Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis

AIM: To determine the eff icacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH). METHODS: Retrospectively, clinical parameters, biochemistry and histology were obtained from patient records. RESULTS: Nine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P = 0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P = 0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P = 0.032), respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P = 0.016), while the degree of f ibrosis tended to decrease (P = 0.049). CONCLUSION: The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of f ibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantial reduction of prednisone dose.

Effect of Prometheus liver assist system on systemic hemodynamics in patients with cirrhosis: A randomized controlled study

AIM： To evaluate treatment safety and hemodynamic changes during a single 6-h treatment with the PrometheusTM liver assist system in a randomized, controlled study. METHODS： Twenty-four patients were randomized to either the study group or to one of two control groups： Fractionated Plasma Separation Adsorption and Dialysis, PrometheusTM system （Study group; n = 8）; Molecular Adsorbent Recirculation System （MARS）TM （Control group 1, n = 8）; or hemodialysis （Control group 2; n = 8）. All patients included in the study had decompensated cirrhosis at the time of the inclusion into the study. Circulatory changes were monitored with a Swan-Ganz catheter and bilirubin and creatinine were monitored as measures of protein-bound and water-soluble toxins. RESULTS： Systemic hemodynamics did not differ between treatment and control groups apart from an increase in arterial pressure in the MARS group （P = 0.008）. No adverse effects were observed in any of the groups. Creatinine levels significantly decreased in the MARS group （P = 0.03） and hemodialysis group （P = 0.04）. Platelet count deceased in the Prometheus group （P = 0.04）.CONCLUSION： Extra-corporal liver support with Prometheus is proven to be safe in patients with endstage liver disease but does not exert the beneficial effects on arterial pressure as seen in the MARS group,

Sildenafil does not influence hepatic venous pressure gradient in patients with cirrhosis

AIM： To investigate if sildenafil increases splanchnic blood flow and changes the hepatic venous pressure gradient （HVPG） in patients with cirrhosis. Phosphodiesterase type-5 inhibitors are valuable in the treatment of erectile dysfunction and pulmonary hypertension in patients with end-stage liver disease. However, the effect of phosphodiesterase type-5 inhibitors on splanchnic blood flow and portal hypertension remains essentially unknown. METHODS： Ten patients with biopsy proven cirrhosis （five females/five males, mean age 54：1：8 years） and an HVPG above 12 mmHg were studied after informed consent. Measurement of splanchnic blood flow and the HVPG during liver vein catheterization were done before and 80 min after oral administration of 50 mg sildenafil. Blood flow was estimated by use of indocyanine green clearance technique and Fick＇s principle, with correction for non-steady state. RESULTS： The plasma concentration of sildenafil was 222 ± 136 ng/mL 80 min after administration. Mean arterial blood pressure decreased from 77 ±7 mmHg to 66 ± 12 mmHg, P = 0.003, while the splanchnicblood flow and oxygen consumption remained unchanged at 1.14 ± 0.71 L/min and 2.3 ± 0.6 mmol/ min, respectively. Also the HVPG remained unchanged （18 ± 2 mmHg vs 16 ± 2 mmHg） with individual changes ranging from -8 mmHg to ±2 mmHg. In seven patients, HVPG decreased and in three it increased. CONCLUSION： In spite of arterial blood pressure decreases 80 min after administration of the phosphodiesterase type-5 inhibitor sildenafil, the present study could not demonstrate any clinical relevant influence on splanichnic blood flow, oxygen consumption or the HVPG.

Ciclosporin does not attenuate intracranial hypertension in rats with acute hyperammonaemia

AIM:To investigate the neuroprotective potential of ciclosporin during acute liver failure. We evaluated the effect of intrathecally administered ciclosporin on intracranial pressure, brain water content and aquaporin-4 expression in a rat model with acute hyperammonaemia.METHODS:Twenty-four male Wistar rats with portacaval anastomosis were randomised into four groups receiving ciclosporin or vehicle and ammonia or saline infusion. Ciclosporin or vehicle was given intrathecally prior to the ammonia or saline infusion. The ammonia or saline infusion was given intravenously for 4 h,while intracranial pressure and arterial pressure was recorded. At the end of the experiment, cerebral cortex and cerebellar brain tissue was analysed for water and aquaporin-4 content.RESULTS:The following intracranial pressures were found at the end of the experiment:ammonia + ciclosporin:10.0±1.7 mmHg, ammonia + vehicle:6.8±1.0mmHg, saline + ciclosporin:3.1±0.5 mmHg, saline +vehicle:3.3 ± 0.6 mmHg. Ammonia infusion had a significant effect on intracranial pressure and brain water content, which both were higher in the groups receiving ammonia(P<0.001, two-way analysis of variance). Treatment with ciclosporin resulted in relevant tissue concentrations of ciclosporin(>0.2 micromolar)but did not reduce intracranial pressure after 4 h. Furthermore, ciclosporin did not attenuate the increase in cerebral water content, and did not affect aquaporin-4expression.CONCLUSION:Intrathecal administration of ciclosporin does not attenuate intracranial hypertension or brain oedema in rats with portacaval anastomosis and 4 h of ammonia infusion.