during World War II, when sulfonamides were used to treat epidemics of tropical sprue in British and Italian troops in India. Antibiotic treatment has since become the standard treatment, and tetracycline has replaced sulfonamides. The recommended length of treatment with tetracycline is 6 months and it is given in combination with folate. The treatment has been shown to normalize mucosal structure in the small intestine and resolve malabsorption in most patients with tropical sprue. However, there is a substantial relapse rate in treated patients who return to, or remain in, endemic areas in the tropics.     

Approaching the patient with chronic malabsorption syndrome.

The causes of chronic malabsorption may be categorized as decreased intestinal absorption, most commonly caused by celiac sprue; or maldigestion caused by pancreatic insufficiency. The initial step in the evaluation of these patients should include stool studies to confirm fat malabsorption. If fat malabsorption is confirmed, endoscopy with small-bowel biopsies and aspirates for bacterial culture usually follows. A normal endoscopic examination should lead to assessment of pancreatic function. In the setting of normal pancreatic function and the absence of bile acid deficiency, a barium radiograph of the small bowel should be made, looking for anatomical abnormalities. Celiac sprue is an intolerance to gluten caused by a combination of genetic, environmental, and immunologic factors. It classically causes malabsorption. However, it is likely that many patients who exhibit only minor manifestations of the disease go unrecognized and untreated. A presumed diagnosis of celiac sprue is confirmed after a clinical and endoscopic response to a gluten-free diet. Serological markers are available with high degrees of sensitivity and specificity, but duodenal biopsy remains the gold standard for diagnosis. A minority of patients are unresponsive to a gluten-free diet, and intestinal lymphoma should be suspected in these cases.     

The Vascular Architecture of the Different Forms of Small Intestinal Villi in the Rat (Rattus norvegicus)

The vascular anatomy of the intestinal villi in the rat was studied by injection with Indian ink and silicone rubber. The vascular pattern in finger- leaf- and tongue-shaped villi is the same. One central arteriole divides into two marginal vessels, giving rise to a capillary net, which in turn collects into two para-axial venues. In ridge-shaped villi there are multiple arterioles and venules. It appears that finger-shaped villi turn into leaf-shaped villi by lateral upgrowth of the lamina propria, and that ridge-shaped villi are also formed by upgrowth of the lamina propria between adjacent leaf-shaped villi.     

The Radiology Corner

Recent advances in immunology have permitted recognition of a group of patients who have gastrointestinal manifestations as part of an immunoglobulin deficiency syndrome. Such immunoglobulin deficiency may be primary or may be secondary to a variety of diseases. We have classified and described the small bowel roentgen features associated with the various immunoglobulin deficiency syndromes as follows: 1. the sprue pattern, as seen in hypogammaglobulinemic sprue and in Ig-A deficient sprue; 2. multiple nodular defects; 3. inflammatory changes secondary to giardiasis, associated with immune deficiency diseases; 4. thickening of the small intestinal folds, as seen in the plasma cell dyscrasias, lymphoma, intestinal lymphangiectasia and amyloidosis.     

Update on gluten-sensitive enteropathy.

Gluten-sensitive enteropathy is a disease in which the small intestinal mucosa of susceptible persons is damaged after eating gluten-containing foods. The damaged intestinal mucosa is incapable of normal function, and the affected patients have malabsorption of one or more dietary components. The childhood and adult forms of the disease are identical.The small intestinal lesion is characterized by villus flattening, cuboidal epithelial cells and infiltration of the lamina propria with lymphocytes and plasma cells. The diagnosis in all cases must be confirmed by intestinal biopsy before and after treatment with a gluten-free diet, since other conditions may produce a similar lesion. The post-treatment biopsy should disclose reversion towards normal. Treatment with a gluten-free diet is lifelong.Various theories have been proposed to account for the pathogenesis of the gluten-induced damage. These include the presence of an enzyme deficiency which allows toxic degradation products of gluten to accumulate and kill the epithelial cell; the presence of surface receptors which allow binding of gluten to the cell surface with cell death the result. A third theory states that immune factors are important since antigluten antibodies are made in the mucosa, and cortisone inhibits the lesion in vivo and in vitro. Genetic studies show a familial pattern of the disease and a preponderance of histocompatibility antigens, HLA-B8 and HLA-DW3. An in vitro technique of culturing biopsy specimens may be useful in making a diagnosis.     

Flow cytometric analysis of intestinal intraepithelial lymphocytes in the diagnosis of refractory celiac sprue

The etiology of refractory celiac sprue (RCS) is unclear. In a high proportion of cases, the clonal nature of intestinal intraepithelial lymphocytes (IEL) can be demonstrated and a pathogenetic implication of intestinal IEL has been postulated. The prognosis of this subgroup of RCS is poor, with a high risk to develop an overt lymphoma and uncontrolled malabsorption despite steroid/immunosuppressive therapy. Cases with a relatively indolent clinical course, however, exist and their early diagnosis may be difficult. To gain insight into the pathogenic implication of intestinal IEL in refractory celiac sprue, we have performed an extensive phenotypic and functional characterization of clonal intestinal IEL in a patient with an indolent form of refractory celiac sprue, using multiparametric flow cytometry. The abnormal lymphocyte infiltrate lacked surface membrane expression of CD3/T-cell receptor (TCR) complexes (TCR(-), CD4(-), CD8(-), sCD3(-)), but contained intracellular CD3(epsilon) (CyCD3(+)) and surface CD103(+) and CD7(+). In particular, these cells showed a unique spontaneous ex-vivo cytokine secretion profile with an increased percentage of CD3(-) IEL containing TNF-alpha and IL-10, in the absence of IL-2, IL-4 and IFN-gamma. Altogether our results suggest that flow cytometry immunophenotyping of intestinal IEL, in cases suspected of celiac disease and their complicated forms, could be of great help in the correct diagnosis of RCS and the understanding of the immunopathogenic mechanisms of the disease and their clinical and/or therapeutical implications.