The economic burden of mental disorders: results from the Netherlands mental health survey and incidence study-2.

OBJECTIVE: Currently, there is a paucity of up-to-date estimates of the economic burden caused by mental disorders. Such information could provide vital insight into one of the most serious and costly-yet to some extent preventable-health challenges facing the world today. METHOD: Data from a national psychiatric-epidemiological cohort study (NEMESIS-2, N = 6506) were used to provide reliable, relevant, and up-to-date cost estimates (in 2019 Euro) regarding healthcare costs, productivity losses, and patient and family costs associated with DSM-IV mental disorders both at individual level, but also in the general population and in the workforce of the Netherlands (per 1 million population). RESULTS: In the general population, the costs of mood disorders, specifically depression, are substantial and rank above those from the anxiety disorders, whilst costs of anxiety disorders are more substantial than those stemming from substance use disorders, even when the per-person costs of drug abuse appear highest of all. In the workforce, specific and social phobias are leading causes of excess costs. The workforce has lower healthcare costs but higher productivity costs than general population. DISCUSSION: The findings suggest that (preventive) healthcare interventions targeting the workforce are likely to become cost-effective and underscore the importance for employers to create healthy work environments. Overall, the results highlight the need to strengthen the role of mental health promotion and prevention of mental disorders in the social domain before people require treatment to reduce the staggering and costly burden caused by mental disorders to individuals and society.

Uptake and metabolism of 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine by human liver-derived cells: HepG2 cells as a model for thyroid hormone handling by human liver.

The uptake and metabolism of T3 and rT3 was studied in human liver-derived HepG2 cells. The results showed a saturable, time-dependent, and ouabain-sensitive increase in nuclear bound T3. The effects of ouabain (0.5 mmol/L) and unlabeled T3 (10 nmol/L and 10 mumol/L) were much more pronounced at the nuclear level, suggesting the presence of a nonspecific component in total cellular binding. Nuclear binding of rT3 remained below the detection limit in all experiments. Comparison of rT3 metabolism in HepG2 cells and primary cultures of rat hepatocytes showed an approximately 10-fold lower iodide production in HepG2 cells. Iodide production was decreased in the presence of ouabain and almost absent in the presence of propylthiouracil (100 mumol/L). Our data confirmed the presence of a carrier-mediated uptake system for both T3 and rT3. Metabolism data indicated functional type I deiodinase activity in HepG2 cells, the presence of glucuronidating enzymes, and the absence of thyroid hormone sulfotransferase activity. Based on these data, we propose that HepG2 cells provide an appropriate model for thyroid hormone handling by human liver. In addition, we suggest that in human liver sulfation of thyroid hormone, and therefore deiodination of T3 is of only minor importance.

Reduced T3 deiodination by the human hepatoblastoma cell line HepG2 caused by deficient T3 sulfation.

Type I deiodination of T3 sulfate occurs at a Vmax that is 30-fold higher as compared to T3, both in rat and in human liver homogenates. We now present data showing lack of T3 deiodination by a human liver derived hepatoblastoma cell line, HepG2, caused by deficient T3 sulfation. Cellular entry of T3 was assessed by its nuclear binding after whole cell incubation. In spite of the presence of type I deiodinase, as confirmed by T4 and rT3 deiodination in homogenates, no deiodination of T3 could be detected. Since HepG2 cell homogenates also deiodinated chemically synthesized T3 sulfate (T3S) and inhibition of type I deiodination by propylthiouracil (PTU) did not cause T3S accumulation in whole cell incubations, we conclude that (i) HepG2 cells show reduced T3 deiodination caused by deficient T3 sulfation, and (ii) sulfation of T3 is an obligatory step prior to hepatic deiodination.

Transport of 3,5,3'-triiodothyronine into the perfused rat liver and subsequent metabolism are inhibited by fasting.

The effects of 48-h fasting on transport of T3 and subsequent metabolism in the isolated perfused rat liver were investigated. Tracer T3 disappearance curves from the recirculating medium consisted of a fast component (FC) and a slow component (SC). Using a two-compartment model, both transport [expressed as the fractional transport rate constant from medium to liver (k21)] and disposal of T3 were calculated. After fasting, k21, total metabolism, and metabolism corrected for differences in mass transfer were diminished, pointing to both decreased transport and metabolism, presumably caused by depletion of liver ATP. Concerning transport, it was shown that only transport into the intracellular liver compartment and not transport to the extracellular liver compartment was decreased after fasting. As for metabolism, T3 glucuronidation was diminished; T3 sulfation and subsequent deiodination were not affected. All mentioned decreased parameters normalized after the addition of a combination of insulin, cortisol, and/or glucose to the medium, possibly by (partially) restoration of cellular energy stores.

Thyroxine and 3,3',5-triiodothyronine are glucuronidated in rat liver by different uridine diphosphate-glucuronyltransferases.

Male Wistar rats were treated with 50 mg 3,3',4,4'-tetrachlorobiphenyl (TCB)/kg BW or vehicle. After 4 days, the livers were isolated and perfused for 90 min with 2 nM [125I]T3 or 10 nM [125I]T4 in Krebs-Ringer medium containing 1% albumin. Deiodination and conjugation products and remaining substrates were determined in bile and medium samples by Sephadex LH-20 chromatography and HPLC. TCB treatment did not affect hepatic uptake and metabolism of T3. However, biliary excretion of T4 glucuronide was strongly increased by TCB, resulting in an augmented T4 disappearance from the medium, although initial hepatic uptake of T4 was not altered. Measurement of the microsomal UDP-glucuronyltransferase (UDPGT) activities confirmed that T4 UDPGT was induced by TCB, whereas T3 glucuronidation was unaffected. T3 UDPGT activity showed a discontinuous variation, which completely matched the genetic heterogeneity in androsterone glucuronidation in Wistar rats. These results indicate that different isozymes catalyze the glucuronidation of T3 and T4.

Euro-Collins solution versus UW-solution for long-term liver preservation in the isolated rat-liver perfusion model.

To compare UW-solution (UW) and Euro-Collins (EC) for long-term liver preservation we investigated the morphology and metabolic capacity of rat liver after 18 and 42-hours cold-storage in either UW or EC. After harvesting the rat liver was transferred to a perfusion chamber where it was perfused for 10 min with UW or EC at 4 degrees C. Thereafter livers were stored at 4 degrees C in UW or EC for 18 hours (both groups n = 6) or for 42 hours (both groups n = 8). After 18-hr or 42-hr cold-storage a 2-hr warm perfusion (37 degrees C) was started with Krebs-Ringer solution with carbogen to which 125Iodine-triiodothyronine (T3) was added. Control livers (n = 8) were immediately perfused with Krebs-Ringer without cold-storage. The following parameters were assessed: ASAT-levels in the perfusate, T3-metabolites in the bile and the perfusate, the perfusion pressure, the volume of bile secreted and light-microscopical morphology at the end of the warm perfusion period. After cold storage in UW-solution the ASAT-levels in the perfusate were lower than after storage in EC as well as the perfusion pressures. These livers demonstrated a better T3-metabolism and secreted more bile than EC-stored livers. Histological examination showed more tissue damage in the EC-stored livers than in the UW stored livers. We conclude that cold-storage of rat liver in UW-solution resulted in a better morphology and metabolic capacity as compared with EC-solution.

Development and use of a mathematical two-pool model of distribution and metabolism of 3,3',5-triiodothyronine in a recirculating rat liver perfusion system: albumin does not play a role in cellular transport.

To describe the T3 kinetics in a recirculating rat liver perfusion system, we have developed a mathematical two-pool model consisting of medium and liver. It appeared that all parameters of the model could be fully resolved by using the time-dependent disappearance of radioactive T3 (2 nM) from the medium only. The model calculates the T3 medium pool, the T3 liver pool, and the amount of hormone metabolized at different times after the start of the perfusion. To check the validity of the model, metabolism was also estimated from the appearance of labeled metabolites (glucuronides, sulfates, and I-) in the medium and the cumulative excretion of T3 and metabolites into the bile. The medium pool was also estimated by the product of medium volume and remaining T3 concentration, and the liver pool as the amount of T3 at time zero minus medium pool minus T3 metabolized). These results were in excellent agreement with the predicted values from the model. Taking the metabolites appearing in medium and bile together, about 38% of the total amount of T3 metabolized during 60 min was converted into T3 glucuronide, 12% into T3 sulfate, and 48% into I-, respectively, while about 3% was excreted in the bile unaltered. The results show that not all T3 transported to the liver is being metabolized, but part is bound outside the cellular compartment. This latter pool of T3 is dependent on the albumin concentration in the medium. The amount of T3 metabolized is solely determined by the free T3 concentration and is independent of total T3 or albumin concentration in the medium.