Hepatic steatosis is associated with mitochondrial oxidative alterations. This study aimed to characterize in a choline–deficient model of rat fatty liver whether this oxidative imbalance is related to an impairment of the capacity of ATP synthesis both under fed conditions and after starvation, which may sensitize mitochondria to oxidative injury. Mitochondria were isolated from normal and fatty livers of fed or 18–hour fasted rats. Oxidative injury was evaluated by measuring the mitochondrial content of thiobarbituric reactive substances, protein carbonyls, glutathione, and protein sulfhydryls. The mitochondrial F₀F₁–ATP synthase content, tissue ATP concentration, and liver histology were also determined. Compared with normal liver, under fed conditions, fatty livers showed a greater mitochondrial content of oxidized lipids and proteins together with a low concentration of sulfhydryls and glutathione. The mitochondrial catalytic β–F₁ subunit of the F₀F₁–ATP synthase was about 35% lower in fatty livers. Hepatic ATP was also significantly reduced in fatty liver. Starvation exacerbated mitochondrial oxidative injury in both groups but to a greater extent in fatty livers. In the steatotic group, fasting induced a significant decrease of the ATP levels, which was accompanied by a 70% fall of the catalytic β–F₁ subunit. These data indicate that the mitochondrial oxidative alterations in fatty livers are associated with an important reduction of the F₀F₁–ATP synthase. These changes, which are greatly exacerbated after starvation, may account for the reduced synthesis of the hepatic ATP observed in the presence of fatty infiltration.

Drug-induced hepatotoxicity is a significant and still unresolved clinical problem. The limitation in current knowledge regarding mechanisms of hepatic toxicity renders most of the preclinical review process failing and most of drug-induced hepatic injury remains unpredictable. Current knowledge on the mechanisms of drug-induced liver cell death is reviewed here. The intervention of both intra- and extracellular factors in determining the appearance of drug-induced cell apoptosis or necrosis is also discussed. Finally, the role of both mitochondria and non parenchymal cells are reviewed with respect to approaches useful to manage drug-induced liver injury.

INTRODUCTION: The aim of this study is to determine the prevalence of hyponatremia, its association with long-term medication use and underlying chronic conditions, the rate of hospitalisation and death within 3 months from its discovery and its management in community-dwelling older people. METHODS: One year of data for ~5635 patients aged >65 years was extracted from the databases of 19 general practitioners (GPs); 2569 (45.6%) were checked for hyponatremia. RESULTS: Hyponatremia occurred in 205 (8.0%) of 2569 checked individuals: 78.5% (161/205) had hypertension, 31.2% (64/205) diabetes, 23.9% (49/205) chronic renal failure; 38.0% (78/205) received diuretics, 36.6% (75/205) renin-angiotensin system antagonists (ACE-I/ARB) and 9.8% (20/205) serotonin reuptake inhibitors. Drug consumption was higher in hyponatremic patients, although only diuretics, ACE-I/ARB, anti-arrhythmics and opioids were significantly associated with hyponatremia. The likelihood of hyponatremia trebled when four drugs were taken, and it was seven-fold higher with the use of six drugs. Hyponatremia was associated with a higher prevalence of chronic illnesses and higher rate of hospitalisation (13.7% vs 7.7%, P = 0.005) and death (3.9% vs 1.8%, P < 0.035). The use of at least one long-term medication was associated with hospitalisation or death in hyponatremic patients (10% vs 6.3%, P = 0.010). Less than 20% of hyponatremic patients had their sodium level checked again after 1 month. DISCUSSION: Hyponatremia is not uncommon among community-living older patients, especially in patients taking medications potentially causing hyponatremia. Hyponatremic patients are likely to encounter more serious events, including hospitalisation and death. Targeted training of GPs is desirable to improve their practice.