Diminished accuracy of biomarkers of fibrosis in low replicative chronic hepatitis B.

BACKGROUND: We evaluated the diagnostic accuracy of aspartate aminotransferase (AST)-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4), AST/alanine aminotransferase (ALT) ratio (AAR), and age-platelet index (API) for significant fibrosis (Metavir F2-4) in low-replicative (HBV DNA <20,000 IU/mL) chronic hepatitis B virus (HBV) patients. METHODS: The sensitivity, specificity, and area under the receiver-operating characteristic curve (AUROC) of HBeAg-negative, low-replicative (n = 213) and high-replicative (HBV DNA ≥20,000 IU/mL, n = 153) patients was assessed. RESULTS: Overall, 113 patients (30.9%) had F2-4 fibrosis. Of the low and high-replicative patients, 40 (18.8%) and 73 (47.7%) had F2-4, respectively (P < 0.0001). APRI ≥0.5 less frequently identified F2-4 fibrosis in low vs. high-replicative patients (48.7% vs. 69.6%, P = 0.032) and AAR identified it more frequently in low-replicative patients (37.5% vs. 19.4%, P = 0.037). FIB-4 and API were not different (P > 0.05) for identifying F2-4 fibrosis in low and high-replicative patients. Higher specificities were seen at the lowest cut-offs in low vs. high-replicative states for APRI (≥0.5, 98% vs. 68.9%), AAR (84.3% vs. 76.6%), FIB-4 (≥1.45, 97.5% vs. 87.8%) and API (>4, 94.8% vs. 93.8%). At ROC-defined thresholds, APRI (≥0.33), AAR (≥0.93), FIB-4 (≥0.70) and API (>2) showed greater AUROCs for F2-4 diagnosis in low replicative (0.80, 0.62, 0.81 and 0.71, respectively) vs. high-replicative patients (0.73, 0.52, 0.67 and 0.69, respectively). CONCLUSION: All 4 biomarkers in both, low and high-replicative HBV demonstrate modest accuracy for fibrosis diagnosis at conventional cut-offs. Lowering the cut-offs may increase the diagnostic relevance of these biomarkers, particularly for APRI and FIB-4 in low-replicative disease.

Proteomic analysis of Class IV lupus nephritis.

BACKGROUND: There have been several attempts to standardize the definition and increase reproducibility in classifying lupus nephritis (LN). The last was made by the International Society of Nephrology and Renal Pathology Society in 2003 where the introduction of Class IV subcategories (global and segmental) was introduced. METHODS: We investigated whether this subdivision is important using a proteomics approach. All patients with renal biopsies along with their clinical outcome of LN were identified and regrouped according to the above 2003 classifications. Fresh-frozen renal biopsies of Class IV LN (global and segmental), antineutrophil cytoplasmic antibody-associated vasculitis and normal tissue were analyzed using two-dimensional gel electrophoresis (2-DE) and mass spectrometry. Differentially expressed proteins were identified and subjected to principal component analysis (PCA), and post hoc analysis for the four sample groups. RESULTS: PCA of 72 differentially expressed spots separated Class IV global and Class IV segmental from both normal and antineutrophil cytoplasmic antibody-associated vasculitis (ANCA). The 28 identified proteins were used in a post hoc analysis, and showed that IV-global and IV-segmental differ in several protein expression when compared with normal and ANCA. To confirm the proteomic results, a total of 78 patients (50 Class IV-Global and 28 Class IV-Segmental) were re-classified according to 2003 classification. There was no difference in therapy between the groups. The renal survival and patient survivals were similar in both groups. CONCLUSIONS: There is no strong evidence to support a different outcome between the two subcategories of Class-IV LN and, they should thus be treated the same until further studies indicate otherwise.

Predictors of significant fibrosis in chronic hepatitis B patients with low viremia.

BACKGROUND AND AIM: The data on the prevalence and predictors of significant fibrosis (≥F2, METAVIR) in chronic hepatitis B virus (HBV) patients with low viremia are limited. We aimed to assess both the prevalence predictors of ≥F2 fibrosis in hepatitis B envelope antigen-negative patients with HBV DNA <20,000 IU/mL. METHODS: Hepatitis B envelope antigen-negative patients (n=213) with mean HBV DNA <2000 IU/mL (n=97) and HBV DNA 2000 to 20,000 IU/mL (n=116) were included and all had liver biopsy. Variables significantly associated with ≥F2 fibrosis on an univariate analysis were included in a multivariate logistic regression model. RESULTS: Overall, 40 (18.8%) patients had ≥F2 fibrosis, with no difference between those with mean HBV DNA <2000 IU/mL (19.6%) compared with patients with HBV DNA of 2000 to 20,000 IU/mL (18.1%; P=0.782). Fibrosis ≥F2 was similar in patients with HBV DNA <2000 versus 2000 to 20,000 IU/mL in relation to varying alanine aminotransferase thresholds (P>0.05), and was less frequent in persistently normal alanine aminotransferase patients (13.6%) when compared with those with elevated or fluctuating levels (25.3%, P=0.030). Fewer patients under 40 years of age had ≥F2 fibrosis (12.5%) as compared with older ones (28.2%; P=0.004). Logistic regression analysis identified higher aspartate aminotransferase [odds ratio (OR), 6.21; 95% confidence interval (CI), 2.48-15.54; P<0.0001], lower albumin (OR, 0.86; 95% CI, 0.78-0.95; P=0.002), platelet count (OR, 0.99; 95% CI, 0.98-0.99; P=0.013), and age (OR, 1.05; 95% CI, 1.01-1.09; P=0.024) as independent predictors of significant fibrosis. CONCLUSIONS: A small but significant minority of HBV patients with low viremia harbor significant fibrosis, although its rate is not different in those with viremia above or below 2000 IU/mL. Our findings may guide in decisions regarding liver biopsy and treatment in this category of patients.

Sporadic insulinoma in a 10-year-old boy: a case report and literature review.

CONTEXT: Insulinoma is an exceedingly uncommon pancreatic islet cell neuroendocrine tumor. Its estimated incidence is approximately four cases per million individuals per year. CASE REPORT: We report the case of sporadic insulinoma in an exceptionally very young 10-year-old boy who presented with a 1-month history of episodic tremulousness, diaphoresis, increased hunger, confusion and fainting. Initial laboratory investigations showed low blood glucose (64 mg/dL) and high blood insulin (6 µU/mL) levels. Patient was admitted in view of frequent hypoglycemic symptoms and possible pancreatic insulinoma. A 48-hour mentored fasting test was done and ceased within 3 hours due to occurrence of hypoglycemic symptoms. During the episode, blood was drawn and results showed low blood glucose level and high insulin, pro-insulin and C-peptide levels. The hypoglycemic symptoms were relieved greatly by glucose administration and Whipple's triad for insulinoma was met. An abdominal contrast-enhanced computed tomography scan showed a 10 x 12 x 17 mm, small, well-demarcated, heterogeneously enhancing lesion within the body of pancreas without dilatation of pancreatic duct. No evidence of lymphadenopathy or distant metastasis was identified. Patient underwent enucleation of pancreatic tumor. Histopathological and immunohistochemical examination of the pancreatic mass confirmed neuroendocrine tumor (insulinoma). Patient had an uneventful recovery. A post-operative 6-month follow-up showed resolution of hypoglycemic symptoms, normalized blood glucose, insulin, pro-insulin and C-peptide levels, and no evidence of recurrence. CONCLUSION: Although rare, sporadic insulinoma should be considered in the differential diagnosis of any young individual presenting with frequent hypoglycemic symptoms (neuroglycopenic and/or autonomic nervous system symptoms). Furthermore, a literature review on insulinoma is presented.

Updated thresholds for alanine aminotransferase do not exclude significant histological disease in chronic hepatitis C.

BACKGROUND AND AIM: Histological changes in hepatitis C virus (HCV)-infected patients with persistently normal alanine aminotransferase (PNALT) have not been evaluated for updated upper limits of normal (ULN; ≤ 19/30 U/L for females/males). We assessed significant fibrosis (≥ F2, METAVIR) in patients with PNALT and persistently elevated alanine aminotransferase (PEALT). PATIENTS AND METHODS: Nine hundred and twenty consecutive, unselected HCV patients were stratified into four groups: Group I: (n = 124) PNALT within the updated ULN [0.5 × ULN (corresponding to ≤ 19 U/L) for females; 0.75 × ULN (corresponding to ≤ 30 U/L) for males]; Group II (n = 173): PNALT ≤ 1 × ULN but greater than Group I; Group III (n = 313): PEALT 1-2 × ULN; and Group IV (n = 310): PEALT > 2 × ULN. PNALT was defined as ≥ 3 determinations within the normal range over ≥ 6 months. RESULTS: Advanced ≥ F3 and ≥ F2 fibrosis increased incrementally across Groups I; II; III; and IV: 24.2 and 45.2%; 25.4 and 56.1%; 36.1 and 64.2%; and 50 and 77.1% respectively (P<0.0001 for both). Multivariable logistic regression analysis identified age [odds ratio (OR), 1.05; 95% confidence intervals (CI): 1.02-1.08; P<0.0001], alanine aminotransferase (ALT) groups (OR 1.38; 95% CI: 1.03-1.83; P = 0.030), presence of moderate-severe steatosis (OR 2.70; 95% CI: 1.19-6.15; P = 0.018) and ≥ A2 necroinflammation (OR 17.9; 95% CI: 8.88-36.20; P < 0.0001) as independent predictors of ≥ F2 fibrosis. Updated ULN for ALT were better at excluding ≥ F2 fibrosis compared with traditional ULN (90.6 vs. 74.2%, P = 0.0041) but less specific (20.8 vs. 44%, P = 0.0007) with similar positive/negative predictive values. CONCLUSIONS: HCV patients with 'updated' normal ALT have the lowest prevalence of significant fibrosis, although utilizing these levels without resorting to biopsy would miss significant fibrosis in almost one-half of such patients.

Missed Gastric Cancer Metastasis to the Appendix: Case Report and Literature Review.

BACKGROUND Gastric cancer metastasis to the appendix is a rare condition that might present with symptoms of acute appendicitis or remain asymptomatic and be diagnosed incidentally. This report summaries 6 previously reported cases in addition to the presented case. CASE REPORT We report a 54-years-old female patient who presented with gastric cancer metastasis to the appendix that was found incidentally in the second surgery when she underwent bowel resection due to bowel entrapment in internal hernia, a complication of her primary gastric cancer surgical intervention. Six case-reports on gastric cancer metastasis to the appendix were reviewed. The metastasis was symptomatic in 4 cases, and solitary in 3 cases. The diagnosis was delayed in 4 cases as there was no evidence of metastasis at the diagnosis of the primary tumor; appendectomy was performed in all cases. The prognosis of the cases varied considerably. CONCLUSIONS We question the real incidence of appendiceal metastasis in gastric cancer, and the benefit-risk ratio of appendectomy in every gastrectomy. Guidelines on management of similar cases is also needed.

Protocol Duodenal Graft Biopsies Aid Pancreas Graft Surveillance.

BACKGROUND: Histological evaluation of the pancreas graft is usually done on demand resulting in significant delays. This analysis reports on endoscopic protocol duodenal graft biopsies at regular intervals to determine feasibility, safety, and monitoring benefits. METHODS: Protocol duodenal graft biopsies in 27 consecutive pancreas transplants (10 simultaneous pancreas kidney [SPK], 17 pancreas after kidney [PAK]) with a follow-up of a minimum of 12 months were performed at days 14, 30, 90, 180, 360, 430. University of Pittsburgh Medical Center classification for intestinal rejection was used. C4d staining was performed when antibody-mediated rejection was suspected. RESULTS: Overall patient and pancreas graft survival was 100% and 93% at a mean follow-up of 2.8 years. One hundred sixty-seven endoscopic biopsy procedures were performed in 27 grafts without any complication. Biopsies revealed rejection in 3 (30%) SPK recipients and in 15 (82%) of PAK recipients as early as 14 days posttransplant. Two patients underwent PAK retransplantation diagnosed with acute rejection at day 180. All except 1 recipient being treated for rejection, showed histological improvement following antirejection treatment. Following transient treatment success, a total of 3 pancreas grafts were lost for immunological reason. One loss was immediate despite antirejection treatment, 1 secondary to nonresolving rejection at 7 months and the third due to recurrent rejection 15 months posttransplantation. Additionally, biopsies detected vascular (venous thrombosis) and overimmunosuppression (cytomegalovirus infection) complications. CONCLUSIONS: Protocol graft duodenal biopsies detect complications after whole-organ pancreas transplantation, are useful in guiding therapy, and carry potential for improving outcome.

Solitary rectal ulcer syndrome: A single-center case series.

BACKGROUND/AIM: Solitary rectal ulcer syndrome (SRUS) is a benign, chronic defecation disorder with varied presentations. The aim of this study is to summarize the clinical features, endoscopic findings, histological appearance, and treatment strategies associated with SRUS. PATIENTS AND METHODS: This is a retrospective study of all patients diagnosed with SRUS at the King Faisal Specialist Hospital and Research Centre in Riyadh from January 2003 to December 2013. Cases were identified using the Department of Pathology database. Data were obtained from medical records that included clinical manifestation, endoscopic findings, and histopathological features. RESULTS: Twenty patients were identified. The mean age was 42.5 years (±18.5) and 55% were females. Most of the patients presented with bleeding per rectum (85%), constipation (75%), and straining (50%), with a mean symptom duration of 26.7 months. The most common associated factors identified were constipation (75%), history of rectal surgery (25%), digital rectal manipulation (20%), and rectal prolapse (20%). Endoscopic findings included a single ulcer (50%) and multiple ulcers (30%); 55% had a polypoidal appearance. On histopathology, there was surface ulceration (95%), fibrosis of the lamina propria (60%), distorted architecture (55%), and muscle hypertrophy with increased mucin production (50%). Patients were treated conservatively and none required surgery. CONCLUSION: SRUS is a rare disorder with variable clinical presentations. Stool softeners, a high fiber diet in addition to topical mesalamine, and biofeedback proved to be effective in this patient population.

The impact of antiphospholipid antibodies in children with lupus nephritis.

BACKGROUND AND OBJECTIVES: To evaluate the frequency of antiphospholipid antibodies (APLa) among patients with childhood lupus nephritis (cLN) and to assess their impact on long-term renal outcomes. DESIGN AND SETTING: This is an observational hospital based study. PATIENTS AND METHODS: Patients with cLN diagnosed by renal biopsy seen between January 2002 and June 2014 were included. APLa positivity was defined if detection was positive on 2 occasions 6-12 weeks apart during their follow up. Demographic features, age at disease onset, disease duration, follow-up duration and clinical and laboratory variables at the time of renal biopsy were collected. The renal biopsy was reviewed for the nephritis class, microthrombi, activity and chronicity indices. Renal outcome measures included the serum creatinine levels, protein/creatinine ratio and end stage renal disease (ESRD). RESULTS: Fifty-nine, (49 female) patients with a mean age of 19.8 years and mean disease duration of 6.8 years were involved. APLa were detected in 46 (78%) patients. Twenty-two patients had class IV nephritis, which was more prevalent in APLa positive patients. The frequencies of class III and V nephritis was similar in 10 patients in each class (7 patients in each class with APLa). The presence of APLa did not correlate with nephritis activity or the chronicity indices. Microthrombosis was found in 10 patients, and 8 of them had APLa. Patients with APLa had a higher frequency of elevated serum creatinine and hypertension, 9 developed ESRD, and 7 had APLa. There was no statistically significant association between the presence of APLa and the accrual damage index and clinical manifestations. Furthermore, there was no association between APLa and other autoantibodies. CONCLUSION: The frequency of APLa in cLN was high. While the association is not statistically significant, APLa positive patients tend to develop renal microthrombi and are probably at higher risk of ESRD.

Familial lecithin-cholesterol acyltransferase (LCAT) deficiency; a differential of proteinuria.

BACKGROUND: Lecithin cholesterol acyltransferase (LCAT) is an important enzyme in cholesterol metabolism that is involved in the esterification of cholesterol. A lack of this enzyme results in deranged metabolic pathways that are not completely understood, resulting in abnormal deposition of lipids in several organs. Clinically, it manifests with proteinuria, dyslipidemia and corneal opacity with progressive chronic kidney disease resulting in end-stage renal disease. CASE PRESENTATION: We herein present a case of a 30-year-old male with proteinuria that was not responsive to empiric management with angiotensin-converting enzyme (ACE) inhibitors and oral steroids. Physical examination revealed corneal ring opacity involving both eyes. Urinalysis revealed an active sediment. The 24-h proteinuria was 3.55 grams. Family history was positive for renal disease and dyslipidemia. Viral serology for human immunodeficiency virus (HIV), hepatitis C virus (HCV) and hepatitis B virus (HBV) were negative. Serum complements were normal and anti-nuclear antibody (ANA) was negative. We elected for a renal biopsy that revealed characteristic features of LCAT deficiency. The diagnosis of LCAT deficiency was established with a combination of clinical and pathological findings. CONCLUSIONS: Currently renal prognosis is poor but conservative management with ACE inhibitors and lipid lowering therapy in addition to steroids has been shown to retard progression to end-stage renal disease. However newer therapies such as gene replacement and recombinant LCAT replacement are being studied with promising preliminary results.

Sporadic pancreatic vasoactive intestinal peptide-producing tumor (VIPoma) in a 47-year-old male.

VIPoma is an exceedingly unusual neuroendocrine neoplasm that autonomously secretes vasoactive intestinal polypeptide (VIP). Its reported incidence is approximately 1 per 10 million individuals per year. Herein, we report the case of sporadic pancreatic VIPoma in a 47-year-old male who presented with a six-month history of chronic, plentiful, watery diarrhea. On physical examination, the patient looked sick, lethargic and had signs of dehydration. Laboratory investigations revealed high VIP hormone level (989pg/mL), hypokalemia, hypercalcemia, hyperglycemia, high blood urea nitrogen, high creatinine, and metabolic acidosis on arterial blood gas. Contrast-enhanced computed tomography (CT) scan showed a 3.1×3.3×4.7cm, well-defined, enhancing lesion involving the pancreatic tail with a cystic component. Moreover, a 5.7×6.1×6.8cm metastatic hepatic lesion was identified. The patient underwent distal pancreatectomy with splenectomy, hepatic lesion resection, and lymph node dissection. Histopathological and immunohistochemical examination of the pancreatic and hepatic lesions revealed neuroendocrine tumor (VIPoma). Postoperatively, the patient received radiofrequency ablation for the hepatic lesion. A post-operative six-month follow-up showed significant symptomatic relief, reduced VIP hormone level (71pg/mL) and normalized electrolyte and acid-base profiles. However, a magnetic resonance imaging (MRI) scan showed a small residual metastatic liver lesion which was considered for hepatic artery embolization (HAE). The patient is still alive with a residual hepatic disease at 18months. We also present a brief literature review on VIPoma.

Diabetes Insipidus and Sclerosing Cholangitis in a child may be a clue to the diagnosis of Langerhans' Cell Histiocytosis: A Case Report.

Langerhans cell histiocytosis (LCH) is a rare disease that usually affects children and young adults. Sclerosing cholangitis (SC) can occur in 10-15% of patients with disseminated form of the disease. Central diabetes insipidus (CDI) is a rare disorder that may be caused by a variety of diseases mainly LCH and germinoma especially in children. In this case report, a- 4-year-old girl who is a known case of CDI and a single bone lesion in the left humerus, presented with jaundice, abdominal distention and itching. The diagnosis of SC was made by histopathology on liver biopsy. In this case, we found a link between CDI and SC through LCH, the diagnosis of which was made by histopathology of the explanted liver. The combination of CDI, liver involvement with SC and a single bone lesion is remarkable, since the histological diagnosis of LCH was made outside the biliary tract in the liver parenchyma.

Successful management of multifactorial colitis in a recipient of hematopoietic stem cell transplant: a case report.

Recipients of allogeneic hematopoietic stem cell transplant can develop life-threatening complications at any time following their transplants. These complications require repeated clinical assessment, appropriate and thorough screening as well as a comprehensive management approach. We report a young adult male who received a sibling allograft in the second complete remission of his acute lymphoblastic leukemia at King Faisal Specialist Hospital and Research Centre in Riyadh. The patient developed severe colitis which was caused by: acute exacerbation of chronic graft versus host disease of the lower gastrointestinal tract, cytomegalovirus disease of the colon and a superadded Salmonella infection caused by food poisoning. The multifactorial colitis was properly investigated and successfully managed. To our knowledge, this is the first case of multifactorial colitis in a recipient of hematopoietic stem cell transplant.