Phui Ly Liew

Hepatic Histopathology of Morbid Obesity: Concurrence of Other Forms of Chronic Liver Disease

Background: Obesity is a chronic inflammatory condition, with related steatohepatitis and liver fibrosis. The authors analyzed the hepatic histopathology in morbidly obese patients and predictors of concurrence of clinical and/ or histopathologic findings of steatohepatitis with other forms of chronic liver disease. Methods: The histopathologic findings in the liver of 160 patients who were undergoing laparoscopic gastric bypass or gastric banding for morbid obesity, were examined. Clinical data (gender, age, BMI and associated diseases) and laboratory evaluation were obtained from the patient records. The degree of steatosis, ballooning degeneration, lobular inflammation and fibrosis were determined and scored. Results: Among the patients, 62.5% (n=100) were females and 37.5% (n=60) were males, age 27 ± 12 years, with mean BMI 43 ± 5.8 kg/m2. 63, 54, 26, 15 and 2 patients were diagnosed as non-nonalcoholic steatohepatitis (non-NASH), NASH, chronic hepatitis B (CHB), alcoholic steatohepatitis and chronic hepatitis C (CHC), respectively. The prevalence of NASH was 33.8%, of which 5 patients (9.2%) had bridging fibrosis, but no cirrhosis was found in the NASH group. The prevalence of CHB was 16.3%, of which 3 patients (11.6%) had bridging fibrosis and/or cirrhosis. Multivariate analysis showed an association between steatosis and AST, ALT, GGT, C-peptide, insulin, HOMA-IR and adiponectin. The predictors of ballooning degeneration were serum sugar and AST, whereas the predictors of lobular inflammation were AST and ALT. There was a trend toward a correlation between abnormal liver function, insulin resistance, steatosis, liver cell injury and Mallory body in the NASH population. BMI, C-peptide, steatosis, ballooning degeneration and portal inflammation were significantly different between NASH and CHB groups, but only steatosis and ballooning degeneration were independent factors of NASH compared with CHB group after multivariate analysis. Overall, AST, AST/ALT ratio, uric acid and portal inflammation were independently associated with advanced fibrosis, while only Mallory body (P=0.033) and portal inflammation (P=0.015) were significantly different between mild-moderate fibrosis and advanced fibrosis in the NASH patients. Conclusion: Hepatic steatosis, features of metabolic syndrome and liver cell injuries were common in morbidly obese patients. Abnormal liver function and portal inflammation were related to hepatic fibrosis. The coexistance of clinical and histologic features of steatohepatitis with another chronic liver disease may reflect the biological significance of the chronic inflammatory condition in the obese population, which requires further investigation.

Gastric Ghrelin Expression Associated with Helicobacter pylori Infection and Chronic Gastritis in Obese Patients

Background: Helicobacter pylori is a major pathogen of stomach. Ghrelin is secreted from the stomach, and it plays a role in the coordination of eating behavior, and facilitates fat storage and weight regulation. The effects of H. pylori infection on gastric ghrelin production are still not well known. Recent exciting studies linked H. pylori infection to ghrelin, then to obesity. The aim of the present study is to investigate gastric ghrelin immunoreactivity associated with H. pylori infection, chronic gastritis and the clinical correlation in obese patients. Methods: The histologic findings of stomach were examined in 156 patients who were undergoing laparoscopic vertical-banded gastroplasty for obesity. Ghrelin immunoreactivity was evaluated immunohistochemically with an anti-ghrelin antibody, and the density of ghrelin-positive cells determined per total glands of the gastric mucosa. Relationship between density of ghrelin-positive cells, histopathology of chronic gastritis scored by the Sydney system and clinical correlation was analyzed. Results: H. pylori was present in 62 (39.7%) out of 156 patients. The density of ghrelin-positive cells was significantly lower for H. pylori-infected patients. There was a significant stepwise decrease in density of ghrelin-positive cells, with progression of histological severity of chronic inflammation, neutrophil activity and glandular atrophy in the corpus. Obese patients positive for H. pylori were associated with older age and abnormal plasma triglyceride level, but not with sex, body mass index, liver function tests or glucose level. There was no relationship between density of gastric ghrelin-positive cells and body mass index. Conclusion: H. pylori infection has a negative impact on density of gastric ghrelin-positive cells in obese patients. Impaired density of gastric ghrelinpositive cells is associated with neutrophil activity, chronic inflammation and glandular atrophy induced by H. pylori infection. The potential role of H. pylori infection and density of gastric ghrelin-positive cells on the development of obesity and their biological significance warrants further investigation.

The Influence of Helicobacter pylori Infection and Corpus Gastritis on the Postoperative Outcomes of Laparoscopic Vertical Banded Gastroplasty

Background: Helicobacter pylori (HP) infection is linked to weight control through gastric inflammation-induced deregulation of satiety-related hormone, and eradication of HP before a weight reduction operation has been advocated. We aimed to examine the impact of HP infection and corpus gastritis on preoperative patient characteristics, postoperative complications and weight loss following laparoscopic vertical banded gastroplasty (LVBG). Methods: A prospective cohort of 152 patients undergoing LVBG was enrolled. Gastric specimens at the corpus were obtained during LVBG operation and scored histologically according to the Sydney classification of gastritis. Excess weight loss, and early and late complications following LVBG, were recorded and correlated. Results: 63 and 89 patients were identified as HP positive and negative groups respectively. The prevalence of individual components of the metabolic syndrome was comparable in both groups except hypertension. The occurrence of early and late complications, either minor or major, in both groups was similar. The severity of gastritis was correlated positively with age and negatively with preoperative BMI and excess weight. Patients with higher neutrophil activity, chronic inflammation, and HP density experienced less excess weight loss at 24 to 48 months follow-up. The impact of gastritis on weight loss became less recognizable after 48 months follow-up. Conclusions: HP infection and gastric inflammation play a significant role in the amount of weight loss after LVBG. Further prospective studies should examine possible mechanisms and long-term effects on weight loss to determine the utility of preventive eradication of HP in different types of bariatric surgery.

Survivin-mediated therapeutic efficacy of gemcitabine through glucose-regulated protein 78 in hepatocellular carcinoma.

BackgroundSurvivin is an antiapoptotic molecule that is widely expressed in cancers, including hepatocellular carcinoma (HCC). Survivin has become a general therapeutic target for cancers because of its selective overexpression in a majority of tumors. However, little is known regarding the effect of survivin expression in combination with gemcitabine on HCC.MethodsWe generated survivin knockdown cells (survivin-KD) via a short interfering RNA (siRNA) technique. The antiproliferation effects of gemcitabine were determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assay, and cell cycle evaluation.ResultsAccording to the MTT assay, we found that survivin-KD cells were more sensitive than parental cells and scrambled control cells to gemcitabine treatment. The apoptotic cell population increased in survivin-KD cells that were treated with gemcitabine in comparison to scrambled control cells, as observed by the cell cycle distribution and TUNEL assays. We found that survivin knockdown resulted in a reduction of glucose-regulated protein 78 (GRP78), which may be responsible for the observed increased survivin-KD cell sensitivity to gemcitabine.ConclusionsWe conclude that survivin knockdown may contribute to a therapeutic effect of gemcitabine through GRP78 on HCC cells.

Enhanced FDG uptake in brown tumors mimics multiple skeletal metastases in a patient with primary hyperparathyroidism

Sir, We recently experienced a patient with primary hyperparathyroidism. Positron emission tomography (PET) with 2-[F-18] fluoro-2-deoxy-D-glucose (FDG) (FDG-PET) revealed enhanced FDG uptake into brown tumors caused by hyperparathyroidism. A parathyroid adenoma failed to be detected by FDG-PET. The patient was a 55-year-old male, presenting with generalized bone pain, weakness, fatigue, depressive mood, body weight loss, hypercalcemia (3.1 mmol/l, normal range 1.9 2.5 mmol/l), and positively imaged Tc-MDP scan regarded as bony metastases. FDG-PET whole-body cancer screening was performed on suspicion of a tumor of unknown origin. PET images were obtained 60 min after an intravenous injection of 300 MBq (8.1 mCi) FDG using a Siemens ACCEL PET scanner. The FDG-PET findings were interpreted as multiple skeletal metastases from a tumor of unknown primary (Fig. 1). Postcontrast whole-body CT scan revealed multiple osteolytic bone lesions in the body. In addition, an irregular hypodense mass, about 3.2 cm in maximum diameter, with heterogeneous enhancement in the right thyroid bed was incidentally found (Fig. 2). Thyroid cancer with multiple bone metastases was our clinical impression. The patient then received a simultaneous right thyroid lobectomy and bone biopsy. A specimen of the right thyroidectomy revealed a welldefined, soft, brownish, and encapsulated nodule, measuring 3.5 2.9 1.8 cm in size, close to the thyroid. Microscopically, the nodule had the appearance of a parathyroid adenoma composed mainly of hyperplastic clear cells, oncocytic cells, and chief cells surrounded by fibrous capsule. Bone biopsy from the left iliac crest demonstrated giantcell reparative granuloma (brown tumor) with prominent fibroblastic stroma containing multinucleated giant cells, areas of stromal hemorrhage, focal hemosiderin-laden macrophages infiltration, and reactive osteoid and bone formation. Finally, brown tumors caused by a parathyroid adenoma were diagnosed. In this case, a parathyroid adenoma failed to delineate using FDG-PET, and the reactive bone lesions (brown tumors) were misinterpreted as skeletal metastases via FDG-PET and Tc-MDP

Roles of hepatic progenitor cells activation, ductular reaction proliferation and notch signaling in morbid obesity

BACKGROUND/AIMS Hepatic progenitor cells (HPCs) activation, proliferative ductular reaction (DR), replicative arrest and Notch signaling have been demonstrated in a variety of human liver diseases. The relationships are poorly understood in morbid obesity. We investigated factors responsible for the HPCs/DR, replicative arrest and Notch signaling in non-NASH and NASH groups. METHODOLOGY Cytokeratin 7 (and 19), p21, CD34, Ki67 and different Notch receptors and ligands immunohistochemical stained biopsies from morbid obese patients with non-NASH (n=10) and NASH (n=25) were studied. These results were correlated with clinicopathological variables. RESULTS NASH patients presented with abnormal liver function tests and had higher HbA1c percentage. Strong association between HPCs and DR was seen (r=0.785, p<0.000). BMI, interface activity and replicative arrest were associated with HPCs expansion and DR in NASH patients. A strong association between CD34 with HPCs and DR was found in non-NASH patients. In NASH group, Notch 3 was important in bile ductular proliferation; whereas Notch 4 was associated with sinusoidal neovessels proliferation and Kupffer cell activation. CONCLUSIONS HPCs and DR played an important role in hepatic regeneration in fatty liver disease of morbid obesity. An altered replication pathway in NASH promotes HPCs activation and DR. Notch-3 and Notch-4 were significantly different between non-NASH and NASH groups.

DEF6 expression in ovarian carcinoma correlates with poor patient survival

BackgroundIncreased expression of DEF6 is correlated with the malignant behavior of various cancers. Both DEF6 and p16 contribute to the regulation of cell cycle progression, and p53 plays important role in the cell cycle checkpoints. This study was designed to elucidate the prognostic significance of DEF6, p53 and p16 immunoexpressions in different histology subtypes of ovarian carcinoma.MethodsImmunohistochemistry results of DEF6, p53 and p16 on ovarian carcinoma were compared with histology subtypes, clinical data, overall survival (OS) and disease-free survival (DFS) by Cox regression and Kaplan-Meier analysis.ResultsWe studied 180 cases of ovarian carcinomas (75 high-grade serous, 41 clear cell, 36 mucinous and 28 endometrioid), including 109 FIGO stage I-II cases and 71 FIGO stage III-IV cases. Ovarian carcinomas positive for both DEF6 and p16 expression were associated with the worst OS (P = 0.027) and DFS (P = 0.023), whereas those negative for both DEF6 and p16 had the best OS and DFS. Aberrant p53 expression combined with positive DEF6 was associated with worst OS (P = 0.031) and DFS (P = 0.028). Kaplan-Meier analysis showed that significantly shorter survival rates were seen in patients with high expressions of DEF6 (P = 0.008) and p16 (P = 0.022). Patients with aberrant p53 expression in high-grade serous carcinoma (P = 0.012) and patients with high DEF6 expression in clear cell carcinoma (P = 0.001) were also associated with shorter overall survival. In univariate analysis, FIGO stage, DEF6 and p16 were associated with poor prognosis. DEF6 expression was the only independent prognostic factor correlated with shorted OS (HR 2.115; P = 0.025) and DFS (HR 2.248; P = 0.016) upon multivariate analysis.ConclusionsDEF6 expression may serve as an independent prognostic factor, and interacted positively with p16 toward high tumor stage and shorter survival.

Hepatic tumor necrosis factor-α, leptin and adiponectin expression in morbid obese patients: Clinicopathological correlations

SUMMARY BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is associated with obesity. We retrospectively studied the clinicopathology and different hepatic adipocytokine expressions between nonalcoholic steatohepatitis (NASH) and non-NASH in morbid obesity. METHODS We enrolled 40 patients undergoing liver biopsy during bariatric surgery. We analyzed hepatic mRNA and immunohistochemistry of TNF-α, leptin, adiponectin and adiponectin receptor. RESULTS Thirty patients (75%) presented with NASH, including 11 with mild fibrosis and 19 with advanced fibrosis. The HbA1c (P = 0.000), AST (P = 0.000), ALT (P = 0.000), GGT (P = 0.016) and liver fibrosis (P = 0.028) have statistically difference between NASH and non-NASH groups. Steatosis was the only significant factor (r = 0.348, P < 0.05) associated with TNF-α mRNA level. Adiponectin mRNA was inversely associated with C-peptide (r = -0.416, P < 0.05) and uric acid level (r = -0.426, P < 0.05). The best predictors for TNF-α immunostain were hemoglobin (r = 0.432, P < 0.01), AST (r = 0.371, P < 0.05), lobular inflammation (r = 0.315, P < 0.05), portal inflammation (r = 0.331, P < 0.05), and NAS (r = 0.365, P < 0.05). Leptin immunostain was correlated with C-peptide (r = 0.356, P < 0.05) and portal inflammation (r = 0.334, P < 0.05). The AdipoRII immunoexpression was negatively correlated with systolic blood pressure (r = -0.481, P < 0.01). Multivariate linear regressions of adipocytokine profile related mostly to age, gender, systolic blood pressure, serum uric acid, steatosis, NAS and portal inflammation. CONCLUSION Although different adipocytokines may be associated with NAFLD progression in morbid obesity, their major correlations in the pathogenesis of obesity-related NASH are not clear. Additional confirmatory studies are deserved.