Effect of exendin (exenatide)--GLP 1 receptor agonist on the thyroid and parathyroid gland in a rat model.

Exenatide or Exendin-4 is a 39-amino acid agonist of the glucagon like peptide (GLP-1) receptor approved for the adjunctive treatment for type 2 diabetes. Recent reports suggest that GLP-1 agonists may also have distant effects including C-cell thyroid hyperplasia. The aim of this study was to evaluate the effect of exendin-4 on the thyroid and parathyroid cells in a rat model. Rat thyroids were stained for calcitonin, H&E and for carcinoembryonic antigen (CEA). Thyroid C-cell hyperplasia was graded on H&E stained slides using cell size and secretory granule numbers, morphological features of the parathyroid glands and the serum calcium concentrations of the rats were also evaluated. Counts of stained cells/high power field and intensity of staining were recorded by two pathologists. Data were analyzed by ANOVA/post-tests. C cell hypertrophy was elevated in exenatide-treated vs. untreated animals (22.5 ± 8.7 vs. 10.5 ± 2.7 cells/HPF). CEA staining failed to show effects by exendin. Calcitonin staining was significantly elevated in exenatide treated controls (P<0.001). Parathyroid glands were histologically normal in both groups, and serum calcium levels were within normal range in all animals. In summary, exenatide was associated with C cell hyperplasia and increased calcitonin staining of thyroids, but was unrelated to CEA levels. These data raise important concerns about the effects of exenatide which, given its wide clinical use, should be clarified with urgency.

Treatment with omega-3 fatty acids but not exendin-4 improves hepatic steatosis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the Western world. The aim of this study was to evaluate the biochemical and histological effects of omega-3 fatty acid and exendin-4 treatment on NAFLD in an animal model. METHODS: Sixty-three 8-week-old outbred Sprague-Dawley male rats were used for this study. Three animals were used as procedure controls, and 30 rats were fed a methionine and choline deficient (MCD) diet and 30 were fed a regular chow diet. In each group of 30 animals, 10 served as controls, 10 received exendin-4, and 10 received omega-3 fatty acids. After 75 days of treatment, the animals were euthanized, the tissues and serum were harvested, and the livers were formalin-fixed for histology. RESULTS: The MCD diet was exceptionally efficient at producing fatty livers. The MCD control animals had a liver steatosis score of 38+/-6.7 (of 50 possible); treatment with exendin-4 was not associated with a significant reduction of steatosis (44+/-5.16, P=0.07) and the omega-3 fatty acid treatment was associated with a significant decrease in the liver steatosis score (15.6+/-13.46, P<0.001) compared with both the controls and the exendin-4 groups. The omega-3 fatty acid treatment increased serum aspartate aminotransferase significantly, whereas exendin-4 had no effect. CONCLUSION: In an animal model of NAFLD, the omega-3 fatty acid therapy was associated with significant improvement in hepatic steatosis compared with exendin-4. These data suggest that omega-3 fatty acid supplements may have a potential therapeutic role in patients with NAFLD.

Predictors of hematological abnormalities in patients with chronic hepatitis C treated with interferon and ribavirin.

Hematological abnormalities including neutropenia, anemia, and thrombocytopenia are commonly seen in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. The aim of this study was to identify factors which would help to predict the development of hematological abnormalities in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. During a 4-year period, all patients with chronic hepatitis C started on treatment with pegylated interferon and ribavirin were identified. Patients were defined as having hematological abnormalities if they had the presence of either anemia, neutropenia, thrombocytopenia, or a combination of the above during treatment with pegylated interferon and ribavirin. A total of 136 patients with chronic hepatitis C were included in this study. Fifty-two (38.2%) of the patients developed significant hematological abnormalities during treatment with pegylated interferon and ribavirin with 28 (20.6%), 30 (22.1%), and 11 (8.1%) developed neutropenia, anemia, and thrombocytopenia, respectively. Genotype 1, history of hypertension, low baseline platelet count, low baseline hemoglobin, as well as a raised creatinine were significant factors associated with the development of hematological abnormalities. Significant hematological abnormalities are commonly present in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. This study identifies pretreatment parameters that may help identify high-risk patients who are more likely to develop hematological abnormalities during treatment for chronic hepatitis C.

Clinicopathological predictors to predict sustained viral response rates in patients with chronic hepatitis C infection.

BACKGROUND: Treatment of patients with chronic hepatitis C virus (HCV) infection remains suboptimal, with the current pegylated interferon (PEG-IFN) and ribavirin combination therapy providing sustained viral response (SVR) rates of 54 - 63%. The aim of this study was to identify clinical, laboratory and histological findings that can predict non-response to this treatment. METHODS: Medical records of patients who had completed PEG-IFN and ribavirin therapy for chronic HCV infection between December 2002 and November 2005 and had undergone a liver biopsy prior to starting treatment were retrospectively reviewed. Data on various clinical and biochemical parameters were extracted and liver biopsy slides were reviewed by a pathologist who was blinded to the clinical and laboratory findings. RESULTS: Of 67 patients studied (mean [SD] age 46.3 [6.3] years; 36 men), 42/57 (74%) had an early viral response (EVR) and 37/64 (58%) had an SVR. On univariate analysis, absence of EVR (p=0.0002), non-white race (p=0.008), AST/ALT ratio > or = 1.0 (p=0.008), INR > or = 1.0 (p=0.02) and presence of steatosis > or = 5% on liver biopsy (p=0.03) were associated with lack of SVR. In multivariate analysis, all of these except INR were significant independent predictors of SVR. CONCLUSIONS: Absence of EVR, non-white race, AST/ALT ratio > or = 1.0 and presence of steatosis > or = 5% on liver biopsy are independent predictors of absence of SVR in patients with chronic HCV infection receiving PEG-IFN and ribavirin combination treatment.

Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease.

BACKGROUND/AIMS: Data from animal models of fibrosis and fatty liver suggest that leptin may mediate the profibrogenic responses in the liver, but the association of leptin and liver fibrosis in human nonalcoholic fatty liver disease (NAFLD) remains undefined. We aimed at determining the relation between leptin and liver fibrosis in human NAFLD. METHODS: Human plasma leptin and several indicators of insulin resistance were measured in 88 NAFLD patients and matched controls. RESULTS: Leptin levels were significantly greater in patients with more advanced fibrosis (P = 0.005). By multivariate analysis, the significant association between leptin and fibrosis was abolished (adjusted P = 0.3) when controlling for confounders including age, gender, BMI, diabetes and insulin resistance. Only age (adjusted P = 0.006) and insulin sensitivity (adjusted P = 0.04) correlated significantly with fibrosis stage. A second liver biopsy was performed in 39 out of the 88 patients at 27.9 +/- 16 months. Leptin levels were not significantly different between patients who had fibrosis progression (n = 10) and those who did not (n = 29). CONCLUSIONS: In human NAFLD, no relationship between leptin levels and fibrosis stage was demonstrated. The correlation of leptin and fibrosis severity seems to be an indicator of the factors that determine leptin production.