Stefan Sjöberg

Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans

Reduced plasma LDL-cholesterol is a hallmark of hyperthyroidism and is caused by transcriptional stimulation of LDL receptors in the liver. Here, we investigated whether thyroid hormone (TH) actions involve other mechanisms that may also account for the reduction in LDL-cholesterol, including effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) and bile acid synthesis. Twenty hyperthyroid patients were studied before and after clinical normalization, and the responses to hyperthyroidism were compared with those in 14 healthy individuals after 14 days of treatment with the liver-selective TH analog eprotirome. Both hyperthyroidism and eprotirome treatment reduced circulating PCSK9, lipoprotein cholesterol, apoB and AI, and lipoprotein(a), while cholesterol synthesis was stable. Hyperthyroidism, but not eprotirome treatment, markedly increased bile acid synthesis and reduced fibroblast growth factor (FGF) 19 and dietary cholesterol absorption. Eprotirome treatment, but not hyperthyroidism, reduced plasma triglycerides. Neither hyperthyroidism nor eprotirome treatment altered insulin, glucose, or FGF21 levels. TH reduces circulating PSCK9, thereby likely contributing to lower plasma LDL-cholesterol in hyperthyroidism. TH also stimulates bile acid synthesis, although this response is not critical for its LDL-lowering effect.

Monoamine precursors, transmitters and metabolites in cerebrospinal fluid: a prospective study in healthy male subjects

In order to elucidate methodological aspects of CSF investigations, 14 healthy male subjects were lumbar-punctured at the L4-5 level following a standardised procedure. CSF concentrations of precursors, transmitters and transmitter metabolites were used as dependent variables, while age, height, body weight, atmospheric pressure and some other factors served as independent variables. 5-HIAA and HVA (but not HMPG) have pronounced concentration gradients. We also found CSF gradients for the precursors tryptophan and tyrosine, as well as for serotonin, dopamine and the dopamine metabolite DOPAC. Dopamine and atmospheric pressure showed a positive intercorrelation. Age correlated curvilinearly (convex upward) with tryptophan but showed a negatively directed linear correlation with serotonin. Serotonin and 5-HIAA showed no intercorrelation. Our results suggest an age-dependent disposition of tryptophan in the CSF. The absence of a correlation between serotonin and 5-HIAA might be inconsistent with the notion that 5-HIAA is a marker of central serotonin turnover. The comparatively high body weight of our volunteers might explain the lack of a gradient for HMPG.

Depressive Symptoms in Hypothyroid Disorder with some Observations on Biochemical Correlates

Lumbar punctures and ratings of depressive symptoms were done in hypothyroid patients before and during L-thyroxine therapy. Before treatment, the most prominent symptoms were concentration difficulties, lassitude, and reduced sexual interest. All patients suffered from sleep disturbances. Suicidal thoughts did not occur at all. Inner tension was negatively correlated with the anxiogenic cholecystokinin tetrapeptide (CCK-4) in the cerebrospinal fluid (CSF), while reduced sexual interest was negatively correlated with CSF tryptophan. Furthermore, failing memory correlated negatively with T3 as well as T4 in serum. A positive correlation was found between failing memory and serum TSH. All patients improved significantly during treatment. No biochemical correlates were found. In conclusion, hypothyroidism is associated with major depressive symptoms. CSF CCK-4 and tryptophan, as well as serum thyroid hormones, may constitute biochemical correlates for some of these symptoms.

Cholecystokinin peptides in cerebrospinal fluid : a study in healthy male subjects

The clinical reliability of measuring cholecystokinin (CCK) peptides in the cerebrospinal fluid (CSF) has not been fully elucidated. Therefore, we have assayed CCK-8S and CCK-4 in CSF obtained from 14 healthy male subjects, lumbar-punctured at the L4-5 level following a strictly standardised procedure. CSF concentrations of free CCK-8S and free CCK-4 were used as dependent variables while age, height, body weight, atmospheric pressure and some other factors served as independent variables. It was shown that the CCK-8S ratio between the second (7-12 ml) and first (0-6 ml) CSF fractions, correlated significantly with the atmosphere pressure at the time of puncture. Neither CCK-8S nor CCK-4 displayed concentration gradients in CSF. The CCK-4 levels, expressed as pmol l-1 in the total amount of CSF were found to be positively correlated with the neuraxis distance in the lying position and negatively with the neuraxis distance in the sitting position. Furthermore, CCK-4, expressed as pmol l-1 per min of tapping-time (pmol l-1 min-1), showed a negative correlation with storage time, presumably mirroring a proteolytic process. CCK-8S and CCK-4 intercorrelated positively independently of whether expressed as pmol l-1 or pmol l-1 min-1. In conclusion, the results of this exploratory study indicate that the neuraxis distance (in the sitting and lying positions) and storage-time have to be accounted for when interpreting data on CSF levels of CCK-4. Attention has to be paid to the potential influence of atmospheric pressure on the concentration ratio of CCK-8S.

CSF taurine level is influenced by plasma cholesterol and the CYP2D6 phenotype

Eight healthy male volunteers, lumbar-punctured before and during simvastatin treatment, were phenotyped for CYP2D6 analysis of the debrisoquine metabolic ratio (the ratio between the urinary recovery of debrisoquine and its 4-hydroxy metabolite) after a single oral dose of debrisoquine. The mean cerebrospinal fluid concentrations of cholesterol and taurine did not differ before and during treatment. During (but not before) treatment taurine in the CSF correlated with the debrisoquine metabolic ratio (r=-0.93, P=0.0007) Our results might indicate an influence of CYP2D6 on the level of taurine in the CSF that was secondary to the change in plasma cholesterol. ⌐ 2003 Elsevier B.V./ECNP. All rights reserved.

CHOLECYSTOKININ PEPTIDES IN CEREBROSPINAL FLUID : A STUDY IN HEALTHY MALE SUBJECTS LUMBAR-PUNCTURED WITHOUT PRECEDING STRICT BED-REST

Summary. In a recent study we analysed the concentrations of two forms of cholecystokinin (CCK), CCK-8S (sulphated) and CCK-4 in cerebrospinal fluid (CSF) obtained from 14 healthy male volunteers lumbar-punctured after a minimum of eight hours of strict bed-rest.We have now lumbar-punctured another group of 14 healthy males, using the same procedure except for the requirement of strict bed-rest prior to puncture.In contrast to our previous study, the concentration of CCK-4 (but not CCK-8S) was significantly higher in the second CSF fraction (7–12 ml) than in the first one (0–6 ml). On using the concentration ratio between the second and first fraction, CCK-8S (but not CCK-4) correlated positively with the atmospheric pressure, which is in contrast to our previous study in which a significant negative correlation was found.When the lumbar CSF concentrations were expressed as the concentration per minute of tapping-time (an estimate of the mass flow), atmospheric pressure, age and the neuraxis distance in the lying position made significant contributions to the variance in CCK-8S. A significant positive correlation with atmospheric pressure was found for CCK-4.In conclusion, the results indicate that the question of strict bed-rest or not prior to lumbar puncture may have to be considered when interpreting data on lumbar CSF concentrations of CCK. A controlled study is warranted.

Cholecystokinin peptides in cerebrospinal fluid: a pilot study in hypothyroid patients

The cholecystokinin tetrapeptide (CCK‐4) and the sulphated octapeptide (CCK‐8) were measured in cerebrospinal fluid obtained from nine hypothyroid patients before and during L‐thyroxine treatment. Before treatment, CCK‐4 and CCK‐8S correlated negatively with S‐TSH, whereas CCK‐8S also showed a positive correlation with S‐T3. During treatment, S‐T4 correlated negatively with CCK‐8S. CSF collection time was significantly shorter during treatment than prior to treatment for the first (0–6 ml) CSF fraction. On taking CSF collection time into account, the levels of both CCK‐4 and CCK‐8S in the first CSF fraction were significantly increased during medication. Our results are consistent with an impact of the hypothyroid disorder and L‐thyroxine treatment on the disposition of CCK compounds in CSF. This might be due to an altered CSF circulation, but other mechanisms (e.g. metabolism or elimination) cannot be ruled out. Copyright

CSF collection time at lumbar puncture is influenced by plasma cholesterol and triglycerides

It is a fairly well-known fact that the CSF collection time (tapping time) at lumbar puncture may influence CSF levels of monoamine compounds (e.g. the serotonin metabolite 5-hydroxyindoleacetic acid, 5-HIAA) and some neuropeptides. Since serum levels of cholesterol and triglycerides and low CSF levels of 5-HIAA have been linked to violent behaviour and impulsivity, we investigated retrospectively whether serum cholesterol and triglycerides affect CSF collection time. The series consists of 14 healthy males lumbar punctured at the L4–5 level. We found that both serum cholesterol and serum triglycerides influenced the CSF collection time for 12 ml of CSF (R = 0.77; p = 0.0067). There was no correlation between cholesterol in serum and CSF, nor between cholesterol in the CSF and collection time. However, we accidentally found a correlation between cholesterol in the CSF and age. The proposed hypothesis tries to explain why cholesterol- and triglyceride-rich lipoprotein particles modify the CSF collection time and influence endothelial function with a subsequent effect on CSF production and/or intraspinal pressure. Thus, it may be of interest to pay attention to serum cholesterol and triglycerides, their effect on CSF collection time and, in the next step, their putative impact on levels of various compounds in the CSF.