Peter Schiedermaier

Biopsychosocial predictors of health-related quality of life in patients with chronic hepatitis C

Objectives: To assess biopsychosocial predictors of health-related quality of life (HRQOL) in patients with chronic hepatitis C. Methods: In 94 consecutive patients with chronic hepatitis C attending a liver center, HRQOL was assessed by the Medical Outcome Study Short Form Health Survey 36 (SF-36) and by the German version of the Chronic Liver Disease Questionnaire. The predictive effect on HRQOL of disease-related worries measured by the worry subscale of the Chronic Liver Disease Questionnaire, psychiatric comorbidity (defined by at least one Hospital Anxiety and Depression Scale German Version Score ≥11), the Child-Pugh score in case of cirrhosis, interferon therapy, and active medical comorbidities was assessed by a multiple regression analysis. Results: From 88 patients (age, 48.6 ± 14.6 years; 50% female), 62 (70%) had no cirrhosis, 15 (17%) Child A, 5 (6%) Child B, and 6 patients (7%) Child C cirrhosis. The mental summary score of SF-36 was predicted by the amount of disease-related worries (corrected R2 = 0.33; &bgr; = 3.2; p < .001) and psychiatric comorbidity (corrected R2 = 0.42; &bgr; = −9.0; p < .001), by the physical summary score of SF-36 by the amount of disease related worries (corrected R2 = 0.33; &bgr; = 4.0; p < .001), and by the number of active medical comorbidities (corrected R2 = 0.39; &bgr; = −2.0; p = .006). Conclusions: The HRQOL in chronic hepatitis C is not determined by the severity of the liver disease but by psychiatric and medical comorbidities and disease-related worries. HRQOL = health-related quality of life; IFN = interferon; HCV = hepatitis C virus; SF-36 = Medical Outcome Study Short Form Health Survey 36; CLDQ-D = German version of the Chronic Liver Disease Questionnaire; HADS-D = German version of the Hospital Anxiety and Depression.

Endotoxin and tumor necrosis factor-receptor levels in portal and hepatic vein of patients with alcoholic liver cirrhosis receiving elective transjugular intrahepatic portosystemic shunt.

Background/aims In cirrhosis portal hypertension can promote bacterial translocation and increase serum endotoxin levels. Vice versa, endotoxin aggravates portal hypertension by induction of systemic and splanchnic vasodilation, and by triggering hepatic inflammatory response via tumor necrosis factor &agr; (TNF&agr;). However, the hepatic elimination of endotoxin in cirrhotic patients with severe portal hypertension, in the absence of acute complications, has not been investigated so far. Methods Twenty patients with alcoholic liver cirrhosis received transjugular intrahepatic portosystemic shunt at an event-free interval for either refractory ascites or recurrent bleeding. During the transjugular intrahepatic portosystemic shunt procedure portal and hepatic venous blood samples were obtained and endotoxin levels were measured by a chromogenic limulus-assay. In 16 of these patients an enzyme-linked immunosorbent assay was used to measure levels of the soluble TNF&agr;-receptors sTNF-R55 and sTNF-R75. Results Portal venous endotoxin levels correlated with portal vein velocity (P=0.03) and arterial systolic blood pressure (P=0.007). Portal endotoxin levels correlated with portal venous sTNF-R75-levels (P=0.039; r=0.521) and hepatic venous sTNF-R55-levels (P=0.009; r=0.669). Hepatic venous levels of both sTNF-R55 and sTNF-R75 correlated directly with the model for end-stage liver disease-score, and inversely with cholinesterase. However, we did not find significant differences in endotoxin levels nor in sTNF-R55-levels and sTNF-R75-levels between portal and hepatic venous blood. Conclusion Endotoxin levels correlated with hemodynamic derangement in cirrhotic severe portal hypertension, and with levels of soluble TNF&agr;-receptors. Soluble TNF&agr;-receptor levels correlated with the severity of liver dysfunction. However, in this study an endotoxin concentration gradient across the liver was absent, suggesting negligible primary hepatic endotoxin elimination in the absence of complications.

Prospective evaluation of a clinical score for 60-day mortality after transjugular intrahepatic portosystemic stent-shunt: Bonn TIPSS early mortality analysis.

Objective Transjugular intrahepatic portosystemic stent-shunt (TIPSS) is increasingly used to treat complications of portal hypertension, but proven tools for risk assessment of early mortality are lacking. Design The prospective evaluation of a new 60-day mortality score. Patients and methods In a tertiary medical centre, 30 consecutive TIPSS patients were analysed for early mortality predictors, such as Child–Pugh score, TIPSS urgency (elective:⩾ 36 h or emergency:< 36 h after variceal bleeding), comorbidity (Acute Physiology and Chronic Health Evaluation [APACHE]-II) and clinical data. Main predictors (P< 0.01) in this group (group-1: Child–Pugh score 10A, 10B, 10C) were graded (1, 2 or 3 points representing low, medium and high risk, respectively) and summarized as a Bonn TIPSS early mortality (BOTEM) score. This score was then tested prospectively in the next 73 TIPSS patients (group-2: Child–Pugh score 14A, 42B, 17C). Results Group 1 early mortality (30%) depended primarily on bilirubin (P< 0.005), APACHE-II (P < 0.001) and TIPSS urgency (P< 0.001). Added risk points (1, 2, 3) for bilirubin (< 3 mg/dl, 3–6 mg/dl, > 6 mg/dl, respectively), APACHE-II (< 10, 10–20, > 20 points, respectively) and urgency (elective, emergency, active bleeding, respectively) represented individual BOTEM score points. BOTEM was the best mortality predictor (P< 0.001);⩽/ > 6 score points was the optimal cut-off, with 56% sensitivity, 100% specificity, 100% positive predictive value, 84% negative predictive value and 87% accuracy. In group 2, early mortality (8.2%) was again best predicted by BOTEM (P < 0.01) with the same cut-off and 67% sensitivity, 99% specificity, 80% positive predictive value, 97% negative predictive value and 96% accuracy. Conclusion BOTEM score based on bilirubin, comorbidity and TIPSS-urgency predicts rather reliably post-TIPSS 60-day mortality and might optimize TIPSS treatment.

Comparison of portal vein velocity and the hepatic venous pressure gradient in assessing the acute portal hemodynamic response to propranolol in patients with cirrhosis

OBJECTIVE:The aim of this prospective study was to compare noninvasive Doppler sonography and invasive measurement of the hepatic venous pressure gradient (HVPG) to determine the acute portal hemodynamic response to propranolol in patients with liver cirrhosis.METHODS:In a blinded study design, portal vein velocity (PVV) and HVPG were simultaneously assessed in 11 cirrhotic patients for 4 h after oral ingestion of 40 mg propranolol.RESULTS:Both HVPG (17.2%± 4.3%, p < 0.0001) and PVV (15.6%± 2.1%, p < 0.0002) showed a highly significant reduction during the study period versus baseline. Based on HVPG measurements, four patients (36%) were classified as nonresponders. These patients had a significantly lower PVV reduction compared to the responders (responders: 18.8%± 2.0% vs nonresponders: 10.0%± 2.1%, p < 0.05). Nonresponders were identified by Doppler sonography with a sensitivity of 1.0, specificity of 0.86, and positive predictive value of 0.9 when a threshold of 20% PVV reduction 120 min after drug intake was applied.CONCLUSIONS:Doppler sonography is a useful tool for assessment of the acute portal hemodynamic effect of propranolol. To distinguish portal hemodynamic nonresponders from responders to propranolol, PVV measurements should be carried out 2 h after drug administration, and PVV reduction should be not <20% in propranolol responders.

Soluble TNF-Alpha-Receptors I Are Prognostic Markers in TIPS-Treated Patients with Cirrhosis and Portal Hypertension

Background TNFα levels are increased in liver cirrhosis even in the absence of infection, most likely owing to a continuous endotoxin influx into the portal blood. Soluble TNFα receptors (sTNFR type I and II) reflect release of the short-lived TNFα, because they are cleaved from the cells after binding of TNFα. The aims were to investigate the circulating levels of soluble TNFR-I and -II in cirrhotic patients receiving TIPS. Methods Forty-nine patients with liver cirrhosis and portal hypertension (12 viral, 37 alcoholic) received TIPS for prevention of re-bleeding (n = 14), therapy-refractory ascites (n = 20), or both (n = 15). Portal and hepatic venous blood was drawn in these patients during the TIPS procedure and during the control catheterization two weeks later. sTNFR-I and sTNFR-II were measured by ELISA, correlated to clinical and biochemical characteristics. Results Before TIPS insertion, sTNFR-II levels were lower in portal venous blood than in the hepatic venous blood, as well as in portal venous blood after TIPS insertion. No significant differences were measured in sTNFR-I levels. Hepatic venous levels of sTNFR-I above 4.5 ng/mL (p = 0.036) and sTNFR-II above 7 ng/mL (p = 0.05) after TIPS insertion were associated with decreased survival. A multivariate Cox-regression survival analysis identified the hepatic venous levels of sTNFR-I (p = 0.004) two weeks after TIPS, and Child score (p = 0.002) as independent predictors of mortality, while MELD-score was not. Conclusion Hepatic venous levels of sTNFR-I after TIPS insertion may predict mortality in patients with severe portal hypertension.

Effects of Different Octreotide Dosages on Splanchnic Hemodynamics and Glucagon in Healthy Volunteers

Aims: This study evaluated the dependence of portal and mesenteric blood flow and plasma glucagon levels on octreotide dosage and its mode of application. Methods: Two groups of 10 individuals each received octreotide either subcutaneously (placebo, 100 and 200 µg) or intravenously (100-µg bolus i.v., 25 and 100 µg/h) in a double-blind, random order. Using Doppler ultrasound, we examined portal and mesenteric blood flow and measured plasma glucagon levels at regular intervals within a 4-hour period under fasting conditions. Results: Contrary to placebo, octreotide caused a decrease in portal blood flow (PVF) and in superior mesenteric artery blood flow (SMAF) together with an increase in the mesenteric pulsatility index (PI). The same total dose of 100 µg octreotide caused a similar PVF response, averaged over 4 h, given either subcutaneously (–28.0 ± 4.8%), intravenously (–29.4 ± 4.3%) or as a continuous infusion (–29.3 ± 4.6%). As concerns intravenous infusions, 100 µg/h was more effective than 25 µg/h (–37.8 ± 6.2 vs. –29.3 ± 4.6%). The PVF reduction remained constant during intravenous infusion, whereas glucagon levels decreased progressively over the entire observation time. Conclusions: The decrease in PVF is dependent on the octreotide dose. However, this is not constantly paralleled by a decrease in plasma glucagon concentration.

Prognostic Impact of Renal Impairment and Sodium Imbalance in Patients Undergoing Transjugular Intrahepatic Portosystemic Shunting for the Prevention of Variceal Rebleeding

Background/Aim: Kidney function and portal pressure have prognostic relevance in nonshunted patients with cirrhosis. Since insertion of a transjugular intrahepatic portosystemic shunt (TIPS) reduces portal pressure and may improve the renal function, the aim of the present study was to investigate the prognostic role of renal impairment and portal hemodynamics in patients with compensated cirrhosis electively shunted due to recurrent variceal hemorrhages. Methods: Data of 101 consecutive and prospectively followed patients with compensated cirrhosis (bilirubin <5 mg/dl) undergoing elective TIPS due to recurrent variceal bleeding (45 died, and 8 were transplanted during the follow-up period) were evaluated in a multivariate Cox model. Results: Creatinine and sodium were identified as the only independent predictors of survival in this model. The 90th percentile of creatinine (>1.7 mg/dl) defined a subgroup with a similar poor prognosis as the 90th percentile of the model for end-stage liver disease (MELD) score. Neither baseline nor post-TIPS portal pressure correlated with the long-term outcome. Conclusions: In compensated patients undergoing TIPS due to variceal bleeding, renal impairment indicates a poor prognosis. Portal hemodynamic parameters are not predictive of survival in TIPS patients.

Circadian rhythm of fasting and postprandial portal blood flow in cirrhosis

Objective. To examine the relationship of both the unstimulated and the postprandial portal blood flow (PVF) to the time of day and to determine its intra-individual reproducibility over time in patients with liver cirrhosis. Material and methods. In 24 cirrhotic patients, 27 PVF measurements were performed during 24 h on day 0 and day 7 using Doppler ultrasound. Three standard liquid meals were given orally. On day 7, the baseline hepatic venous pressure gradient (HVPG) was also measured. Results. Circadian area under the time curve of PVF was highly reproducible within individuals (r=0.959, p<0.001). It did not correlate with HVPG. Cosinor analysis showed a significant circadian rhythm of PVF (acrophase at 11:44 and amplitude of 9.44%). Maximal postprandial increase in PVF was significantly higher in the morning than at noon or in the evening. Conclusions. PVF is subject to a circadian rhythm and postprandial portal hyperemia shows a diurnal variability. Both are highly reproducible.

Hemodynamic Effects of Propranolol and Nitrates in Cirrhotics with Transjugular Intrahepatic Portosystemic Stent-Shunt

Background: The combination of tailored TIPS with vasoactive drugs might allow reduction of the rate of subsequent shunt-related sequelae. Methods: We studied cirrhotic patients 8 weeks (median) after TIPS insertion (8-10 mm) for variceal bleeding. Nitrate (0.1 mg/kg) and propranolol (0.15 mg/kg) alone or combined (same dosages) were infused (1 h) sequentially at 1-h intervals ( n = 17). Similarly, propranolol was randomly compared to placebo (NaCl, n = 14). We measured mean arterial pressure (MAP, mmHg), heart rate (HR) and portal pressure gradient (PPG: portal minus central venous pressure) prior to and after drugs. Results: Propranolol reduced PPG (mean ± s , mmHg) significantly (14.8 ± 3.7 versus 12.1 ± 3.7; -21% ± 10%; P < 0.001), while nitrates alone (14.3 ± 3.4 versus 13.7 ± 3.4; -11% ± 3%; P = 0.06) or nitrates plus propranolol (12.9 ± 4 versus 12.4 ± 4; -7% ± 8%; P = 0.2) induced only minor additive effects on portal pressure. However, nitrate reduced MAP ( P < 0.001) and increased HR ( P < 0.01), whereas propranolol reduced only HR ( P < 0.001) with unchanged MAP, and the combination decreased MAP ( P < 0.001). Compared to placebo (no effect), propranolol decreased PPG (14.4 ± 5.6 versus 11.1 ± 5.5; -23% ± 11%; P < 0.001) and HR ( P < 0.001). Overall, most patients (92%) responded to propranolol and 54% showed a marked PPG decrease (>20%). Conclusions: Propranolol significantly reduced portal pressure in cirrhotic patients after TIPS, whereas nitrates induced only minor benefit. TIPS-treated patients might therefore profit from additive propranolol therapy allowing limited shunts to be applied initially and/or to reduce the need for TIPS revisions in the case of shunt-dysfunction during follow-up.

Serum plant sterols and biliary cholesterol secretion in humans studies with ursodeoxycholic acid

Ratios of cholestanol, campesterol, and sitosterol to cholesterol in serum are known to reflect cholesterol absorption efficiency. Here, a possible link between these ratios and biliary secretion rates of cholesterol was investigated. Biliary lipid secretion rates and serum sterols were determined in 13 patients with gallstones. Seven were treated with ursodeoxycholic acid (UDCA) (1,000 mg/d). Serum cholesterol and non-cholesterol sterols were also measured in a cross over study in 20 healthy volunteers, who received either placebo or UDCA (750 mg/d). Biliary cholesterol secretion was significantly lower, whereas the non-cholesterol sterols and their ratio to cholesterol were higher in patients with gallstones treated with UDCA. A highly significant negative linear correlation between the ratios of non-cholesterol sterols to cholesterol and biliary cholesterol secretion was observed. In volunteers, administration of UDCA for 4 weeks was followed by a significant increase in non-cholesterol sterols and their ratios. Even 4 weeks after discontinuing UDCA administration, campesterol and sitosterol were still significantly higher than pretreatment levels, which was also true for the campesterol-cholesterol ratio after 8 weeks. The results suggest that the ratios of cholestanol, campesterol, and sitosterol to cholesterol can be used as indicators of changes in biliary cholesterol secretion rates.