Suppression of bile acid synthesis, but not of hepatic cholesterol 7alpha-hydroxylase expression, by obstructive cholestasis in humans.

Regulation of bile acid synthesis, a key determinant of cholesterol homeostasis, is still incompletely understood. To elucidate the feedback control exerted on bile acid biosynthesis in humans with obstructive cholestasis, 16 patients with bile duct obstruction were studied. In vivo 7alpha-hydroxylation, reflecting bile acid synthesis, was assayed in 13 of them by tritium release analysis. Serum 27-hydroxycholesterol was determined by gas chromatography-mass spectrometry. In a subgroup, hepatic cholesterol 7alpha-hydroxylase mRNA was assayed by real-time polymerase chain reaction (PCR), enzyme activity was determined by isotope incorporation, and microsomal cholesterol content was assayed by gas chromatography-mass spectrometry. Age-matched control subjects were studied in parallel. Hydroxylation rates were lower in cholestatic patients (108 +/- 33 mg of cholesterol per day, mean +/- SEM; controls: 297 +/- 40 mg/d; P <.01). The reduction was proportional to the severity of cholestasis, and synthetic rates were normalized in 4 subjects restudied after resolution of biliary obstruction. Consistent findings were obtained by analysis of serum 7alpha-hydroxycholesterol levels. On the other hand, hepatic cholesterol 7alpha-hydroxylase mRNA, microsomal enzyme activity, and cholesterol content tended to be increased in cholestasis. Finally, serum 27-hydroxycholesterol levels were slightly reduced in cholestatic subjects and were not related with the severity of the disease. Suppression of in vivo bile acid synthesis with no corresponding reduction in tissue 7alpha-hydroxylase expression and activity is consistent with nontranscriptional, posttranslational levels of regulation; these may play a role in the feedback control of bile acid synthesis in particular conditions. Alteration of the alternate biosynthetic pathway seems unlikely according to the present data.

Review article: effect of bile salt pool composition on hepatic and biliary functions.

The enterohepatic recirculation of bile salts exerts important regulatory effects on many hepatic, biliary and intestinal functions: such regulation is likely to depend, to a large extent, on the physical-chemical property of hydrophobicity of the recirculating pool. The present review summarizes the main experimental evidence carried out by our research group over the past two decades, in the attempt to investigate systematically the relationships between structural properties and biological effects of bile acids in humans. Hydrophobic bile acids (chenodeoxycholic acid, deoxycholic acid), but not hydrophilic acids (ursodeoxycholic acid), significantly suppressed hepatic activity of HMG-CoA reductase, the limiting step of cholesterol synthesis, and in vivo cholesterol 7alpha-hydroxylation, the limiting step of bile acid synthesis. The output of biliary cholesterol and phospholipid was also directly related to the hydrophobicity of the bile acid pool. Finally, treatment with chenodeoxycholic acid, but not with ursodeoxycholic acid, significantly decreased gall-bladder emptying rates. When turning to the in vitro model of HepG2 cells, hydrophobic bile acids were found to induce greater cytotoxic and pro-apoptotic effects. From this series of studies, we conclude that the regulatory effects of bile acids on the liver and biliary tract are largely dependent on the hydrophobic-hydrophilic balance of the recirculating bile acid pool.

Influence of age and sex on serum concentrations of total dimeric activin A.

Several studies have shown that activin A is secreted in substantial amounts into the systemic circulation. The changes that occur during menstrual cycle and pregnancy suggest a correlation with reproductive function. At present, however, no definitive evidence has confirmed this pattern throughout adult life; moreover, neither the origin nor the physiological implications of this circulating growth factor have been clearly defined. The aim of the present study was to evaluate whether circulating concentrations of activin A change in adult men and women according to age and sex, and to examine the possible correlation with serum concentrations of FSH. Total dimeric activin A was measured using a specific two-site enzyme immunoassay in serum specimens collected from a cohort of normal individuals enrolled in an epidemiological survey. A group of men (n = 106) and one of women (n=151) were subdivided into six age groups (20-30, 30-40, 40-50, 50-60, 60-70 and 70-90 years). In a small group of 8 men and 11 women, serum concentrations of activin A were evaluated twice, in specimens collected at an interval of 10 years. Serum FSH concentrations were also measured in all specimens. Serum concentrations of activin A were not significantly different in men and women and showed an age-related progressive increase between 20 and 50 years of age (P<0.01, those aged 40-50 compared with those aged 20-30 years). After the age of 50 years, activin A concentrations remained in the same range of values in women, whereas they increased significantly in men, reaching peak values between 70 and 90 years (P<0.01 compared with the group aged between 20 and 50 years). From the age of 50 years, activin A concentrations were significantly greater in men compared with those in women in the corresponding age groups (P<0.001). Activin A concentrations correlated with age in men, but not in women. No significant correlation between concentrations of activin A and FSH was found in either sex. Activin A concentrations in specimens collected 10 years apart showed an increase in seven of eight men, but not in women. Finally, no significant variations of activin A concentrations were observed when fertile and postmenopausal women were compared. The present data indicate that circulating concentrations of activin A vary according to age; furthermore, men older than 50 years have greater concentrations than women. These changes, which occur irrespectively of FSH concentrations, indicate that circulating activin A is not a hormone of the reproductive axis.

Thoracic intervertebral disc protrusions.

Intervertebral disc protrusions occur most frequently in the lumbar spine, much less frequently in the cervical spine and very rarely in the thoracic spine. The symptomatology of thoracic protrusions is both aspecific and polymorphic. The diagnosis is therefore difficult and necessarily depends on myelography and computerised axial tomography (CAT scanning). The treatment is surgical and should be undertaken early if pain and neurological damage are to be relieved.