ATP8B1, ABCB11, and ABCB4 Genes Defects: Novel Mutations Associated with Cholestasis with Different Phenotypes and Outcomes.

OBJECTIVES: To characterize the clinical, laboratory, histologic, molecular features, and outcome of gene-confirmed progressive familial intrahepatic cholestasis (PFIC) 1-3 among Arabs and to evaluate for "genotype-phenotype" correlations. STUDY DESIGN: We retrospectively reviewed charts of 65 children (ATP8B1 defect = 5, ABCB11 = 35, ABCB4 = 25) who presented between 2008 and 2019 with cholestasis. The clinical phenotype of a disease was categorized based on response of cholestasis and itching to ursodeoxycholic acid and ultimate outcome, into mild (complete response), intermediate (partial response, nonprogressive), and severe (progression to end-stage liver disease). RESULTS: Overall, 27 different mutations were identified (ATP8B1, n = 5; ABCB11, n = 11; ABCB4, n = 11), comprising 10 novel ones. Six patients with heterozygous missense mutations (ATP8B1, n = 2; ABCB11, n = 4) had transient cholestasis. Of the remaining 3 patients with PFIC1, 2 developed severe phenotype (splicing and frameshift mutations). Of the remaining 31 patients with PFIC2, 25 developed severe disease (15 due to frameshift and splicing mutations). Of 25 patients with PFIC3, 10 developed a severe phenotype (1 splicing and 3 frameshift mutations; 6 missense). Patients with PFIC2 had significantly shorter survival time and more rapid disease progression than patients with PFIC3 (P < .001). Patients with frameshift mutations in ABCB11 gene (p.Thr127Hisfs∗6) and ABCB4 gene (p.Phe210Serfs∗5) had significantly shorter survival time than missense mutations (P = .011; P = .0039, respectively). CONCLUSIONS: We identified genotype-phenotype correlations among mutations in ABCB11 and ABCB4 genes, which underscore the prognostic value of early genetic diagnosis. The disease course in patients with PFIC3 could be favorably modified by ursodeoxycholic acid therapy.

Deamidated Gliadin Antibodies: Do They Add to Tissue Transglutaminase-IgA Assay in Screening for Celiac Disease?

OBJECTIVES: Use of deamidated gliadin peptide (DGP) test kits as adjunctive to tissue-transglutaminase-IgA (TTG-IgA) for the diagnosis of celiac disease (CD) has been a controversial issue. The objectives of our study were to evaluate the diagnostic performance of DGP antibodies compared with TTG-IgA and to evaluate the correlation between DGP-antibody titers and degree of enteropathy. METHODS: We included children who underwent endoscopy and biopsies because of positivity of any of the serology tests in the "celiac profile" (TTG-IgA, DGP-IgA, and DGP-IgG) from 2012 to 2019. We divided children into clinically suspected cases of CD (group 1) and asymptomatic cases screened as they were from a high-risk group (group 2). RESULTS: Group 1 constituted 52 children and group 2 included 81 children (76 type-1 diabetes [T1D]). The sensitivity and positive-predictive value (PPV) of DGP-IgG in group 1 (90%, 98%) and group 2 (91%, 85.5%) were comparable with TTG-IgA (98%, 92% in group 1; 100%, 80% in group 2). By adding DGP-IgG to TTG-IgA, the performance of TTG-IgA has improved marginally in group 1 (sensitivity 100%, PPV 92.3%). All cases with DGP-IgG titer 2 times ULN in group 1, and >4 times ULN in group 2 had villous atrophy. All T1D patients with TTG IgA >10 times ULN had villous atrophy. CONCLUSIONS: DGP-IgG assay did not add to the performance of TTG-IgA. DGP-IgG titer correlated with enteropathy. The diagnosis of CD can be made in asymptomatic T1D child with TTG-IgA titer >10 times ULN and positive endomyseal antibodies.

Mass Screening for Celiac Disease Among School-aged Children: Toward Exploring Celiac Iceberg in Saudi Arabia.

OBJECTIVES: We conducted this mass screening study to determine the prevalence of celiac disease (CD) and characterize the celiac iceberg among Saudi pediatric population in Riyadh, the capital city of Saudi Arabia. METHODS: During the study period (January 2014-June 2016), we have conducted a cross-sectional, mass screening, immunoglobulin A-tissue transglutaminase (TTG-IgA)-based study on 7930 Saudi students from primary and intermediate schools in Riyadh. Students with positive TTG-IgA (>20 U/L) were called in the hospital to undergo a repeat of TTG-IgA; in those with borderline positive TTG-IgA (20-60 U/L), IgA-endomyseal antibody (EMA-IgA) test was performed. Children with TTG-IgA >60 U/L and children with borderline positive TTG-IgA and positive EMA-IgA were advised to undergo upper endoscopy and intestinal biopsies. RESULTS: We identified 221 students with positive TTG-IgA (2.8%). CD was diagnosed in 119 cases (1.5%, 1:67 Saudi children) (mean age 11.5 ±â€Š2.62 years; girls 81 [68%]). Another 51 children had persistently borderline positive TTG-IgA but negative EMA (0.64%) and the remaining 51 had transiently positive TTG-IgA. We have identified 3 clinical patterns in the screening-identified cases with CD: a silent form (37%), a mild symptomatic form characterized by gastrointestinal symptoms in presence of normal growth or overweight/obesity (48%), and gastrointestinal symptoms associated with impaired growth in 15%. CONCLUSIONS: Our study provided evidence of a high prevalence of CD among Saudi children (1.5%), a rate that is at least twice the average prevalence rate in Europe and North America.

Features of nonalcoholic steatohepatitis in severely obese children and adolescents undergoing sleeve gastrectomy.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is an underrecognized co-morbidity of obesity. The characteristic features and severity of NAFLD in severe childhood obesity remain unknown. OBJECTIVES: To investigate features of NAFLD in obese children and identify predictors of significant disease. SETTING: Academic center with a standardized pathway for pediatric bariatric surgery and a dedicated multidisciplinary team. DESIGN: This is a baseline cross-sectional analysis for a data set obtained from a prospective clinical outcome study that included severely obese children (≤14 yr of age) and adolescents (14-21 yr of age) who underwent laparoscopic sleeve gastrectomy between March 2008 and March 2015. Patients with syndromic obesity, history of alcohol intake, parenteral nutrition, liver disease, intake of medications that may affect NAFLD and weight, and insufficient tissue biopsy were excluded. Prevalence and features of nonalcoholic steatohepatitis (NASH) and clinically significant liver fibrosis in different pediatric age groups and noninvasive predictors in severe childhood obesity were evaluated. RESULTS: The 296 patients in the study group (1:1 sex distribution) had a mean body mass index and age of 48.4±9.8 kg/m2 and 14.5±3.6 years, respectively. According to histopathology assessment, 225 (76%) patients had NAFLD, of whom 118 patients (39.9% of the total cohort) had NASH. Additionally, 110 (37.2%) had clinically significant (stage 2+) fibrosis and 256 (86.5%) had portal inflammation. Those with NASH were younger than those without NASH (P = .02; prevalence of NASH in children aged≤10 yr = 64.9%) and were more likely to be male (P = .003). Of children aged≤10 years, 60% had clinically significant fibrosis compared with 32% of older patients (P = .03). High-density lipoproteins, triglycerides, glycated hemoglobin, alanine transaminase, and systolic and diastolic blood pressure levels were most predictive of fibrosis. For NASH, triglycerides, homeostatic model assessment of insulin resistance, glycated hemoglobin, alkaline phosphatase, aspartate transaminase, and alanine transaminase were most predictive. CONCLUSIONS: In our setting, 65% of severely obese young children had NASH, and 60% had clinically significant liver fibrosis. Young age, male sex, and features of metabolic syndrome were significantly associated with NASH and liver fibrosis in severely obese pediatric patients.

Spontaneous gastric ulcer perforation and acute spleen infarction caused by invasive gastric and splenic mucormycosis.

Mucormycosis is a rare life-threatening fungal infection mostly affecting immunocompromised hosts. The main categories of human disease with the Mucorales are sinusitis/rhinocerebral, pulmonary, cutaneous/subcutaneous, gastrointestinal and disseminated disease. Other disease states occur with a much lower frequency and include cystitis, vaginitis; external otitis and allergic disease. We report a diabetic patient with comorbidities, who developed gastric perforation clinically indistinguishable from perforated peptic ulcer due to invasive gastric mucormycosis complicated by spleen infarction.

Primary squamous cell carcinoma of thyroid: a case report and review of literature.

BACKGROUND: Thyroid gland lacks squamous epithelium (except in some rare situations like embroyonic remnants or in inflammatory processes); for that reason the primary squamous cell carcinoma (SCC) of thyroid is extremely rare entity, seen only in less than 1% of all thyroid malignancies and is considered almost fatal. So, far, only few case reports have been published in literature. CASE PRESENTATION: Herein we present a 54 years old Saudi female with 3 months history of progressive neck swelling and hoarse voice, who was referred to us by her primary care physician as suspected case of anaplastic carcinoma of thyroid for radical external beam radiation therapy (EBRT). Fine Needle aspiration cytology (FNAC) revealed squamous cell carcinoma. Computed tomography (CT) neck showed 10 × 10 cm mass in left lobe of thyroid invading trachea and skin. Extensive staging work up ruled out the possibility of any primary site of SCC other than thyroid gland. Tumor was found unresectable and was referred to radiation oncology. She received palliative EBRT 30 Gy in 10 fractions. After completion of EBRT, there was progression of disease and patient died 3 months after completion of EBRT by airway compromise. CONCLUSION: Primary SCC of thyroid is rare and aggressive entity. FNAC is reliable and effective tool for immediate diagnosis. Surgery is a curative option, but it is not always possible as most of cases present as locally advanced with adjacent organs involvement. EBRT alone was found ineffective. Aggressive combined modality (debulking surgery, radiation and chemotherapy) shall be considered for such cases.

Efficacy of peginterferon α-2a and predictors of response in HBeAg-negative, genotype D-naive patients.

BACKGROUND: Peginterferon (PEG-IFN) α-2a has been shown to induce a sustained virologic response (SVR) in 20-30% of "hepatitis B e antigen (HBeAg)"-negative patients. AIM: To determine the safety and efficacy of PEG-IFN α-2a in HBeAg-negative, genotype D-naive patients and to analyze the predictors of response. METHODS: This prospective, multicenter, open-label, nonrandomized trial was conducted at four hospitals. A total of 35 consecutive HBeAg-negative naive genotype D patients received PEG-IFN α-2a for 48 weeks. RESULTS: Based on a cutoff of hepatitis B virus (HBV) DNA <400 copies ml(-1), an early virologic response (EVR) at week 12, end of treatment virologic response (ETVR) at week 48, and SVR at week 72 were achieved by 3 (9%), 9 (26%), and 8 patients (23%), respectively. The EVR rate improved to 43%, ETVR to 49%, and SVR to 57%, when a HBV DNA cutoff level of <20,000 copies ml(-1) was used. Pretreatment HBsAg level was not a predictor for SVR on univariate analysis, but correlated with decline in HBV DNA levels at weeks 48 and 72. On multivariate logistic regression analysis, low body weight, high alanine aminotransferase (ALT), low HBV DNA, and low triglyceride levels were identified as baseline predictors of SVR. CONCLUSION: HBeAg-negative genotype D-naive patients treated with PEG-IFN α-2a achieved SVR in 23 (HBV <400 copies ml(-1)) and 57% (HBV <20,000 copies ml(-1)) of patients, a better response than previously reported that might be related to the absence of drug resistance in these naive patients. Pretreatment predictors of SVR were low body weight, high ALT, low HBV DNA, and low triglycerides.

Herpes simplex ulcerative esophagitis in healthy children.

Herpes simplex virus is a common cause of ulcerative esophagitis in the immunocompromised or debilitated host. Despite a high prevalence of primary and recurrent Herpes simplex virus infection in the general population, Herpes simplex virus esophagitis (HSVE) appears to be rare in the immunocompetent host. We report three cases of endoscopically-diagnosed HSVE in apparently immunocompetent children; the presentation was characterized by acute onset of fever, odynophagia, and dysphagia. In two cases, the diagnosis was confirmed histologically by identification of herpes viral inclusions and culture of the virus in the presence of inflammation. The third case was considered to have probable HSVE based on the presence of typical cold sore on his lip, typical endoscopic finding, histopathological evidence of inflammation in esophageal biopsies and positive serologic evidence of acute Herpes simplex virus infection. Two cases received an intravenous course of acyclovir and one had self-limited recovery. All three cases had normal immunological workup and excellent health on long-term follow-up.

A modern regimen of pre-operative concurrent chemo-radiation therapy in locally advanced rectal cancer.

PURPOSE: To evaluate the efficacy and toxicity of preoperative concurrent capecitabine and radiotherapy in the treatment of resectable locally advanced rectal cancer (LARC). MATERIALS AND METHODS: We conducted a phase II trial to assess pathological complete response, tumor downstaging, toxicity and survival of capecitabine (825 mg/m(2) orally, twice daily) with radiotherapy (50.4 Gy/28 fractions) in 31 patients with LARC (cT3/T4 or N+) staged by endoscopic ultrasound (EUS). RESULTS: Median age was 53 years; with M:F ratio of 1:1.58; 77.4% had Eastern Cooperative Oncology Group performance status of 1. EUS showed that 67.7% of tumors were T3, 19.4% were T4, and 58% were node positive. Of 30 patients who had surgery, 6.5% achieved pathological complete remission (pCR). Tumor and nodal downstaging were achieved in 53.9% and 50% of patients, respectively. Grade 3/4 toxicities were mainly diarrhea (35.5%) and proctitis (32.3%). Sphincter preservation was achieved in 4/21 (15%) of patients initially planned for abdominoperineal resection. The median follow-up was 46 months (Range: 1.47-63.9), and the 3-year disease-free and overall survival were 59.8% and 76.6%, respectively. CONCLUSION: Capecitabine given concurrently with radiation therapy is generally well tolerated, and proved to be an effective radiosensitizer in the neoadjuvant treatment of locally advanced rectal cancer, yielding results comparable to those reported with 5-FU.

Liver transplant for hepatocellular carcinoma: experience in a Saudi population.

OBJECTIVES: We present our experience with deceased-donor liver transplant and living-donor liver transplant for hepatocellular carcinoma. Between 2001 and 2007, we transplanted 133 organs (84 deceased-donor liver transplants, 49 living-donor liver transplants) in 126 patients (4 retransplants). Twenty-three patients had hepatocellular carcinoma (14 deceased-donor liver transplants and 9 living-donor liver transplants). MATERIALS AND METHODS: The medical records of these patients were reviewed for recipient clinical, biochemical, and imaging characteristics. Slides of explants were assessed. Overall survival and tumor recurrence states were determined. All characteristics were tested for their prognostic significance. RESULTS: The median age of the patients was 55 years and the median Mayo End-stage Liver Disease score was 16. The alpha-fetoprotein was >or= 400 ng/mL in 4 patients. Histopathology revealed incidental cholangiocarcinoma in 2 patients and a hepatoblastoma in 1. The mean tumor size was 4 cm; the mean number of lesions was 2. Most tumors were graded as well or moderately differentiated; 4 were poorly differentiated. Gross macrovascular invasion was seen in 2 patients, while microvascular invasion was seen in 9. After a mean follow-up of 736 days, overall patient and graft survival rates were 80.9% and 76.2%; overall disease-free patient and graft survival rates were 76.2% and 71.4%. Two patients died of primary graft nonfunction within 1 week of the transplant. Three had tumor recurrence at 10, 13, and 18 months after transplant; 2 of these occurred in patients with cholangiocarcinoma. Two of these 3 died from an advanced tumor within few months. Significant risk factors for recurrence were gross major vessel invasion, microvascular invasion, tumor size, poor histologic differentiation, and absence of pretransplant tumor control therapy. The latter 2, in addition to Mayo End-stage Liver Disease score and preoperative alpha-fetoprotein, were independent predictors of mortality. CONCLUSIONS: In our small experience, deceased-donor liver transplant and living-donor liver transplant for hepatocellular carcinoma showed good long-term outcomes. Liver transplant for hepatocellular carcinoma accompanying cholangiocarcinoma had a poor outcome with late tumor recurrence. Use of marginal donors in patients with hepatocellular carcinoma might compromise the outcome in these patients.

Nuclear expression of E-cadherin in solid pseudopapillary tumors of the pancreas.

CONTEXT: Solid pseudopapillary tumors of the pancreas are rare and have recently been shown to harbor mutations of the beta-catenin gene with resultant nuclear localization of beta-catenin protein to the nucleus. Moreover, there is a close relationship between beta-catenin and E-cadherin. OBJECTIVE: To explore the protein expression of E-cadherin in a series of solid pseudopapillary tumors of the pancreas. PARTICIPANTS: Eighteen cases of solid pseudopapillary tumors of the pancreas. DESIGN: The cases were studied using a tissue microarray that was constructed as follows: for each case, 4 to 14 cores measuring 1.0 mm each were drilled from the blocks. Tissue cores from normal pancreas were used as controls and for orientation purposes. MAIN OUTCOME MEASURES: The slides were stained with the following commercially available antibodies: CD10, CD56, vimentin, alpha-1-antitrypsin, alpha-1-antichymotrypsin, neuron-specific enolase, chromogranin, synaptophysin, beta-catenin and E-cadherin. RESULTS: All the tumors were CD10, vimentin, alpha-1-antitrypsin and alpha-1-antichymotrypsin diffusely positive (50% or more of the tumor cells staining) and CD56 showed focal positivity in all cases with 5-10% of tumor cells displaying immunolabeling. All cases were negative for chromogranin and synaptophysin. All 18 cases displayed cytoplasmic and nuclear localization of beta-catenin protein. Similarly, E-cadherin protein was localized to the nucleus in all 18 cases, with loss of the characteristic membranous decoration of cells. CONCLUSION: This study is the first demonstration of aberrant nuclear localization of E-cadherin protein in solid pseudopapillary tumors of the pancreas. Whilst the exact mechanism is not know and nuclear E-cadherin is not related to tumor aggression, this staining pattern may be of diagnostic value in concert with beta-catenin staining.

Paucicellular infiltrating ductal carcinoma of pancreas: an unusual variant.

A 65-year-old man presented with obstructive jaundice from a 3-cm mass in the head of the pancreas. A Whipple resection was performed. Histologic examination of the tumor showed scanty tumor cells arranged in a single-file manner set within a desmoplastic sclerotic stroma. In other areas, the tumor was arranged around preexisting ducts in a targetoid fashion. Very focal ductal and signet-ring cell differentiation was noted. This unusual variant of pancreatic cancer was characterized by paucicellularity and a pattern of invasion resembling lobular carcinoma of breast.