Robert D. Zipser

Presentations of adult celiac disease in a nationwide patient support group

Recent epidemiological studies primarily from Europe document that adult celiac disease often lacks the classic presentation of steatorrhea and weight loss. There are few surveys of adult celiac disease in the United States. We surveyed the large population of a nationwide patient support group to determine their disease presentations. In the initial survey (N = 1032 respondents), the median age at onset was 46 years, and the diagnosis of adult celiac disease was often delayed (median 12 months, with 21% delayed over 10 years). Only 32% of adults were underweight, and only about 50% reported frequent diarrhea and weight loss. A second survey documented that common presenting symptoms were fatigue (82%), abdominal pain (77%), bloating or gas (73%), and anemia (63%). Initial physician diagnoses were often irritable bowel syndrome (37%), psychological disorders (29%), and fibromyalgia (9%). These initial presentations are similar to those in Europe and often resemble irritable bowel syndrome.

Role of eicosanoids in human and experimental colitis

Prostaglandins, thromboxanes, and leukotrienes (collectively called eicosanoids) are increased at sites of inflammation and contribute to the manifestations of inflammation, such as hyperemia, hyperalgesia, edema, and inflammatory cell infiltration. Inhibition of eicosanoid production is the basic mechanism of action of corticosteroids and of nonsteroidal antiinflammatory drugs. Eicosanoid synthesis is also increased in human and experimental inflammatory bowel disease. Leukotriene B4 is the most potent proinflammatory eicosanoid, and in vivo production of this compound is the predominant eicosanoid in colitis. Recent experimental data demonstrate that selective inhibition of leukotrienes may be a therapeutic strategy to reduce inflammation in inflammatory bowel disease.

Exaggerated prostaglandin production by colonic smooth muscle in rabbit colitis

Enhanced production of arachidonic acid metabolites by colonic mucosa has been reported in ulcerative colitis as well as in experimental models of colitis. However, production of these compounds by colonic smooth muscle from colitis subjects has not been described. To evaluate arachidonic acid metabolism in colonic tissue, we studied the production of prostaglandin E2 (PGE2) by mucosa and muscularis propria in two experimental models of acute colitis in which inflammation was virtually confined to the mucosa. Colitis was induced in New Zealand white rabbits by either of two methods, dinitrochlorobenzene (DNCB) sensitization or formalin followed by intravenous soluble immune complexes (F-IC). Arachidonic acid metabolites were identified from in vitro incubations of tissue with [14C]arachidonic acid by thin layer chromatography followed by autoradiography. The major eicosanoid metabolites of colitis mucosa and muscularis were14C-labeled prostaglandin E2, prostaglandin F2a and 6-keto prostaglandin f1a. PGE2 was quantitated from incubations without labeled arachidonic acid by radioimmunoassay. PGE2, expressed as picograms per milligram protein per 20 min (mean±sem), was increased in F-IC mucosa (1093±141 vs 645±189, P < 0.05) and DNCB mucosa (1354±487 vs 527±222, P < 0.05) compared to normals. PGE2 production by uninflamed colitis muscularis propria was also increased five-to eightfold compared to normals for F-IC muscularis (1594±329 vs 189±35, P < 0.005) and DNCB muscularis (1287±171 vs 225±72, P < 0.005). Thus, the adjacent inflammation in colonic mucosa may induce increased eicosanoid production by the uninflamed smooth muscle. Increased PGE2, in turn, may contribute to the smooth muscle dysfunction seen in colitis.

Role of renal prostaglandins and the effects of nonsteroidal anti-inflammatory drugs in patients with liver disease

Renal prostaglandins have several key functions in patients with severe liver disease and ascites. Increased activity of vasodilatory prostaglandins counters the underlying impairment in renal perfusion and the effects of vasoactive hormones. Prostaglandins also participate in renin secretion, renal diluting ability, sodium excretion, the action of diuretics, and, possibly, the development of the hepatorenal syndrome. Nonsteroidal anti-inflammatory drugs inhibit these compensatory actions of prostaglandins and cause a functional reduction in glomerular filtration rate and an impairment in sodium and fluid excretion. The severity of these nephrotoxic effects depends on the potency of the drug in inhibiting renal prostaglandins and on patient susceptibility. Patients with ascites and avid sodium retention, sodium-restricted diets, or concurrent diuretic use are most at risk. If nonsteroidal anti-inflammatory drugs must be administered to these patients, the type of drug should be carefully selected and renal function should be closely monitored.

Assay methods for 6-keto-prostaglandin F1α in human urine : Comparison of chromatographic techniques with radioimmunoassay and gas chromatography—negative-ion chemical-ionization mass spectrometry

6-Keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in human urine is considered to be a reflection of renal prostacyclin production. Because of the large amounts of unidentified eicosanoid metabolites in urine that may potentially bind to 6-keto-PGF1 alpha antisera, most radioimmunoassays include chromatographic purification of urine. A comparison of chromatographic techniques and of antisera to 6-keto-PGF1 alpha for the assay of human urine is described. Gas chromatography--negative-ion chemical-ionization mass spectrometry (GC--NICI-MS) was used as the reference method. Radioimmunoassays were performed with each of four antisera combined with each of three chromatographic purification systems (silicic acid, Sephadex LH-20, reversed-phase high-performance liquid chromatography). There was marked variability in the results; however, there was at least one chromatographic method for each antiserum that yielded results comparable to GC--NICI-MS. Direct radioimmunoassay of urine without chromatography yielded markedly elevated and variable results for the four antisera. In contrast, the four antisera gave very similar results with direct assay of media from isolated perfused organs. Thus, for the radioimmunoassay of 6-keto-PGF1 alpha in human urine, each antiserum is sensitive to different contaminants in urine and must be individually matched to a chromatographic purification system.

Brief report: Physician awareness of celiac disease

AbstractBACKGROUND: Celiac disease is a common disorder (up to 0.7%); however, it is uncommonly diagnosed in the United States. OBJECTIVE: We sought to determine physician awareness of celiac disease. DESIGN: Surveys completed by 2,440 (47%) of 5,191 patients in a support group were analyzed for frequency of diagnosis by physician specialties. Questionnaires were then sent to primary care physicians (PCPs) (n=132) in a southern California county to assess knowledge of celiac disease. RESULTS: In patient surveys, only 11% were diagnosed by PCPs (internists and family physicians) versus 65% by gastroenterologists. Physician surveys (70% response) showed that only 35% of PCPs had ever diagnosed celiac disease. Almost all physicians (95%) knew of wheat intolerance, but few (32%) knew that onset of symptoms in adulthood is common. Physicians were well aware (90%) of diarrhea as a symptom, but fewer knew of common symptoms of irritable bowel syndrome (71%), chronic abdominal pain (67%), fatigue (54%), depression and irritability (24%) or of associations with diabetes (13%), anemia (45%) or osteoporosis (45%), or of diagnosis by endomysial antibody tests (44%). CONCLUSIONS: Lack of physician awareness of adult onset of symptoms, associated disorders, and use of serology testing may contribute to the underdiagnosis of celiac disease.

Celiac Disease in the Elderly

Accessible online at: www.karger.com/ger Celiac disease is a common immunemediated disorder characterized by variable degrees of atrophy of the small intestinal villi and malabsorption in response to ingestion of gluten and related cereal proteins. Traditionally considered a childhood disease, it is now increasingly diagnosed in adulthood. Initial presentations of celiac disease in elderly patients have been well described in several European studies [1–3], including a recent multicenter Italian survey reported by Gasbarrini et al. [4]. This Italian survey documented that approximately 4% of adults with celiac disease are diagnosed after age 65, typically with long delays. There have not been any similar analyses of elderly patients over age 65 with celiac disease in the United States. A nationwide patient support group, the Celiac Disease Foundation, has an ongoing database currently of 2,440 patients who registered with the organization from 1993 to 2004. The database includes demographic data, duration of symptoms, and initial diagnoses, as described in an earlier report of 1,032 patients [5]. Of the 2,440 patients of all ages, approximately 15% (256 women and 110 men) reported that they were first diagnosed after age 64 (range 65–90, mean 71.6 B 6.9 years). The elderly patients accounted for 18% of the adult patients, compared to 4% in the Italian survey. The male/ female ratio was similar to the Italian study (2.33 vs. 2.75). There were also similar long delays in diagnosis, with patients reporting duration of symptoms averaging 11 B 19 years and reporting consultations with an average number of 4.4 physicians prior to diagnosis. Only 9.6% of patients were initially diagnosed as celiac disease or dermatitis herpetiformis by their physician. Table 1 lists the other major diagnoses given to these patients by their physicians to explain their symptoms. We recently surveyed family physicians to determine their awareness of adult celiac disease [6]. Most physicians still considered celiac disease to be a childhood disorder, although over 80% of celiac disease patients in the United States are diagnosed in adulthood [5, 7]. Indeed, the current survey suggests that the number of patients diagnosed under age 18 years (16%) is similar to the number of elderly patients (15%). Both the surveys from Italy and from the United States document long delays in diagnosis of celiac disease in elderly patients. Thus, there appears to be under-recognition of celiac disease in the elderly. One of the most striking observations is the number of elderly patients incorrectly diagnosed as irritable bowel syndrome, who generally had the longest delays in diagnosis. Based on European and American surveys, we strongly encourage consideration of the diagnosis of celiac disease in the elderly, especially in those with symptoms of irritable bowel syndrome, unexplained chronic diarrhea or unexplained anemia.

Mediators of inflammation in inflammatory bowel disease

The etiologies of ulcerative colitis and Crohns disease are unknown, although there is an abundance of theories and data to implicate genetic predisposition, immunologic alterations, infectious agents, and other environmental factors (1). Most of the clinical manifestations are related to inflammation, including symptoms of pain, diarrhea, hemorrhage, and fever. In Crohns disease, this process may lead to fistulas and abscesses. Chronic fibrotic changes, strictures, and possibly neoplastic changes may also be attributed to chronic and recurring inflammation. As yet there is no intervention that prevents the disease nor is there a specific therapy that removes the causal factor, other than perhaps surgical resection. Instead, medical therapy is directed at reducing acute inflammation and treating its manifestations and complications. Over the last 10-20 years, great advances have been made in the understanding of the inflammatory process. Previously, our knowledge was limited to a simple three-stage process: (1) an irritant, immune process, or infectious agent activates leukocytes; (2) these cells release enzymes and inflammatory mediators such as histamine, prostaglandins, and serotonin; and (3) these products cause pain, heat, edema, and loss of function. We now know that the process is far more complicated. It is clear that mediators of inflammation also arise from cells other than leukocytes. Prostaglandins arising from fibroblasts, muscle, and other cells modulate blood flow and intestinal motility in the inflamed colon. Interleukin 1 released from vascular

Physician awareness of celiac disease

Purpose: Celiac disease is a common disorder (up to 0.7%), but still infrequently diagnosed. In our recent survey of over 1000 patients with celiac disease only 6% were diagnosed by their primary care physicians. We sought to determine physician awareness of celiac disease presentations, symptoms, associated disorders and diagnostic tests. Methods: Surveys with multiple-choice questions were mailed to all family physicians (FPs) (n 140) and gastroenterologists (GIs) (n 31) listed in telephone books and on-line yellow pages in San Bernardino County, California. This county includes a medical school, large rural areas and populous metropolitan suburbs. Results: Over 50% of FPs and GIs responded to the survey. Almost all physicians were aware that celiac disease involved sensitivity to wheat products, but only 33% of FPs and 35% of GIs knew that onset of symptoms was much more common in adulthood than in childhood. Celiac disease is common in patients with type 1 diabetes (2%-6% prevalence), but only 13% of FPs and 47% of GIs were aware of the association. There was more awareness of the associations with thyroid disease (23% FPs, 53% GIs) and IgA deficiency (34% FPs, 59% GIs). When questioned on symptoms of celiac disease, almost all FPs knew that diarrhea was frequent, but symptoms resembling irritable bowel syndrome (68%), psychological disorders (43%) and fibromyalgia-like illnesses (39%) were less well appreciated. All GIs but less than one-half of FPs were aware that irondeficiency anemia and osteoporosis were mainfestations of celiac disease, and few knew that untreated celiac disease may cause infertility (7% of FPs, 47% of GIs). In response to questions on diagnostic techniques, all GIs and most FPs were aware of the use of small bowel biopsy; however, only 43% of FPs were aware of blood tests to screen for celiac disease. Despite an average of over 19 years in practice, less than one-third (28%) of family physicians had ever diagnosed a patient with celiac disease. All GIs had diagnosed multiple patients with celiac disease. Conclusions: These data are consistent with surveys of patients reporting that their primary care physicians infrequently made the diagnosis of celiac disease. The survey results from this county suggest a need to increase awareness of celiac disease, particularly among primary care physicians, and particularly the recognition of adult presentations, the associated disorders, and the use of serologic screening tests.