Universal Index for Cirrhosis (UIC index): The development and validation of a novel index to predict advanced liver disease.

AIM: The purpose of this study was to create and validate a novel serological diagnostic index to predict cirrhosis of all etiologies. METHODS: This was a retrospective observational study of 771 patients, age >18 years, who underwent a liver biopsy. The stage of fibrosis and routine laboratory values were recorded. The data were randomly separated into 2 datasets (training 50% and testing 50%). A stepwise logistic regression model was used to develop the novel index. The area under the curve of receiver operating characteristic (AUROC) was applied to compare the new index to existing ones (Fibro-Q, FIB4, APRI, AAR), which was also validated in the testing dataset. RESULTS: Variables associated with the presence of cirrhosis were first assessed by univariate analysis then by multivariable analysis, which indicated serum glutamic-oxaloacetic acid transaminase, serum glutamic-pyruvic transaminase, international normalized ratio, albumin, blood urea nitrogen, glucose, platelet count, total protein, age, and race were the independent predictors of cirrhosis (P<0.05). Regression formula for prediction of cirrhosis was generated and a novel index was subsequently created. The diagnostic performance of the novel index for predicting cirrhosis was assessed using the receiver operating characteristic curve. The new index had significantly higher AUROC (0.83, 95% CI: 0.79-0.87) than Fibro-Q (0.80, 95% CI: 0.76-0.85), FIB4 (0.79, 95% CI: 0.74-0.83), APRI (0.74, 95% CI: 0.69-0.78), and AAR (0.72, 95% CI: 0.67-0.78). CONCLUSION: The novel index had the highest AUROC curve when compared with current indices and can be applied to all etiologies of chronic liver disease.

Liver function tests in identifying patients with liver disease.

BACKGROUND AND AIMS: Many patients with liver disease come to medical attention once they have advanced cirrhosis or acute decompensation. Most often, patients are screened for liver disease via liver function tests (LFTs). There is very limited published data evaluating laboratory values with biopsy-proven stages of hepatic fibrosis. We set out to evaluate whether any correlation exists between routine LFTs and stages of hepatic fibrosis. METHODS: A large retrospective observational study on 771 liver biopsies was conducted for evaluating the stage of fibrosis with AST, ALT, INR, BUN, creatinine, platelets, alkaline phosphatase, bilirubin, and albumin. Mean and 95% confidence intervals were used to describe the distributions of serum markers in different fibrosis stages. Multivariable generalized linear models were used and a two-tailed P-value was calculated. RESULTS: ALT was not statistically significant for any stage, and AST was statistically significant for stage 3 and 4 fibrosis. INR was statistically significant only in stage 4 disease but remained near the upper limit of normal range. Albumin failed to show a clinically relevant association. Platelets remained within normal laboratory range for all stages. The remaining laboratory values failed to show statistical and clinical significance. CONCLUSION: The health care burden from chronic liver disease (CLD) will likely continue to rise, unless clinicians are made aware that normal or near normal laboratory findings may be seen in asymptomatic patients. Earlier identification of asymptomatic patients will allow for treatment with new promising modalities and decrease morbidity and mortality from CLD. Our study shows that laboratory values correlate poorly with liver disease.

Treatment of orofacial granulomatosis: a case report.

BACKGROUND: Orofacial granulomatosis is a relatively recent term coined by Wiesenfield et al. in 1985 to define granulomatous lesions of oral mucosa without intestinal involvement. When it presents in a triad encompassing facial nerve palsy, lip swelling, and fissured or furrowed tongue it is called Melkersson-Rosenthal syndrome while monosymptomatic or oligosymptomatic forms are referred to as granulomatous cheilitis. It is an uncommon clinicopathologic entity which is distinct from classic Crohn's disease. The NOD2 variant which is commonly associated with Crohn's has not been shown to have any association with orofacial granulomatosis. CASE PRESENTATION: We present a case of a 31-year-old white man who had painful swelling of the lip with oral ulcers and difficulty eating for 2 to 3 years. He was diagnosed as having granulomatous cheilitis based on characteristic biopsy findings. There was serologic evidence of Crohn's disease with anti-Saccharomyces cerevisiae antibodies. However, he was not found to have any gastrointestinal involvement based on computed tomography enterography, and upper and lower endoscopies. He failed to respond to nonsteroidal anti-inflammatory drugs, steroids, and dapsone therapy but responded well to high doses of infliximab. CONCLUSIONS: Our case questions whether granulomatous cheilitis really exists or is it simply a variant of Crohn's disease with only oral presentation. Our patient did not have symptoms of Crohn's disease; moreover, endoscopic studies and computed tomography enterography were unremarkable for evidence of intestinal involvement. Our case is also the first reported case where high-dose infliximab alone has been used with sustained response for approximately 8 months. In conclusion, more research is needed to assess the underlying pathology as well as ideal treatment options for patients with orofacial granulomatosis. We propose that high-dose infliximab should be considered in patients who do not respond to traditional therapies.

An unusual association between hemophagocytic lymphohistiocytosis, mixed connective tissue disease, and autoimmune hemolytic anemia: A case report.

RATIONALE: In the adult patient, hemophagocytic lymphohistiocytosis (HLH) is uncommon and frequently difficult to diagnose due to its nonspecific presentation and numerous complications. PATIENT CONCERNS: Herein, we present the case of a 25-year-old female who initially presented for evaluation of persistent fevers and fatigue. She was found to have splenomegaly, generalized lymphadenopathy, pancytopenia, and acute hepatic failure. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Her course was further complicated by the development of nephrotic syndrome and autoimmune hemolytic anemia (AIHA). Antinuclear antibody and ribonucleoprotein were positive, with concurrent physical examination findings, indicating underlying mixed connective tissue disease (MCTD). Ferritin was greater than 40,000 ng/dL. Viral studies, including hepatitis A, B, and C, cytomegalovirus, and Epstein-Barr virus were negative. On the basis of her clinical presentation, a diagnosis of HLH secondary to MCTD was made. This was later confirmed on liver biopsy. She was started on high-dose prednisone and her symptoms completely resolved. She was then transitioned to azathioprine, hydroxychloroquine, prophylactic antibiotics, and a prednisone taper for long-term management. LESSONS: This case is notable for the association of both AIHA and MCTD with HLH, providing support for a possible relationship between these 3 conditions.

Inhibition of SIRT2 suppresses hepatic fibrosis.

Liver fibrosis can progress to cirrhosis and result in serious complications of liver disease. The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs), the underlying mechanisms of which are not fully known. Emerging evidence suggests that the classic histone deacetylases play a role in liver fibrosis, but the role of another subfamily of histone deacetylases, the sirtuins, in the development of hepatic fibrosis remains unknown. In this study, we found that blocking the activity of sirtuin 2 (SIRT2) by using inhibitors or shRNAs significantly suppressed fibrogenic gene expression in HSCs. We further demonstrated that inhibition of SIRT2 results in the degradation of c-MYC, which is important for HSC activation. In addition, we discovered that inhibition of SIRT2 suppresses the phosphorylation of ERK, which is critical for the stabilization of c-MYC. Moreover, we found that Sirt2 deficiency attenuates the hepatic fibrosis induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). Furthermore, we showed that SIRT2, p-ERK, and c-MYC proteins are all overexpressed in human hepatic fibrotic tissues. These data suggest a critical role for the SIRT2/ERK/c-MYC axis in promoting hepatic fibrogenesis. Inhibition of the SIRT2/ERK/c-MYC axis represents a novel strategy to prevent and to potentially treat liver fibrosis and cirrhosis.

Microvascular injury in persistent gastric ulcers after yttrium-90 microsphere radioembolization for liver malignancies.

Yttrium-90 microsphere radioembolization ((90)Y MRE) is a therapy for liver malignancies by permanently implanting (90)Y-containing microspheres into tumors via hepatic artery. The etiology of persistent gastric ulcerations in patients presenting months after treatment remains unclear. Three patients who presented with gastric ulceration 4 to 13 months after (90)Y MRE were examined by esophagogastroduodenoscopy and biopsies. Pathological examinations showed multiple (90)Y microspheres scattered within the lamina propria and submucosa. Most of the microspheres were distributed in a linear fashion, consistent with an intravascular location; however, the vascular lumen and endothelial cells were not present. The microspheres were surrounded by fibrotic tissue infiltrated by chronic inflammatory cells and rare neutrophils. Epithelial granulation without pititis and miniaturized glands with intervening fibrosis were noted, compatible with chronic ischemic changes. These findings suggest that the persistent gastric ulceration is a result of localized ischemic injury in response to (90)Y MRE-induced vascular damage.

Behçet's disease departs the 'Silk Road': a case report and brief review of literature with geographical comparison.

Behçet's disease (BD) is a chronic multisystem inflammatory disease most prevalent in Eastern Asia and along the Mediterranean basin, an area referred to as the 'Silk Road'. The diagnosis of BD is largely based on the International Study Group (ISG) criteria, which are more specific than sensitive. ISG criteria do not include intestinal manifestations, a feature more commonly seen in the West. Intestinal BD is one of several findings that are not typically seen along the 'Silk Road'. Herein we report a rare case of intestinal BD and compare Western versus traditional BD. A 25-year-old male with a history of painful oral aphthous ulcers, pericarditis, and diffuse papulopustular rash presented to the emergency department with two terminal ileal perforations. Pathology demonstrated mucosal necrosis with active inflammation and no chronic inflammatory changes. Post-surgical laboratory studies showed an elevated c-reactive protein of 35.57 mg/dL, erythrocyte sedimentation rate of 82 mm/h, and a positive anti-Saccharomyces cerevisiae antibody. Rheumatological workup including ANA, RF, PR3 antibody, MPO antibody, ANCA, SSA and SSB, Smith antibody, SCL-70, and anti-Jo-1 antibodies were all negative. His pericarditis symptoms improved with colchicine and prednisone prior to discharge. Our patient did not meet the current ISG criteria for traditional BD; however, he clearly showed findings typically seen in Western patients with BD, which include intestinal manifestations, cardiac involvement, and lack of pathergy reaction and ocular changes. Our investigation demonstrates that the clinical manifestations common to this disorder vary among geographic and ethnic populations. Commonly used criteria for the diagnosis of BD may not be sensitive for some populations, such as Western BD, potentially leading to underdiagnoses and mismanagement. Recognition and select inclusion of these differences may be one way to assist with diagnosing Western BD in the future. As our knowledge of BD continues to evolve, so must the population-specific criteria used to define BD.

Low-Level Expression of the E1B 20-Kilodalton Protein by Adenovirus 14p1 Enhances Viral Immunopathogenesis.

Adenovirus 14p1 (Ad14p1) is an emergent variant of Ad serotype 14 (Ad14) that has caused increased severity of respiratory illnesses during globally distributed outbreaks, including cases of acute respiratory distress syndrome and death. We found that human cell infection with Ad14p1 results in markedly decreased expression of the E1B 20-kilodalton (20K) protein compared to that with infection with wild-type (wt) Ad14. This reduced Ad14p1 E1B 20K expression caused a loss-of-function phenotype of Ad-infected cell corpses that, in contrast to cells infected with wt Ad14, either failed to repress or increased NF-κB-dependent, proinflammatory cytokine responses of responder human alveolar macrophages. A small-animal model of Ad14-induced lung infection was used to test the translational relevance of these in vitro observations. Intratracheal infection of Syrian hamsters with Ad14p1 caused a marked, patchy bronchopneumonia, whereas hamster infection with wt Ad14 caused minimal peribronchial inflammation. These results suggest that this difference in E1B 20K gene expression during Ad14p1 infection and its modulating effect on the interactions between Ad14-infected cells and the host innate immune response could explain the increased immunopathogenic potential and associated increase in clinical illness in some people infected with the Ad14p1 outbreak strain.IMPORTANCE We previously reported that Ad-infected human cells exhibit E1B 19K-dependent repression of virally induced, NF-κB-dependent macrophage cytokine responses (J. R. Radke, F. Grigera, D. S. Ucker, and J. L. Cook, J Virol 88:2658-2669, 2014, http://dx.doi.org/10.1128/JVI.02372-13). The more virulent, emergent strain of Ad14, Ad14p1, causes increased cytopathology in vitro, which suggested a possible E1B 20K defect. Whether there is a linkage between these observations was unknown. We show that there is markedly reduced expression of E1B 20K in Ad14p1-infected human cells and that this causes an increased proinflammatory cytokine response of human alveolar macrophages and more severe inflammatory lung disease in infected hamsters. This is the first evidence of a clinical relevance of differential expression of the small Ad E1B gene product. The results suggest that there is a low, critical threshold of E1B 19/20K expression that is needed for viral replication and infection transmission but that a higher level of E1B 19/20K expression is required for the usual repression and control of the Ad-triggered host innate immune response.

Should all branch-duct intraductal papillary mucinous neoplasms be resected?

BACKGROUND: The relationship between branch-duct intraductal papillary mucinous neoplasms (IPMNs) and malignancy remains controversial and difficult to assess. METHODS: Between January 1, 1999 and January 1, 2013, we identified 84 patients with IPMN who underwent resection. RESULTS: Preoperatively, 55 patients underwent endoscopic ultrasounds and 58 underwent biopsy. Only 7 lesions were specified preoperatively as branch-duct, which inconsistently correlated with the surgical specimen. Of the 82 patients where the duct was specified, there were 33 malignant lesions. There was no correlation between branch-duct origin and invasive carcinoma. Malignant tumor size did not significantly differ by the duct of origin. Of the 28 patients with invasive carcinoma, branch-duct lesions were significantly associated with the presence of positive lymph nodes, perineural invasion, and lymphovascular invasion. CONCLUSIONS: Our study supports the resection criteria for branch-duct IPMN based on size and symptoms. However, it also questions the reliability of our preoperative testing to rule out malignant branch-duct IPMN lesions.

The Association between Survival and the Pathologic Features of Periampullary Tumors Varies over Time.

Introduction. Several histopathologic features of periampullary tumors have been shown to be correlated with prognosis. We evaluated their association with mortality at multiple time points. Methods. A retrospective chart review identified 207 patients with periampullary adenocarcinomas who underwent pancreaticoduodenectomy between January 1, 2001 and December 31, 2009. Clinicopathologic features were assessed, and the data were analyzed using univariate and multivariate methods. Results. In univariate analysis, perineural invasion had a strong association with 1-year mortality (OR 3.03, CI 1.42-6.47), and one lymph node (LN) increase in the LN ratio (LNR) equated with a 5-fold increase in mortality. In contrast, LN status (OR 6.42, CI 3.32-12.41) and perineural invasion (OR 5.44, CI 2.81-10.52) had the strongest associations with mortality at 3 years. Using Cox proportional hazards, perineural invasion (HR 2.61, CI 1.77-3.85) and LN status (HR 2.69, CI 1.84-3.95) had robust associations with overall mortality. Recursive partitioning analysis identified LNR as the most important risk factor for mortality at 1 and 3 years. Conclusions. Overall mortality was closely related to the LNR within the first year, while longer follow-up periods demonstrated a stronger association with perineural invasion and overall LN status. Therefore, the current staging for periampullary tumors may need to be updated to include the LNR.