Role of biopsy in diagnosis and treatment of adult celiac disease.

Celiac disease (CD) is an immune-mediated enteropathy that characteristically responds to treatment with a gluten-free diet. In most, clinical features improve with resolution of diarrhea and weight loss. Serological studies also tend to normalize. Small intestinal biopsies from the duodenum reveal a severe to moderately severe architectural disturbance showing crypt epithelial hyperplasia with increased numbers of epithelial cell mitotic figures along with villous "flattening", increased numbers of lamina propria plasma cells and lymphocytes and increased numbers of intra-epithelial lymphocytes in untreated disease. With a gluten-free diet, these changes can be expected to resolve to normal. In some patients, this mucosal inflammatory process may persist, especially in the proximal small intestine for variable periods of time. In CD, resolution of histopathological changes can occur within 6 months, but often, more than a year is required, and sometimes, 2 years or more. Changes are not only time-dependent, but appear to be gender-dependent with resolution more readily achieved in females compared to males, and age-dependent with more persistence of the inflammatory process in the elderly compared to younger patients. Future studies need to take into account the individual nature of the normal mucosal healing process in CD treated with a gluten-free diet.

Dietary compliance in celiac disease.

Celiac disease is an immune-mediated disorder that causes severe architectural disturbance in the small intestinal mucosa of genetically-predisposed individuals. Impaired absorption of multiple nutrients results and diarrhea and weight loss develop. Evidence has accumulated that a strict gluten-free diet can result in resolution of diarrhea, weight gain and normalization of nutrient malabsorption. In addition, histopathological changes also normalize, but this histopathological response appears to be time-dependent, sex-dependent and age-dependent. Compliance to a gluten-free diet is difficult and costly resulting in poor compliance and only a limited clinical response. This poses a risk for later long-term complications, including malignancy. A major practical clinical problem is the assessment of compliance to the gluten-free diet. Although symptoms may resolve and serological antibody markers may improve, multiple studies have documented ongoing architectural disturbance and inflammatory change, and with these continued inflammatory changes, a persistent risk for long-term complications. Recent immunological studies have suggested that peptides can be detected in both urine and fecal specimens that may be indicative of limited compliance. At the same time, multiple biopsy studies have demonstrated that complete normalization of the mucosa may occur in some patients within 6 mo of initiation of a gluten-free diet, but more often, up to 2 years or more may be required before repeated biopsies eventually show mucosal recovery and mucosal healing.

Endocrine manifestations in celiac disease.

Celiac disease (CD) is an autoimmune small intestinal mucosal disorder that often presents with diarrhea, malabsorption and weight loss. Often, one or more associated endocrine disorders may be associated with CD. For this review, methods involved an extensive review of published English-language materials. In children and adolescents, prospective studies have demonstrated a significant relationship to insulin-dependent or type 1 diabetes, whereas in adults, autoimmune forms of thyroid disease, particularly hypothyroidism, may commonly co-exist. In some with CD, multiple glandular endocrinopathies may also occur and complicate the initial presentation of the intestinal disease. In others presenting with an apparent isolated endocrine disorder, serological screening for underlying subclinical CD may prove to be positive, particularly if type 1 diabetes, autoimmune thyroid or other autoimmune endocrine diseases, such as Addison's disease are first detected. A number of reports have also recorded hypoparathyroidism or hypopituitarism or ovarian failure in CD and these may be improved with a strict gluten-free diet.

Iron deficiency anemia in celiac disease.

Iron is an important micronutrient that may be depleted in celiac disease. Iron deficiency and anemia may complicate well-established celiac disease, but may also be the presenting clinical feature in the absence of diarrhea or weight loss. If iron deficiency anemia occurs, it should be thoroughly evaluated, even if celiac disease has been defined since other superimposed causes of iron deficiency anemia may be present. Most often, impaired duodenal mucosal uptake of iron is evident since surface absorptive area in the duodenum is reduced, in large part, because celiac disease is an immune-mediated disorder largely focused in the proximal small intestinal mucosa. Some studies have also suggested that blood loss may occur in celiac disease, sometimes from superimposed small intestinal disorders, including ulceration or neoplastic diseases, particularly lymphoma. In addition, other associated gastric or colonic disorders may be responsible for blood loss. Rarely, an immune-mediated hemolytic disorder with increased urine iron loss may occur that may respond to a gluten-free diet. Reduced expression of different regulatory proteins critical in iron uptake has also been defined in the presence and absence of anemia. Finally, other rare causes of microcytic anemia may occur in celiac disease, including a sideroblastic form of anemia reported to have responded to a gluten-free diet.

Clinical relevance of intestinal peptide uptake.

AIM: To determine available information on an independent peptide transporter 1 (PepT1) and its potential relevance to treatment, this evaluation was completed. METHODS: Fully published English language literature articles sourced through PubMed related to protein digestion and absorption, specifically human peptide and amino acid transport, were accessed and reviewed. Papers from 1970 to the present, with particular emphasis on the past decade, were examined. In addition, abstracted information translated to English in PubMed was also included. Finally, studies and reviews relevant to nutrient or drug uptake, particularly in human intestine were included for evaluation. This work represents a summary of all of these studies with particular reference to peptide transporter mediated assimilation of nutrients and pharmacologically active medications. RESULTS: Assimilation of dietary protein in humans involves gastric and pancreatic enzyme hydrolysis to luminal oligopeptides and free amino acids. During the ensuing intestinal phase, these hydrolytic products are transported into the epithelial cell and, eventually, the portal vein. A critical component of this process is the uptake of intact di-peptides and tri-peptides by an independent PepT1. A number of "peptide-mimetic" pharmaceutical agents may also be transported through this carrier, important for uptake of different antibiotics, antiviral agents and angiotensin-converting enzyme inhibitors. In addition, specific peptide products of intestinal bacteria may also be transported by PepT1, with initiation and persistence of an immune response including increased cytokine production and associated intestinal inflammatory changes. Interestingly, these inflammatory changes may also be attenuated with orally-administered anti-inflammatory tripeptides administered as site-specific nanoparticles and taken up by this PepT1 transport protein. CONCLUSION: Further evaluation of the role of this transporter in treatment of intestinal disorders, including inflammatory bowel disease is needed.

Emerging drugs for celiac disease.

INTRODUCTION: Celiac disease is an immune-mediated gluten-dependent disorder, primarily affecting the small intestine in genetically predisposed individuals. The disorder has a very heterogeneous clinical and histopathological spectrum. Current treatment with a gluten-free diet is very effective, but the diet is difficult to maintain and remains costly. AREAS COVERED: Alternatives to the gluten-free diet have been proposed to either replace this current treatment, or at least, to supplement use of the gluten-free diet. Studies in the published English language literature relevant to this review were examined for this report. EXPERT OPINION: Most recent published double-blind, placebo-controlled clinical trials have focused on an orally administered recombinant glutenase (ALV003) showing significant but limited benefit to celiac disease patients already compliant with a gluten-free diet. Other studies have addressed other immune mechanisms that may play a role in its pathogenesis and have not been so positive. Added investigations, particularly over the long-term, in other larger and more heterogeneous populations are needed.

Spontaneous free perforation of the small intestine in adults.

Spontaneous free perforation of the small intestine is uncommon, especially if there is no prior history of visceral trauma. However, free, even recurrent, perforation may complicate a defined and established clinical disorder, such as Crohn's disease. In addition, free perforation may be the initial clinical presentation of an occult intestinal disorder, such as a lymphoma complicating celiac disease, causing diffuse peritonitis and an acute abdomen. Initial diagnosis of the precise cause may be difficult, but now has been aided by computerized tomographic imaging. The site of perforation may be helpful in defining a cause (e.g., ileal perforation in Crohn's disease, jejunal perforation in celiac disease, complicated by lymphoma or collagenous sprue). Urgent surgical intervention, however, is usually required for precise diagnosis and treatment. During evaluation, an expanding list of other possible causes should be considered, even after surgery, as subsequent management may be affected. Free perforation may not only complicate an established intestinal disorder, but also a new acute process (e.g., caused by different infectious agents) or a longstanding and unrecognized disorder (e.g., congenital, metabolic and vascular causes). Moreover, new endoscopic therapeutic and medical therapies, including use of emerging novel biological agents, have been complicated by intestinal perforation. Recent studies also support the hypothesis that perforation of the small intestine may be genetically-based with different mutations causing altered connective tissue structure, synthesis and repair.

Natural history and long-term clinical course of Crohn's disease.

Crohn's disease is a chronic inflammatory disease process involving different sites in the gastrointestinal tract. Occasionally, so-called metastatic disease occurs in extra-intestinal sites. Granulomatous inflammation may be detected in endoscopic biopsies or resected tissues. Genetic, epigenetic and environmental factors appear to play a role. Multiple susceptibility genes have been described in both familial and non-familial forms while the disease is phenotypically heterogeneous with a female predominance. The disorder occurs over a broad age spectrum, from early childhood to late adulthood. More than 80% are diagnosed before age 40 years usually with terminal ileal and colonic involvement. Pediatric-onset disease is more severe and more extensive, usually with a higher chance of upper gastrointestinal tract disease, compared to adult-onset disease. Long-term studies have shown that the disorder may evolve with time into more complex disease with stricture formation and penetrating disease complications (i.e., fistula, abscess). Although prolonged remission may occur, discrete periods of symptomatic disease may re-appear over many decades suggesting recurrence or re-activation of this inflammatory process. Eventual development of a cure will likely depend on identification of an etiologic cause and a fundamental understanding of its pathogenesis. Until now, treatment has focused on removing risk factors, particularly cigarette smoking, and improving symptoms. In clinical trials, clinical remission is largely defined as improved numerical and endoscopic indices for "mucosal healing". "Deep remission" is a conceptual, more "extended" goal that may or may not alter the long-term natural history of the disease in selected patients, albeit at a significant risk for treatment complications, including serious and unusual opportunistic infections.

Non-dietary forms of treatment for adult celiac disease.

At present, treatment for celiac disease includes a strict gluten-free diet. Compliance, however, is difficult and gluten-free food products are costly, and, sometimes very inconvenient. A number of potential alternative measures have been proposed to either replace or supplement gluten-free diet therapy. In the past, non-dietary forms of treatment were used (e.g., corticosteroids) by some clinicians, often to supplement a gluten-free diet in patients that appeared to be poorly responsive to a gluten-free diet. Some of new and novel non-dietary measures have already advanced to a clinical trial phase. There are still some difficulties even if initial studies suggest a particularly exciting and novel form of non-dietary treatment. In particular, precise monitoring of the response to these agents will become critical. Symptom or laboratory improvement may be important, but it will be critical to ensure that ongoing inflammatory change and mucosal injury are not present. Therapeutic trials will be made more difficult because there is already an effective treatment regimen.

Natural history and long-term outcomes of patients treated for early stage colorectal cancer.

BACKGROUND: The long-term natural history of early stage colon cancer and the outcome of long-term colonoscopic surveillance in routine specialist clinical practice after removal of the incident cancers have not been fully defined. In the present long-term evaluation up to 25 years, metachronous neoplasia, including both advanced adenomas and carcinomas, was defined. METHODS: All early stage colorectal cancer patients evaluated consecutively from a single clinical practice underwent follow-up colonoscopic evaluations after removal of the incident cancer and clearing of neoplastic disease. Colonoscopic surveillance was planned for two phases - initially on an annual basis for five years, followed by continued surveillance every three years up to 25 years with removal of any metachronous neoplastic lesion. RESULTS: A total of 128 patients (66 men and 62 women) with 129 incident early stage colorectal cancers were evaluated. Virtually all patients were symptomatic, usually with clinical evidence of blood loss. Incident early cancers were located throughout the colon, especially in the rectosigmoid, and showed no pathological evidence of nodal or other metastases. All patients evaluated during the first five years did not experience recurrent disease or have metachronous cancer detected. After five years, a total of 94 patients were evaluated up to 25 years; six of these patients were found to have seven metachronous colon cancers. All developed cancer more than seven years after removal of the incident colorectal cancer, including six asymptomatic adenocarcinomas, of which only one had evidence of single node involvement. Another patient in this cohort developed a poorly differentiated neuroendocrine carcinoma of the colon. In addition, 45% of patients had a total of 217 adenomas removed, including 11% of patients with 33 advanced adenomas. Among 14 patients with advanced adenomas, seven (50%) developed ≥1 late metachronous cancers. CONCLUSIONS: Following removal of an incident symptomatic early stage colorectal cancer, the risk of later metachronous neoplasia persists for an extended period more than five years after removal of the incident colorectal cancer. Moreover, risk for late metachronous cancer appears to be predicted by the presence of multiple adenomas or advanced adenomas; most metachronous cancers in this cohort were detected using colonoscopy before onset of symptoms and at an early stage.

Detection of adult celiac disease with duodenal screening biopsies over a 30-year period.

BACKGROUND: Serological studies suggest that celiac disease may be present in approximately 0.5% to 1% of the North American population. Screening data based on small intestinal biopsy performed during routine endoscopic evaluations are not available. METHODS: Patients referred between January 1982 and December 2011 for evaluation of gastrointestinal symptoms and requiring elective investigative upper endoscopic evaluation underwent duodenal biopsies to determine whether changes of adult celiac disease were present. RESULTS: A total of 9665 patients, including 4008 (41.5%) males and 5657 (68.5%) females, underwent elective endoscopies and duodenal biopsies. Of these, 234 (2.4%) exhibited changes of celiac disease including 73 males (1.8%) and 161 females (2.8%). During the first 20 years, the number of biopsy-positive patients in five-year intervals progressively decreased and, subsequently, during the next 10 years, the number progressively increased. CONCLUSIONS: Celiac disease is far more common in specialist practice than has been suggested in the evaluation of healthy populations using serological screening studies. Endoscopic duodenal biopsy is an important method of identifying underlying celiac disease and should be routinely considered in all patients undergoing an elective endoscopic evaluation. Noninherited factors, possibly environmental, may play a role in the appearance of biopsy-defined celiac disease and alter detection over time.

Long-term follow-up of patients with malignant pedunculated colon polyps after colonoscopic polypectomy.

BACKGROUND: Previously published studies have suggested that patients with resected colon cancer have an increased risk for early metachronous colon cancer. Current screening guidelines recommend intense surveillance by colonoscopy for the initial five years after the initial colon cancer has been resected. Information regarding endoscopically removed malignant polyps is limited. METHODS: In the present study, 25 consecutive patients (14 male, 11 female) with malignant pedunculated colon polyps treated with snare cautery polypectomy were followed for more than one decade up to 20 years. Five patients required an additional resection to ensure that removal of the original cancer was complete. Annual colonoscopies were planned for five years. If an adenoma was detected in the fifth year, colonoscopy was performed annually until no adenomas were detected. Otherwise, colonoscopy was planned every three years after five years. RESULTS: In the present study, there was no mortality from colon cancer and no patient developed either recurrent colon cancer or an early metachronous colon cancer during the initial five-year period of surveillance. Two patients (one male, one female) ultimately developed late cecal cancers almost one decade after the original colon cancers were resected. One had an early stage cancer that was resected, while the other had an infiltrating mucinous carcinoma complicating a small tubulovillous adenoma with extension to a single lymph node. After surgical removal and adjuvant chemotherapy, no further neoplastic disease has been detected. CONCLUSIONS: Overall, patients with malignant pedunculated polyps do extremely well if appropriately managed at the time of the initial polypectomy. Short-term outcomes after removal of a malignant polyp(s) appear to be similar to those with a nonmalignant polyp. However, late metachronous colon cancer may still occur. Long-term follow-up should be considered in each patient, assuming reasonable life expectancy, because risk of additional adenomas and metachronous colon cancer persists even after the initial five years of currently recommended surveillance. Patients with resected malignant polyps may represent a special patient subgroup that requires surveillance for more extended periods than current guidelines have recommended.

Early stage colon cancer.

Evidence has now accumulated that colonoscopy and removal of polyps, especially during screening and surveillance programs, is effective in overall risk reduction for colon cancer. After resection of malignant pedunculated colon polyps or early stage colon cancers, long-term repeated surveillance programs can also lead to detection and removal of asymptomatic high risk advanced adenomas and new early stage metachronous cancers. Early stage colon cancer can be defined as disease that appears to have been completely resected with no subsequent evidence of involvement of adjacent organs, lymph nodes or distant sites. This differs from the clinical setting of an apparent "curative" resection later pathologically upstaged following detection of malignant cells extending into adjacent organs, peritoneum, lymph nodes or other distant sites, including liver. This highly selected early stage colon cancer group remains at high risk for subsequent colon polyps and metachronous colon cancer. Precise staging is important, not only for assessing the need for adjuvant chemotherapy, but also for patient selection for continued surveillance. With advanced stages of colon cancer and a more guarded outlook, repeated surveillance should be limited. In future, novel imaging technologies (e.g., confocal endomicroscopy), coupled with increased pathological recognition of high risk markers for lymph node involvement (e.g., "tumor budding") should lead to improved staging and clinical care.

Colitis associated with biological agents.

In the past, there has been considerable focus on a host of drugs and chemicals that may produce colonic toxicity. Now, a variety of new biological monoclonal antibody agents, usually administered by infusion, have appeared in the clinical realm over the last decade or so to treat different chronic inflammatory or malignant disorders.For some of these agents, adverse effects have been documented, including apparently new forms of immune-mediated inflammatory bowel disease. In some, only limited symptoms have been recorded, but in others, severe colitis with serious complications, such as bowel perforation has been recorded. In others, adverse effects may have a direct vascular or ischemic basis, while other intestinal effects may be related to a superimposed infection. Some new onset cases of ulcerative colitis or Crohn's disease may also be attributed to the same agents used to treat these diseases, or be responsible for disease exacerbation. Dramatic and well documented side effects have been observed with ipilimumab, a humanized monoclonal antibody developed to reduce and overcome cytotoxic T-lymphocyte antigen 4, a key negative feedback regulator of the T-cell anti-tumor response. This agent has frequently been used in the treatment of different malignancies, notably, malignant melanoma. Side effects with this agent occur in up to 40% and these are believed to be largely immune-mediated. One of these is a form of enterocolitis that may be severe, and occasionally, fatal. Other agents include rituximab (an anti-CD20 monoclonal antibody), bevacizumab (a monoclonal antibody against the vascular endothelial growth factor) and anti-tumor necrosis factor agents, including infliximab, adalimumab and etanercept.