Vol.4, Issue 1 by Hugh Freeman
Celiac disease is an immune-mediated small intestinal mucosal disorder with characteristic, but n... more Celiac disease is an immune-mediated small intestinal mucosal disorder with characteristic, but non-specific histopathological changes. A number of heterogeneous disorders may produce similar changes in small bowel biopsies, but these fail to respond to a gluten-free diet. Recently, it has become increasingly appreciated that different medications may cause this sprue-like intestinal disease, including a specific angiotensin II receptor antagonist, olmesartan, an agent often used for treatment of hypertension. This enteropathy appears to occur as an apparently rare adverse event, often presenting with severe diarrhea, malabsorption and weight loss following chronic long-term use of the drug. Serological studies, particularly for tissue transglutaminase IgA antibodies, are negative and biopsies may show moderate to severe changes in mucosal architecture similar to celiac disease. Sub-epithelial collagen deposits may also occur. Clinical and biopsy changes fail to respond to a strict gluten-free diet, but cessation of olmesartan use appears to result in resolution.
Papers by Hugh Freeman
Frontiers in Nutrition, Oct 19, 2020
The Canadian journal of gastroenterology, 2003
Data on the natural history of longstanding Crohn's disease are very limited. After searching a c... more Data on the natural history of longstanding Crohn's disease are very limited. After searching a clinical database of over 1000 patients with Crohn's disease, it was determined that eight patients (five women, three men) had disease documented for over 50 years. In spite of complex histories with either stricturing or penetrating complications, all currently have either no symptoms or minimal disease activity, often without the need for ongoing pharmacological treatment. Most significantly, their clinical courses were all characterized by prolonged asymptomatic periods, often for more than a decade, before the recurrence of symptomatic disease. Pathological findings in all patients revealed granulomatous inflammatory disease, often recurring intermittently over many decades. Moreover, the location of the findings implied that the disease has a tendency to evolve, not only in a temporal dimension, but also extending geographically within the gastrointestinal tract. These clinical and pathological features in longstanding Crohn's disease suggest that recurring or multiple discrete initiating events, rather than a single initiating event, could be involved in the etiology and pathogenesis of Crohn's disease.
The Canadian journal of gastroenterology, 1997
C olonization of the gastric mucosa with Helicobacter pylori has been associated with gastritis a... more C olonization of the gastric mucosa with Helicobacter pylori has been associated with gastritis and ulcer disease. In 1983 Warren (1) and Marshall (2) reported detection of an 'unidentified' curved bacilli, similar to other Campylobacter species, in gastric mucosa. Subsequently Marshall et al (3) reported development of a self-limited gastritis after cimetidine pretreatment and ingestion of a cultured isolate; of note, the bacteria were found in gastric biopsies 10 days later but not 14 days after ingestion. Tinidazole treatment was then administered with concomitant symptom resolution. This HJ FREEMAN. Disappearance of helicobacter without antibiotics in 12 patients with gastritis. Can J Gastroenterol 1997;11(2): 167-172. Detection of Helicobacter pylori in endoscopic gastric biopsies has been associated with a variety of diseases, including ulcers and gastritis. Although the natural history of H pylori in the gastric mucosa is unknown, antibiotic regimens have been used for eradication. Gastric biopsies from 6050 endoscopic procedures done by a single gastroenterologist from 1981 to 1994 were evaluated. Of these, 2860 from April 1, 1991 to September 30, 1994 had silver-stained biopsies to facilitate H pylori detection, and at least two upper endoscopic procedures were done with gastric biopsies in 188 patients. Twelve of the 188 patients with an initially positive H pylori gastric biopsy became H pylori-negative without antibiotic treatment for H pylori or other infection; 10 received omeprazole and two received no drug treatment. In two of the 12 patients recurrent H pylori in the gastric mucosa was also documented. These findings indicate that H pylori may disappear and reappear in the gastric mucosa with no specific antibiotic eradication regimen, although omeprazole may eradicate H pylori in vivo in some patients. The natural history of H pylori in gastric biopsies is poorly understood. Improved understanding, especially regarding the pathogenesis of upper gastrointestinal ulcerative and inflammatory disease processes, is essential before recommendations for specific antibiotic eradication regimens can be made.
Canadian Journal of Cardiology, Dec 1, 2010
I nflammatory bowel diseases, including ulcerative colitis and Crohn's disease, may be associated... more I nflammatory bowel diseases, including ulcerative colitis and Crohn's disease, may be associated with extraintestinal disorders, often during an exacerbation of the disease. Cardiac complications occur, particularly with ulcerative colitis (1). Although considered uncommon, clinically significant cardiac changes may occur more often than currently appreciated. For example, up to one-third of patients may develop myocarditis or pleuropericarditis during the course of their disease (2). An array of symptoms may result in myopericarditis, ranging from shortness of breath to chest pain. These may resolve without specific therapy, or rapidly evolve and progress to cardiogenic shock and death (3). In ulcerative colitis, viral agents are often thought to be responsible, but other causes may occur including drug reactions (eg, 5-aminosalicylates [5-ASAs]) (4).
The Canadian journal of gastroenterology, 1989
Antibimic associated diarrhea appears to be largely due to Closcridium difficile and may have, at... more Antibimic associated diarrhea appears to be largely due to Closcridium difficile and may have, at least in part. a toxin mediated pathogenesis. Because a poor correlation exists between measurable toxin titres and symptoms, additional copathogenic factors may be important. All patients seen during a two year period with diarrhea within four weeks of antibiotic therapy, a positive $tool culture for C difficile and a positive stool cytotoxin assay specific for C difficile were investigated. All patients had stools cultured for cnteric bacterial pathogens including Salmonella , Shigella. Campylobacter, Aeromonas and Yersinia species. Seven patients had Yersinia species isolated during the course of their illness; no other entcric pathogens were identified. In four patients, Y enrerocolitica was cultured simultaneously with C difficile prior to treatment, and in one of these, Y fredriksenii was also isolated. Of six patients with persistent or recurrent sympcoms after treatment fo r C difficile (ie, vancomycin in five and mecronidazole in one patient), four had positive yersinia cultures at the conclusion of therapy (Y enrerocolicica in three and Y fredriksenii in two patients). All but one of these patients had been yersinia culture negative prior to therapy for C difficile Patients with and without yersinia isolates were then compared with respect to age, sex, clinical symptoms and sigmoldoscopic as well as rectal biopsy findings. The presence of yersinia was associated with male sex, younger age and abdominal pain; other features including hematochezia, fever, arthralgia, cytotoxin titre , sigmoidoscopy and rectal biopsy could not distinguish patients with and without Yc.-rsinia species. Thus, ycrsinia may be associated with an antibiotic related diarrheal illness usually attributed to C difficile alone and may be observed in the setting of persistent or recurrent symptoms followi ng treatment for C difficile diarrhea. Can J Gastro• enterol 1989;3(1)121-25
Gut, Feb 1, 1979
In experimental animals with massive proximal intestinal resection, in vivo ileal absorption of a... more In experimental animals with massive proximal intestinal resection, in vivo ileal absorption of an amino acid mixture containing L-leucine and glycine as well as two different dipeptides, L-leucyl-glycine and glycyl-L-leucine, were compared. Both amino acid and dipeptide absorption were markedly enhanced in the ileal segments. However, the absorption rates from the two perfused dipeptides differed. L-leucine absorption from L-leucyl-glycine was much greater than from glycyl-L-leucine. Brush border amino-peptidase activities after resection were also increased but dissociation between absorption and hydrolytic activity occurred. This study indicates that certain dipeptides are handled differently by adapting ileal segments. Furthermore, the changes observed probably reflect mucosal cellular hyperplasia occurring in association with intestinal adaptation. Amino acids are absorbed by different transport mechanisms from the intestinal lumen depending upon whether they are present in free form or as peptides (Silk, 1974; Matthews, 1975; Matthews and Adibi, 1976). Some, but not all, amino acids are more efficiently absorbed from peptides than free amino acid mixtures (Adibi and Phillips, 1968; Craft et al., 1968; Matthews, 1977). Furthermore, peptide transport appears to be less disturbed compared with amino acid transport in some small intestinal disorders (
Digestive Diseases and Sciences, Apr 1, 2004
Classification of architectural changes in the small intestinal biopsy may be clinically useful t... more Classification of architectural changes in the small intestinal biopsy may be clinically useful to define the cause of diarrhea or suspected malabsorption, especially in adults. Pathologic changes may include severe (flat) or variably severe (mild or moderate) abnormalities. For some disorders, small bowel biopsy findings may be very distinctive and lead to a specific diagnosis. For others, like adult celiac disease, biopsy changes are less specific. Indeed, it is becoming increasingly appreciated that several conditions can produce similar histopathologic changes. Serological assays, including endomysial antibodies and tissue transglutaminase antibodies, may be very useful tools for screening and case finding in clinical practice. However, demonstration of characteristic changes in the small intestinal biopsy is critical, along with a gluten-free diet response.
Gastroenterology, 1995
Glucocorticoids induce amiloride-sensitive electrogenic Na + transport in rat distal colon. In th... more Glucocorticoids induce amiloride-sensitive electrogenic Na + transport in rat distal colon. In this study Na+ channel activity and expression of alpha subunit mRNA were determined in co[onocytes from rat distal colon of normal and carcinogen treated rats. Methods. Colon carcinogenesis was induced in rats by 5 x weekly s.c injections of DMH (18 mg/kg). Dexamethasone (6mg/kg) was injected for 3 days prior to experiment& Colonic cell populations were sequentially harvested from the distal colon from dexamethasonetreated rats by a Ca 2+ chelation method. Membrane vesicles were prepared from isolated cells and activity of amiloride-sensitive Na ÷ channels assayed. Electrogenic Na + transport was determined for each population by the effect of 10 micmol amiloride on 2=Na + uptake in valinomycin treated membrane vesicles. Total mRNA from colonocyte populations was subjected to Northern blot analysis using a cDNA probe, (EcoR 1-BamH 1,2.2 kbase fragment) derived from the alpha subunit of the Na + channel. Results. Electrogenic amiloride-sensitive Na" transport in membrane vesicles from control rats was confined to cells harvested from upper crypt zones and was not detectable in lower crypt populations. None of the colonic cell populations harvested from DMH-treated rats exhibited electrogenic Na* transport. However, luminal colonocytes from both control and DMH-treated rats equally expressed transcripts of the alpha subunit of the Na ÷ .channel. Conclusion. This study indicates that expression of,dexamethasoneinduced alpha subunit of the Na ÷ channel is compartmentalized to the upper crypt regions in distal colons of normal and DMH-treated rats. However, an active sodium transport protein is not induced by glucocorticoids in colonic membrane vesicles during chemical carcinogenesis.
International Journal of Celiac Disease, 2016
Celiac disease is an immune-mediated intestinal disorder that may be associated with other immune... more Celiac disease is an immune-mediated intestinal disorder that may be associated with other immune-mediated extra-intestinal disorders, including immune-mediated endocrine diseases, such as autoimmune thyroiditis, most often with hypothyroidism. Other monoglandular autoimmune endocrine disorders may also occur, including autoimmune adrenal insufficiency (Addison’s disease). In celiac disease, clinical features of adrenal failure may be limited, difficult to differentiate from symptoms that might be attributed to celiac disease, or even life-threatening. In others with celiac disease, a polyglandular autoimmune syndrome has also been reported. Recent screening studies from multiple countries, particularly in , have indicated that patients with autoimmune adrenal failure or Addison’s disease should be carefully screened for occult or silent celiac disease. Up to 10% of Addisonian patients may be serologically positive and histopathological features of untreated celiac disease may be de...
International Journal of Celiac Disease, 2019
A woman with long-standing weight loss and malabsorption demonstrated a severe sprue-like enterop... more A woman with long-standing weight loss and malabsorption demonstrated a severe sprue-like enteropathy. She insidiously developed persistent and progressive muscle weakness caused by inclusion body myositis, an uncommon muscle disorder. Treatment with a gluten-free diet, steroids, calcium, zinc and vitamin supplements, including empirical vitamin E resulted in weight gain, but failed to histologically improve her small intestinal mucosa or the muscle weakness which became profound. The myopathic process could reflect a co-existent autoimmune disorder, or, possibly a direct result of long-standing and superimposed nutrient deficits. An alternative explanation may be a hitherto unrecognized syndrome manifested as inclusion body myositis and a form of sprue-like enteropathy.
American Journal of Physiology-Renal Physiology, 1987
Renal brush-border membrane D-glucose transport was studied in vesicles prepared from early proxi... more Renal brush-border membrane D-glucose transport was studied in vesicles prepared from early proximal tubules (outer cortical tissue) and late proximal tubules (outer medullary tissue). Kinetics of sodium-dependent D-glucose uptake, determined with zero trans sodium gradient of 200 mM at 21 degrees C demonstrated a curvilinear Woolf-Augustinsson-Hofstee plot in both cortical and medullary vesicles. Three sodium-dependent systems were discerned in the cortex, possessing Km values of 12.35 +/- 2.2 mM, 520 +/- 39 microM, and 12 +/- 1 microM, respectively. In contrast, only the high-affinity, low-capacity systems were present in the medullary tissue; with respective Km values of 484 +/- 95 microM and 11 +/- 1 microM and mean Vmax values of 2.4 +/- 0.1 and 0.44 +/- 0.08 nmol X mg protein-1 X min-1. The high-affinity systems were more abundant in the medulla than in the cortex. These studies support the notion of multiple transport processes for sodium-dependent D-glucose transport in the ...
Canadian Journal of Gastroenterology, 1993
old female with previously diagnosed lobular breast carcinoma presented with clinical radiographi... more old female with previously diagnosed lobular breast carcinoma presented with clinical radiographic and endoscopic features of a diffuse gastric infiltrative process. Multiple gastric biopsies revealed characteristic histological features of a metastatic lobular breast carcinoma. In patients with a history of breast carcinoma, distinction between primary and secondary gastric malignancy is important as treatment options may differ substantially. Recognition that the scirrhous changes in the stomach are due to metastatic breast carcinoma, particularly of the lobular histological type, may lead to further palliative pharm.acologic therapy that could benefit the patient and improve survival.
Canadian Journal of Gastroenterology, 1996
A 68-year-old female presented with an enlarged and nontender palpable gallbladder and clinical f... more A 68-year-old female presented with an enlarged and nontender palpable gallbladder and clinical features of obstructive jaundice. Subsequent laboratory investigations confirmed the presence of cholestasis associated with an obstructing mass in the region of the common hepatic duct. Pathological evaluation of the mass revealed a localized abdominal lymphoma. Treatment with chemotherapy and radiation resulted in complete clinical remission (for almost 14 years at the last evaluation). Primary abdominal lymphoma may involve the hilar region and present as a localized mass. Precise tissue diagnosis is essential to permit an aggressive management approach with the potential for significant clinical benefit.
Canadian Journal of Gastroenterology, 2001
Cytokines play a role in the inflammatory process in colitis and may have therapeutic potential. ... more Cytokines play a role in the inflammatory process in colitis and may have therapeutic potential. Interleukin-10 (IL-10) has both immunomodulatory and anti-inflammatory properties. IL-10-deficient mice develop intestinal inflammation with increased tissue levels of other cytokines, including tumour necrosis factor-alpha. In patients with inflammatory bowel disease, impaired IL-10 production by lamina propria T cells occurs and human recombinant IL-10 improves clinical parameters in inflammatory bowel disease (eg, Crohn's disease). There seem to be conflicting results in differing animal models, and the timing of administration of IL-10 relative to onset of colitis may be critical, possibly due to rapid clearance of IL-10. Interestingly, in IL-10 gene-deficient mice raised in germ-free conditions, the intestinal inflammatory changes normally observed in conventional nongerm-free conditions are not detected, suggesting a role for luminal bacteria in the pathogenesis of the inflamma...
Best Practice & Research in Clinical Gastroenterology, Feb 1, 2002
Carolina Digital Repository (University of North Carolina at Chapel Hill), 2014
Objective: To compare persistence with tumor necrosis factor alpha (TNF) antagonists among rheuma... more Objective: To compare persistence with tumor necrosis factor alpha (TNF) antagonists among rheumatoid arthritis patients in British Columbia. Treatment persistence has been suggested as a proxy for real-world therapeutic benefit and harm of treatments for chronic non-curable diseases, including rheumatoid arthritis. We hypothesized that the different pharmacological characteristics of infliximab, adalimumab and etanercept cause statistically and clinically significant differences in persistence. Methods: We conducted a population-based cohort study using administrative health data from the Canadian province of British Columbia. The study cohort included rheumatoid arthritis patients who initiated the first course of a TNF antagonist between 2001 and 2008. Persistence was measured as the time between first dispensing to discontinuation. Drug discontinuation was defined as a drug-free interval of 180 days or switching to another TNF antagonist, anakinra, rituximab or abatacept. Persistence was estimated and compared using survival analysis. Results: The study cohort included 2,923 patients, 63% treated with etanercept. Median persistence in years (95% confidence interval) with infliximab was 3.7 (2.9-4.9), with adalimumab 3.3 (2.6-4.1) and with etanercept 3.8 (3.3-4.3). Similar risk of discontinuation was observed for the three drugs: the hazard ratio (95% confidence interval) was 0.98 (0.85-1.13) comparing infliximab with etanercept, 0.95 (0.78-1.15) comparing infliximab with adalimumab and 1.04 (0.88-1.22) comparing adalimumab with etanercept. Conclusions: Similar persistence was observed with infliximab, adalimumab and etanercept in rheumatoid arthritis patients during the first 9 years of use. If treatment persistence is a good proxy for the therapeutic benefit and harm of these drugs, then this finding suggests that the three drugs share an overall similar benefit-harm profile in rheumatoid arthritis patients.
International Journal of Celiac Disease, May 18, 2021
A 43-yr old female with two prior renal transplants for renal failure associated with diabetes, r... more A 43-yr old female with two prior renal transplants for renal failure associated with diabetes, retinopathy and coronary artery disease developed diarrhea. Her medications included mycophenolate mofetil, an immunosuppressive medication documented to cause sprue-like mucosal changes in the small intestine. Later studies revealed a small intestinal mucosal lesion characterized by marked crypt hyperplasia, villous atrophy and increased intra-epithelial lymphocytes. Serological studies for celiac disease were negative and repeated biopsies despite a strict gluten-free diet, revealed histopathological persistence of a severely abnormal sprue-like enteropathy. Eventually, further biopsies of her small intestine revealed superimposed changes characterized by dense sub-epithelial collagen deposits histochemically staining positive for trichrome, typical of collagenous sprue and representing an expansion of published pathological features of mycophenolate-associated small intestinal mucosal disease.
The Canadian journal of gastroenterology, 2011
Case presentation and images A 78-year-old woman experienced intermittent watery diarrhea for mor... more Case presentation and images A 78-year-old woman experienced intermittent watery diarrhea for more than one year. There was no previous antibiotic use, travel or other medical history. The physical examination was normal. Laboratory studies, including bloodwork and fecal cultures, were negative. Colonoscopy revealed sigmoid diverticulosis and a broad-based sessile, 'carpet-like' polypoid lesion at the hepatic flexure appearing to occupy approximately 40% to 50% of the colonic circumference; consequently, the lesion was biopsied only (Figure 1) and ink-tattooed (for later laparoscopic removal). Biopsy sections (Figures 2 and 3) showed collagenous colitis with thickening of the basal collagen plate, an irregular lower border, entrapped nuclei, loss of overlying surface epithelium and increased inflammatory cells in the lamina propria. Subepithelial multinucleated giant cells were present (arrows). A trichrome stain highlighted the thickened basal collagen plate with entrapped nuclei (Figure 4). Over the next few weeks, her diarrhea completely resolved on a high-fibre diet regimen alone.
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Vol.4, Issue 1 by Hugh Freeman
Papers by Hugh Freeman