Concentration-dependent response to pioglitazone in nonalcoholic steatohepatitis.

BACKGROUND: Pioglitazone is a safe and effective option to manage patients with type 2 diabetes and nonalcoholic steatohepatitis (NASH). However, there is marked variability in treatment response. AIM: To evaluate the relationship between concentrations of pioglitazone and its active metabolites and treatment outcomes in patients with NASH. METHODS: Pioglitazone concentrations were measured in patients with NASH treated with pioglitazone 45 mg/day for 18 months; liver biopsy samples were obtained at baseline and after treatment. The primary outcome was a ≥2-point reduction in NAFLD activity score (NAS) with at least one-point improvement in more than one liver histology category and without worsening of fibrosis. A novel marker, the pioglitazone exposure index, was calculated to consider the concentrations of pioglitazone as well as the two active metabolites. RESULTS: The response to pioglitazone was concentration-dependent as evidenced by the significant relationship between both pioglitazone concentration and pioglitazone exposure index with changes in NAS (r=.48, P=.0002 and r=.51, P<.0001, respectively), steatosis (r=.41, P=.002 and r=.46, P=.0005), and inflammation (r=.44, P=.0009 and r=.40, P=.0003). The pioglitazone exposure index was also associated with a change in ballooning (P=.04). The pioglitazone exposure index was higher in patients with NASH resolution (2.85±1.38 vs 1.78±1.48, P=.018). A predictive model for the primary outcome was developed that incorporated baseline NAS and pioglitazone exposure index (AUC=0.77). CONCLUSIONS: This study demonstrates the importance of pioglitazone exposure to variable response in patients with NASH, and indicates potential factors that may identify patients most likely to benefit from chronic pioglitazone treatment.

Isolated hypoaldosteronism: An overlooked cause of hyponatraemia.

We report three patients with hyponatraemia due to isolated hypoaldosteronism. Addison's disease was ruled out in each of these patients by a normal short synacthen test. Two patients had severe hyponatraemia and fluid restriction helped improve the sodium level only marginally. One was treated with demeclocycline, which did not prove to be effective. Subsequently, all three patients were found to have aldosterone deficiency and treatment with fludrocortisone caused their sodium levels to return to normal.

Silent growth hormone secreting pituitary adenomas: IGF-1 is not sufficient to exclude growth hormone excess.

Circulating insulin-like growth factor-1 (IGF-1) is increasingly being used as a screening test and in ongoing monitoring of treated acromegaly. We here present three cases of women (two of whom were on the oestrogen containing contraceptive pill at the time of presentation) who had normal circulating IGF-1 and no overt clinical features of acromegaly at the time of their pituitary surgery. Postoperatively, all were confirmed to have growth hormone excess in keeping with the presence of active somatotroph pituitary adenomas. We suggest that for optimal patient management, formal evaluation of growth hormone status with oral glucose tolerance testing should ideally be performed on all individuals for whom pituitary surgery is planned.

Diabetes associated with atypical antipsychotic treatment may be severe but reversible: case report.

OBJECTIVE: To draw attention to severe presentations of atypical neuroleptic related diabetes and to document that a marked degree of remission can take place after drug withdrawal. METHOD: We describe two patients who presented with diabetic ketoacidosis after treatment with quetiapine and risperidone, respectively. RESULTS: Both patients were negative for islet cell antibodies. They both required treatment with insulin, one in very high dosage, but their insulin requirements fell progressively after the atypical antipsychotic was withdrawn. After several months, neither patient required antidiabetic treatment. CONCLUSIONS: Atypical antipsychotic-induced diabetes does not always take a "type 2" presentation in which weight gain and insulin resistance are implicated. Sometimes the presentation is with diabetic ketoacidosis, requiring insulin treatment, which can nevertheless be reversible.