Raffi Karagozian

Obesity-associated mechanisms of hepatocarcinogenesis

Obesity has been recognized as a key component of the metabolic syndrome, a cluster of risk factors associated with diabetes and cardiovascular morbidity. In addition, obesity has been linked to higher frequency of cancers in a variety of tissues including the liver. Liver cancer most often occurs as hepatocellular carcinoma (HCC) complicating cirrhosis due to chronic viral infection or toxic injury and remains the third leading cause of cancer death in the world. However, HCC is increasingly diagnosed among individuals with obesity and related disorders. As these metabolic conditions have become globally prevalent, they coexist with well-established risk factors of HCC and create a unique challenge for the liver as a chronically diseased organ. Obesity-associated HCC has recently been attributed to molecular mechanisms such as chronic inflammation due to adipose tissue remodeling and pro-inflammatory adipokine secretion, ectopic lipid accumulation and lipotoxicity, altered gut microbiota, and disrupted senescence in stellate cells, as well as insulin resistance leading to increased levels of insulin and insulin-like growth factors. These mechanisms synergize with those occurring in chronic liver disease resulting from other etiologies and accelerate the development of HCC before or after the onset of cirrhosis. Increasingly common interactions between oncogenic pathways linked to obesity and chronic liver disease may explain why HCC is one of the few malignancies with rising incidence in developed countries. Better understanding of this complex process will improve our strategies of cancer prevention, prediction, and surveillance.

Increased Mortality and Length of Stay Among Patients With Inflammatory Bowel Disease and Hospital-Acquired Infections

BACKGROUND & AIMS Hospitalized patients with inflammatory bowel disease (IBD) could be at increased risk for hospital-acquired infections (HAIs). By using HAI outcome data from Pennsylvania, we examined the influence of HAIs on in-patient mortality and length of stay (LOS) in the hospital among patients with IBD. METHODS Data were generated by linking the Clinical Research Databases from CareFusion (formerly MediQual), which includes all acute care hospitals in Pennsylvania, with publicly reported HAI data from Pennsylvania. The study population included all patients discharged in 2004 with International Classification of Diseases, 9th Clinical Modification codes of 555.x or 556.x (2324 IBD cases from 161 hospitals). Controls were selected using risk-score matching with a 5:1 ratio. Mortality and LOS end points were estimated and corroborated with regression methods. RESULTS Among the IBD patients studied, there were 20 deaths and 22 reported cases of HAI. The mortality from HAI among patients with IBD was 13.6%, compared with 0.9% among controls (P = .0146, Fisher exact test). The odds ratio for mortality was 17.2 (95% confidence interval, 1.7-174.3). The median LOS for patients with IBD and HAI was 22 days, versus 6 days for controls (P < .001, Wilcoxon). Of the 22 cases with HAIs, 15 were urinary tract infections, 5 were blood stream infections, and 2 were from multiple sources. CONCLUSIONS Results from a population-based data set indicate that mortality and LOS are increased among IBD patients who develop HAIs. A majority of the HAIs were from urinary sources. Although HAIs are low-frequency events, increased vigilance to avoid HAI among patients with IBD could improve outcomes.

Serum Adiponectin Is Associated with Worsened Overall Survival in a Prospective Cohort of Hepatocellular Carcinoma Patients

Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. The rise in metabolic syndrome has contributed to this trend. Adipokines, such as adiponectin, are associated with prognosis in several cancers, but have not been well studied in HCC. Methods: We prospectively enrolled 140 patients with newly diagnosed or recurrent HCC with Child-Pugh (CP) class A or B cirrhosis. We examined associations between serum adipokines, clinicopathological features of HCC, and time to death. We also examined a subset of tumors with available pathology for tissue adiponectin receptor (AR) expression by immunohistochemistry. Results: The median age of subjects was 62 years; 79% were men, 59% had underlying hepatitis C, and 36% were diabetic. Adiponectin remained a significant predictor of time to death (hazard ratio 1.90; 95% confidence interval 1.05-3.45; p = 0.03) in a multivariable adjusted model that included age, alcohol history, CP class, stage, and serum E-fetoprotein level. Cytoplasmic AR expression (AR1 and AR2) in tumors trended higher in those with higher serum adiponectin levels and in those with diabetes mellitus, but the association was not statistically significant. Conclusions: In this hypothesis-generating study, we found the serum adiponectin level to be an independent predictor of overall survival in a diverse cohort of HCC patients. Impact: Understanding how adipokines affect the HCC outcome may help develop novel treatment and prevention strategies. i 2014 S. Karger AG, Basel

Obesity paradox in advanced liver disease: obesity is associated with lower mortality in hospitalized patients with cirrhosis.

To investigate how obesity impacts inpatient mortality, length of stay (LOS) and costs in patients with cirrhosis. Obesity is a growing epidemic associated with multiple co‐morbidities, increased morbidity, and a significant economic burden on healthcare. Despite the overall harmful impact of obesity, the ‘obesity paradox’ has been described as decreased mortality among obese vs non‐obese patients in various chronic medical conditions.

Spontaneous bacterial peritonitis is a risk factor for renal failure requiring dialysis in waitlisted liver transplant candidates.

To examine the relationship between and impact of spontaneous bacteria peritonitis (SBP) and renal failure requiring dialysis in waitlisted liver transplant (LT) candidates.

Pancreatoblastoma: an Atypical Presentation and a Literature Review

Pancreatoblastoma is a rare, malignant epithelial neoplasm of the pancreas. It primarily occurs in the pediatric population and is extremely uncommon in adults. Annual incidence is around 0.004 cases per 100,000 persons. However, it can account for up to 25% of pancreatic malignancies in children less then 10 years of age [1]. To date, 40 case reports of pancreatoblastomas have been identified since first described in 1986 in patients between the ages of 18 to 78 years [2, 3]. Presenting symptoms are nonspecific, and abdominal pain is the most common initial complaint (44%). A palpable mass, weight loss, jaundice, diarrhea, melena, splenomegaly, abdominal distention, and symptoms from mass effect on adjacent organs may also be present [3–5]. Although slow growing, the long-term prognosis of a pancreatoblastoma is poor. Complete surgical resection is the initial preferred treatment, and the Italian Tumori Rari in Eta’ Pediatrica project has developed chemotherapy guidelines consisting of cisplatin followed by doxorubicin [6]. Here, we describe an atypical presentation and a literature review of metastatic pancreatoblastoma arising in the pancreatic tail of a 34-yearold male, associated with an elevation of cancer antigen 19-9 (Ca 19-9).

Bleeding ectopic duodenal varix: use of a new microvascular plug (MVP) device along with transjugular intrahepatic portosystemic shunt (TIPSS)

Ectopic varices (ECV) occur along the gastrointestinal (GI) tract outside the common variceal sites and represent 2%–5% of all GI variceal bleeds with mortality rates up to 40%. Management is challenging because of inaccessibility and increased risk of rebleeding. We report what is to our knowledge the first clinical use of a new microvascular plug (MVP) with transjugular intrahepatic portosystemic shunt (TIPSS) for a bleeding duodenal varix (DV). A 68-year-old man presented with melena. Endoscopy demonstrated a grade II varix in the second part of the duodenum with red wale sign. TIPSS was performed and portogram revealed a single DV. Poststent placement venogram revealed a persistent varix and hence a 5–7 mm MVP was deployed. Subsequent imaging showed cessation of blood through the DV. The patient had no further bleeding. TIPSS with embolisation is an effective treatment for ECV. This MVP offers advantages due to its size and compatibility and can be redeployed in case of suboptimal placement.

Sa1064 Baseline Hematologic Indices With Albumin Predict Clinical Decompensation in Patients With HCV Cirrhosis Who Do Not Respond to Antiviral Therapy

Background: Patients with cirrhosis have lower response rates to the current standard treatments for hepatitis C and are at greater risk of clinical decompensation (CD) with continued infection. The risk of CD should be considered when treatment decisions for HCV are made. CD is associated with portal hypertension (PH). Because the assessment of PH requires invasive studies not widely available in the US, there is need for non-invasive markers. Abnormal hematological indices (HI), both thrombocytopenia (TH) and leukopenia (LE) have been associated with clinically significant PH. The purpose of this study is to determine if baseline HI can be used to predict decompensation prior to anti-viral therapy in a cohort of patients who did not respond to treatment. Methods: The study was a retrospective individual chart review on 427 patients identified in the Partners Research Data Repository who received HCV treatment. Inclusion criteria: .18 years, therapy with Peginterferon and Ribavirin, compensated liver disease and Metavir score of 4 on biopsy. Exclusion criteria: early stage fibrosis, post-liver transplant, HIV co-infection, untreated HCV. Baseline characteristics including HI were collected. Abnormal HI was defined as TH , 150,000, LE, 4,000 and Anemia, 13.5 g/dl (male) 11.5 g/dl (female).The primary outcome was long term occurrence of first CD defined by new ascites, jaundice, encephalopathy or variceal hemorrhage after completion of HCV therapy. Students t test was used to compare means, Fisher exact test to compare proportions, multivariate logistic regression to identify predictors for CD. Results: 153 patients met criteria. 37 (24 %) patients had an SVR. Among the 116 patients who did not respond to therapy, at baseline, 40 (34 %) had TH, 24 (21 %) had LE and 38 (33 %) had anemia. CD occurred in 35 (30%). None of the SVR patients had CD. Among decompensation events, jaundice occurred in 74 %, encephalopathy in 54 %, ascites occurred in 51 %, and variceal hemorrhage in 6 %. Univariate analysis showed baseline TH OR 13.8 ( p-value , 0.001 ) and LE OR 3.8 (p-value = 0.006) ) were associated with CD. Anemia at baseline OR 1.6 (p-value = 0.27) was not associated with CD and not considered in further analysis. On multivariate analysis controlled for baseline abnormal HI, TH and/or LE OR 10.3 (p-value , 0.001) and albumin OR 0.14 (p-value 0.001) predicted CD while age OR 1.00 (p-value 0.88) and MELD OR 1.02 (p-value 0.83) did not. The table shows the SVR and CD rates in patients with or without abnormal HI or albumin , 4.0 g/ dl in different combinations. Conclusion: Patients with abnormal HI at baseline who do not respond to anti-viral therapy have an increased risk for CD. Using the baseline albumin and HI, an assessment of SVR and CD rates should be considered when initiating antiviral therapy. Decompensation and SVR Among Different Pre-Treatment Patient Characteristics 81% Treatment Naive (124/153) ( * Albumin in g/dL, ¥ HI=Hematologic Indices)