Immunohistochemical and T-cell receptor gene rearrangement analyses as predictors of morbidity and mortality in refractory celiac disease.

BACKGROUND: Classification of refractory celiac disease (RCD) is based on the presence or absence of monoclonal expansions of intraepithelial lymphocytes (IELs) with an aberrant immunophenotype. GOALS: To investigate the contribution of IEL parameters toward mortality and morbidity in RCD. STUDY: IEL phenotype by immunohistochemistry and T-cell receptor (TCR) gene rearrangement by polymerase chain reaction were assessed in 73 RCD patients (type I=67, type II=6). Detection of a monoclonal TCR gene rearrangement and presence of <50% CD3 CD8 IELs were considered abnormal. Time to worsening of clinical symptoms and predictors of worsening were calculated by Kaplan-Meier and Cox proportional hazard analyses. RESULTS: Fewer than 50% CD3 CD8 IELs were detected in 30 patients and monoclonal TCR rearrangements in 6. Three patients died and 40 suffered clinical worsening despite treatment. Estimated 5-year survival rates decreased from 100% in patients with >50% CD3 CD8 IELs and polyclonal TCR to 88% and 50% in patients with <50% CD3 CD8 IELs and monoclonal TCR, respectively. Clinical worsening was more frequent (100%) among patients harboring a monoclonal TCR gene rearrangement with <50% CD3 CD8 IELs. These patients also showed shorter median time to clinical worsening (11 mo) when compared to patients with <50% CD3 CD8 IELs alone (21 mo), polyclonal TCR (38 mo), or >50% CD3 CD8 IELs alone (66 mo). After adjusting for age and gender, only the presence of <50% CD3 CD8 IELs was associated with increased risk for clinical worsening despite negative celiac serologies (hazard ratio=4.879; 95% confidence interval, 1.785-13.336; P=0.002). CONCLUSIONS: Presence of <50% CD3 CD8 IELs is a risk factor for clinical worsening in RCD and combined with a monoclonal TCR gene rearrangement result is associated with increased mortality. IEL phenotype and TCR gene rearrangement analyses provide differential information regarding morbidity and mortality in RCD.

Celiac disease: similar presentations in the elderly and young adults.

BACKGROUND/AIMS: Studies have shown that celiac disease can affect individuals in all age groups. However, few studies have described the disease in the elderly. The goal of this study is to characterize celiac disease in the elderly by comparing to a population of young adults with celiac disease. METHODS: Review of a tertiary center database of patients with celiac disease was performed to identify two groups of patients, an elderly cohort ≥ 65 years and a young adult cohort aged 18-30 years, with biopsy-confirmed celiac disease. Information obtained included symptom duration, clinical presentation, small intestinal pathology, associated conditions, and the presence of bone disease. RESULTS: Included in the study were 149 young adult and 125 elderly patients; the latter represented 12.4% of the patients in our database. The duration of symptoms prior to diagnosis was similar, 5.8 ± 12 years and 6.14 ± 12.6 years in the young adult and elderly cohorts, respectively (p = 0.119). There was no significant difference in the mode of presentation of illness. Diarrhea was the main presenting symptom (49% in young adults vs. 50% in the elderly, p = 0.921). There was a similar prevalence of autoimmune disease (19% in young adults vs. 26% in the elderly, p = 0.133). Thyroid disease and neuropathy were more prevalent in the elderly (p = 0.037 and p = 0.023, respectively). The degree of villous atrophy and prevalence of bone disease were similar in each group. CONCLUSIONS: Surprisingly, the presentation of celiac disease both clinically and histologically is similar in elderly and young adult patients. The factors triggering disease at any given age remain unclear and warrant further study.

Body mass index in celiac disease: beneficial effect of a gluten-free diet.

BACKGROUND: There is concern about celiac disease patients being overweight and gaining more weight while on a gluten-free diet (GFD). AIM: To investigate body mass index (BMI) and effect of GFD on BMI of celiac disease patients in the United States where obesity is a systematic problem. METHODS: BMI at diagnosis and after 2.8 years (mean) on a GFD were compared with national data. RESULTS: Among our patients (n=369, 67.2% female), 17.3% were underweight, 60.7% normal, 15.2% overweight, and 6.8% obese. All patients were followed by a dietitian. Compared with national data, females had lower BMI (21.9 vs. 24.2, P<0.0001) and fewer were overweight (11% vs. 21%, P<0.0001); more males had a normal BMI (59.5% vs. 34%, P<0.0001) and fewer were underweight (9.1% vs. 26.7%, P<0.0001). Factors associated with low BMI were female sex, Marsh IIIb/c histology, and presentation with diarrhea. On GFD, 66% of those who were underweight gained weight, whereas 54% of overweight and 47% of obese patients lost weight. CONCLUSIONS: A GFD had a beneficial impact on BMI, underweight patients gained weight and overweight/obese patients lost weight. The improvement in BMI adds to the impetus to diagnose celiac disease. Expert dietary counseling may be a major factor in the beneficial effects we noted.

The association between celiac disease, dental enamel defects, and aphthous ulcers in a United States cohort.

GOALS AND BACKGROUND: European studies have demonstrated that dental enamel defects and oral aphthae are observed in celiac disease (CD). We investigated this association in a US population. STUDY: Biopsy proven CD patients and controls were recruited from a private dental practice and from CD support meetings. History of aphthae was taken and dental examination was performed by a single dentist. Teeth were photographed and enamel defects graded according to the Aine classification. A second dentist reviewed all photographs. RESULTS: Among patients (n=67, mean age 34.8+/-21.6 y) compared with controls (n=69, mean age 28.1+/-15.7 y), there were significantly more enamel defects [51% vs. 30%, P=0.016, odds ratio (OR) 2.4, 95% confidence interval (CI) 1.2-4.8]. This was confined to children (87% vs. 33%, P=0.003, OR 13.3, 95% CI 3.0-58.6), but not adults (32% vs. 29%, P=0.76, OR 1.2, 95% CI 0.5-2.8). This was reflected in defects being observed in those with mixed dentition compared with those with permanent dentition (68.4% vs. 29.6%, P<0.0001). The degree of agreement between the 2 dentists was good (kappa coefficient=0.53, P<0.0001), aphthous ulcers were more frequent in CD than controls (42.4% vs. 23.2%, P=0.02). CONCLUSIONS: This study supports that CD is highly associated with dental enamel defects in childhood, most likely because of the onset of CD during enamel formation; no such association was found in adults. Our study also supports the association between CD and aphthous ulcer. All physicians should examine the mouth, including the teeth, which may provide an opportunity to diagnose CD. In addition, CD should be added to the differential diagnosis of dental enamel defects and aphthous ulcers.

The use of corticosteroids and nonsteroidal antiinflammatory medication for the management of pain and inflammation after third molar surgery: a review of the literature.

The use of medication to relieve pain and inflammation after removal of third molars has been explored thoroughly in the literature. Narcotic analgesics, nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, and combinations of these all have a role in the postoperative management of pain and swelling within this group of patients. This article addresses the use of NSAIDs and corticosteroids after third molar surgery, along with a review of the literature, which is incorporated to provide practitioners helpful, quick, and reliable information regarding patients undergoing third molar surgery.

Off-label use of recombinant human bone morphogenetic protein-2 (rhBMP-2) for reconstruction of mandibular bone defects in humans.

PURPOSE: The off-label use of recombinant human bone morphogenetic protein-2 (rhBMP-2) for the treatment of mandibular bone defects was evaluated in 5 patients. The rhBMP-2 was used as an alternative to autogenous bone grafting. PATIENTS AND METHODS: A total of 5 patients had mandibular defects reconstructed with rhBMP-2, 1.5 mg/mL, soaked collagen sponges alone or in combination with bone marrow cells and allogenic cancellous bone chips. Four of the patients had mandibular continuity defects and the fifth patient had 2 large bone cavities following removal of dentigerous cysts. Radiographs and clinical examinations were used to evaluate healing. The longest patient follow-up was 22 months after reconstruction. RESULTS: Radiographic and clinical assessments revealed bone regeneration and restoration of the mandibular defects in 3 of the 5 patients. The rhBMP-2 failed in 2 patients with continuity defects. Both patients with failed rhBMP-2 grafts were successfully repaired using autogenous harvested from the iliac crest. CONCLUSION: Mandibular bone defects can be successfully reconstructed using rhBMP-2 soaked sponges with and without including bone marrow cells and allogenic bone. Further studies are needed to determine the ideal combination of components that will predictably and reliably regenerate bone in different types of bone defects.

Budesonide in the treatment of refractory celiac disease.

OBJECTIVE: Corticosteroids are used in patients with refractory celiac disease. In order to minimize their systemic side effects, we assessed the role of a locally active sustained release corticosteroid with minimal systemic bioavailability in patients with refractory celiac disease in an open labeled noncontrolled study. METHODS: Patients who received budesonide for refractory celiac disease were classified according to whether they were primarily or secondarily unresponsive to the diet, and whether they had a polyclonal (type I) or clonal (type II) expansion of intraepithelial lymphocytes. The response to budesonide was assessed globally and by reduction in bowel movements. RESULTS: Patients (N = 29, 72% female) received budesonide for a mean of 6.7 +/- 8.5 months, 5 patients (18%) had type II disease (clonal T-cell population); 76% responded to the medication, 55% completely. Response occurred when budesonide was used alone or with oral corticosteroids and/or azathioprine. There was an objective improvement in the number of bowel movements in those that responded. Response occurred in those with either primary or secondary refractory disease and in those with type II disease, irrespective of the presence of microscopic colitis (N = 7). There was no improvement in the duodenal biopsy over the study period and there were no side effects of budesonide. CONCLUSIONS: Budesonide may be of value in the management of refractory celiac disease.

A protocol for the management of frontal sinus fractures emphasizing sinus preservation.

PURPOSE: The purpose of this retrospective study is to review the incidence and etiology of frontal sinus fractures at an urban trauma center and validate a treatment protocol by assessing the outcome of a consecutive series of patients treated over a 10-year period. PATIENTS AND METHODS: All patients with frontal sinus fractures admitted to our trauma service from 1995 to 2005 were managed by the same surgeons using similar treatment philosophies based on the amount of displacement or comminution of the anterior and/or posterior table, the integrity of the nasofrontal duct, and the neurologic status of the patient as determined by clinical and radiographic examination. Using information obtained from the Trauma Registry and from individual physician chart notes, a database was created for the purpose of assessing outcome, defined as complications, length of hospital stay, and death. Demographics, injury severity score, fracture pattern, mechanism of injury, length of hospital stay, the number of operations, concomitant maxillofacial injuries, treatment, follow-up, and complications were statistically described. Outcome measures were evaluated by Student's t test using continuous variables. RESULTS: One thousand two hundred seventy-five patients with facial fractures were identified during the study period, of which 144 patients (11.3%) carried the diagnosis of frontal sinus fracture; 28 patients had inadequate records, leaving a study group of 116 patients. The majority of patients were male, had a mean age of 33.7 years, and presented with significant injuries demonstrated by a mean injury severity score of 23.7 and mean length of hospital stay of 8.9 days. The most common mechanisms of injury were blunt trauma resulting from a motor vehicle collision, fall, assault, or other accidents. Sixty-six patients presented with nondisplaced frontal sinus fractures that were managed nonoperatively; 50 patients had frontal sinus injuries that required surgical repair consisting of: 1) open reduction and internal fixation of the anterior table alone, with preservation of the sinus membrane (n = 29); 2) removal of all sinus mucosa, obliteration of the frontal sinus with autogenous abdominal fat, and reconstruction of the anterior table (n = 5); and 3) removal of all sinus mucosa, cranialization of the frontal sinus, and lining of the nasofrontal recess with a pericranial flap (n = 16). Six patients died of concomitant injuries. With follow-up ranging between 0 and 90 weeks, there were no known complications in the patients treated nonoperatively; 82% of the patients maintained normal sinus function and anatomy and the overall complication rate was 6.9%. Complications occurred in 16% of those patients treated surgically: including brain abscess, contour deformity, osteomyelitis, hematoma, meningitis, and mucocele. There was no statistically significant association between complications and other patient variables (P > .05), other than the test for injury severity score, which was different between survivors and nonsurvivors (P < .01). CONCLUSION: Application of the management protocol described in this report results in functional sinus preservation for the majority of patients, with relatively few significant perioperative complications.

Change in lipid profile in celiac disease: beneficial effect of gluten-free diet.

PURPOSE: Celiac disease is associated with hypocholesterolemia, which is thought to contribute to a favorable cardiovascular risk profile. This led to suggestions that the diagnosis of celiac disease and its treatment with a gluten-free diet may result in elevation of the serum cholesterol level and worsen this risk profile. However, no study proves this in adults. We therefore examined the effect of a gluten-free diet on the lipid profile in patients with celiac disease. SUBJECTS AND METHODS: We identified 132 patients with celiac disease who adhered to a gluten-free diet and had lipid profiles performed before and after a median of 20.5 months on the diet. The patients lacked diseases that may affect serum lipids. RESULTS: There were significant increases in total cholesterol and high-density lipoprotein (HDL) cholesterol (P < .0001) but not low-density lipoprotein (LDL) cholesterol (P=.06). The LDL/HDL ratio decreased by 0.36+/-0.7 (P < .0001). Both men and women had a significant increase in total cholesterol and HDL and a significant decrease in the LDL/HDL ratio. Only men had increases in LDL (P=.02). The greatest increase in lipid values was seen in those with the lowest initial values. The largest increase in HDL was seen in subjects with more severe disease as indicated by low albumin level and presence of total villous atrophy. CONCLUSIONS: Diagnosis of celiac disease and its treatment with a gluten-free diet resulted in improvement in the lipoprotein profile, which included an increase in HDL and a decrease in the LDL/HDL ratio.

Celiac disease in African-Americans.

Celiac disease is generally under diagnosed in the United States and it is unclear whether the disease is encountered in ethnic minorities. Our purpose is to describe a case series of African-American patients with celiac disease. Nine (1.3%) African-American patients with celiac disease were identified from a prospectively generated database of 700 patients with biopsy proven celiac disease and seen between 1981 and 2004. Females predominated, with seven, compared to two males. Diarrhea was the presentation in only two patients, while three presented with iron deficiency anemia. One third had at least one autoimmune disease. Compliance with a gluten-free diet, the only medical therapy of this disease, was poor. Only four patients adhered strictly to the diet. Celiac disease occurs in African-Americans and may well be underdiagnosed. Special attention needs to be given to methods that encourage adherence to the diet in minority groups.

Utility in clinical practice of immunoglobulin a anti-tissue transglutaminase antibody for the diagnosis of celiac disease.

BACKGROUND & AIMS: The diagnosis of celiac disease often relies on the anti-tissue transglutaminase (tTG) antibody test. The aim of this study was to evaluate its sensitivity and specificity in clinical practice with the use of commercial laboratories, in which the test characteristics might differ from research laboratories. METHODS: We identified 122 patients with suspected celiac disease who had anti-tTG antibody serologies as well as upper endoscopy with duodenal biopsies. Those with celiac disease were classified as either classic (with diarrhea or other symptoms of malabsorption) or silent (asymptomatic). Biopsies from celiac disease patients were classified as either partial (Marsh IIIA) or total (Marsh IIIB or IIIC) villous atrophy. RESULTS: The overall sensitivity, specificity, and positive and negative predictive values of the anti-tTG antibody test were 70.6%, 65.0%, 91.1%, and 30.2%, respectively. The sensitivity was 90.0% for patients with total villous atrophy and 42.3% for patients with partial villous atrophy (P < .0001). There were differences in both sensitivity and specificity between the 2 most commonly used commercial laboratories. The sensitivity for Lab #1 was 40.0% versus 86.4% for Lab #2 (P < .0001). The specificity for Lab #1 was 100.0%, and it was 41.7% for Lab #2 (P = .02). CONCLUSIONS: The sensitivity of the anti-tTG antibody in clinical practice is not as high as previously reported in research laboratories. The sensitivity is significantly lower in patients with partial villous atrophy. There is also significant variability in test characteristics among major commercial laboratories in the United States. These results need to be confirmed in prospective studies.

Trends in the presentation of celiac disease.

PURPOSE: Screening studies have revealed that celiac disease is common in the United States; however, there are scant data on the mode of presentation. We analyzed the trends in clinical presentation over the last 52 years in a large cohort of biopsy-proven patients seen in 1 center. SUBJECTS AND METHODS: Patients (n = 590) were divided into 6 groups based on the year of diagnosis (1952-2004). Groups were compared for trends in age at diagnosis, childhood diagnosis, duration of symptoms, mode of presentation (diarrhea, bone disease, anemia, incidental at esophagogastroduodenoscopy, screening), and presence of malignancy. RESULTS: Diagnosis was at an older age since 1980 (P = .007), and there was a significant negative linear trend in patients presenting with diarrhea (P<.001) over time and a positive linear trend in asymptomatic patients detected on screening (P<.001). There was a significant negative linear trend in patients with a malignancy (P = .02) and duration of symptoms before diagnosis of celiac disease (P = .001), although only the subgroup without diarrhea had improvement in delay of diagnosis of celiac disease (assessed by a shorter duration of symptoms) (P = .05). Comparison of patients with and without diarrhea showed no significant difference in age (42.9 years vs 43.7 years, P = .59), gender (29.3% M vs 34.6%, P = .59), and presence of childhood disease (8.0% vs 9.8%, P = .43) or malignancies (9.8% vs 8.9%, P = .71). CONCLUSION: There is a trend toward fewer patients presenting with symptomatic celiac disease characterized by diarrhea and a significant shift toward more patients presenting as asymptomatic adults detected at screening.

Effect of gender on the manifestations of celiac disease: evidence for greater malabsorption in men.

OBJECTIVE: Because celiac disease is a female-predominant disease we investigated the influence of gender on clinical manifestations of the disease in the United States. MATERIAL AND METHODS: Data were obtained on biopsy-proven adult patients with celiac disease from a database of patients seen between 1981 and 2001 in a University-based referral center. Z scores were calculated to adjust for age, ethnicity and gender using the National Health and Nutrition Examination Survey database as controls. RESULTS: The cohort consisted of 323 patients (211 F, 112 M). Men had a shorter duration of symptoms than women (p=0.006). There was no gender difference in the age at diagnosis or mode of presentation. Body mass index (BMI), mean hemoglobin and ferritin values were lower in women than in men, but the Z scores for these values were not significantly different, indicating that the differences are physiological. All lipid values were low (negative Z scores). Men had lower total cholesterol (162.0+/-46.5mg/dl) compared to women (181.0+/-40.0mg/dl), p=0.02 and lower Z scores (-1.10+/-1.1) compared to women (-0.71+/-0.9), p=0.04. Men had lower bone density T scores at the radius (p=0.07). Autoimmune diseases were present in 30.7% with a female to male ratio of 1:1, compared to the general population in which 3.2% have autoimmune diseases with a female predominance. CONCLUSIONS: Most gender differences in celiac disease are physiological. However, men have indirect evidence of greater malabsorption than females and have female-predominant associated diseases when they present with celiac disease.

Preemptive rofecoxib and dexamethasone for prevention of pain and trismus following third molar surgery *.

Objective The goal of this preliminary randomized prospective clinical trial was to compare the analgesic efficacy and the reduction in trismus of preoperative rofecoxib, intraoperative dexamethasone, and both rofecoxib and dexamethasone following third molar extraction surgery. Study design Thirty-five subjects requiring surgical removal of at least 1 partial bony impacted mandibular third molar were invited to participate in this double-blind and double-dummy placebo-controlled clinical trial. Subjects were randomly assigned into 1 of 4 treatment groups: (1) placebo po preoperatively and placebo IV intraoperatively; (2) rofecoxib 50 mg po preoperatively and placebo IV intraoperatively; (3) placebo po preoperatively and dexamethasone10 mg IV intraoperatively; and (4) rofecoxib 50 mg po preoperatively and dexamethasone 10 mg IV intraoperatively. Subjects completed a diary assessing postoperative pain onset and intensity using categorical and visual analogue scales. Interincisal opening was assessed 1, 2, 3, and 7 days postoperatively using a Therabite ruler. Results This randomized controlled clinical trial enrolled 35 subjects. Two subjects did not meet the inclusion criteria and 4 did not return completed diaries. The mean age of the remaining 29 subjects (11 males, 18 females) was 22.8 years (+/- 0.6 year). The active treatments tended to delay the need for initial pain medication. When compared to other active treatments and to placebo, the combination of preoperative rofecoxib and intraoperative dexamethasone significantly reduced initial pain intensity ( P < .05). Baseline interincisal opening was 52.6 mm (+/- 6.2). The greatest decrease in interincisal opening was 43.3% for the placebo group at 24 hours. Preoperative rofecoxib alone showed a decrease in interincisal opening of 42.3% ( P = ns) at 24 hours. Intraoperative dexamethasone alone showed a decrease in the interincisal opening of 24.1% of baseline ( P < .05 vs placebo). The group receiving the combination of rofecoxib and dexamethasone showed a decrease in interincisal opening of 23.7% of baseline ( P < .05 vs placebo). Conclusions The results of this trial indicate that the use of intraoperative dexamethasone is an effective therapeutic strategy for limiting trismus following surgical removal of impacted third molars. The combination of preoperative rofecoxib 50 mg and intraoperative dexamethasone 10 mg was most effective in minimizing pain and trismus following third molar surgery.