John Colman

Early detection of protein depletion in alcoholic cirrhosis : role of body composition analysis

BACKGROUND Malnutrition is common in alcoholic cirrhosis. Bedside nutritional assessment techniques may be unreliable in patients with chronic liver disease. The aim of this study was to quantify changes in body composition and compare methods for measuring body composition in alcoholic cirrhosis. METHODS Thirty-eight men with alcoholic cirrhosis were compared with 16 age-matched healthy men. Body composition was assessed using anthropometry and bioelectrical impedance to determine fat-free mass and body fat, deuterium oxide dilution to measure total body water, in vivo neutron activation analysis to measure total body protein, and dual energy x-ray absorptiometry to measure bone mineral content and total body fat mass. RESULTS With increasing severity of cirrhosis, total body water increased, whereas total body protein decreased with a significant decrease in serum albumin levels. Total body protein levels, expressed as an index, were a more sensitive indicator of protein depletion than serum albumin levels. When patients were assessed by anthropometry and bioelectrical impedance for fat-free mass, there was no reduction compared with controls. CONCLUSIONS Anthropometry and bioelectrical impedance do not accurately reflect changes in body composition associated with chronic liver disease. Quantification of body composition changes in alcoholic cirrhosis requires the use of direct methods such as in vivo neutron activation analysis, dual energy x-ray absorptiometry, or deuterium oxide dilution.

Increased Sympathetic Nervous Activity and the Effects of Its Inhibition with Clonidine in Alcoholic Cirrhosis

OBJECTIVE To study disturbances in sympathetic nervous system function in patients with alcoholic cirrhosis and the effect of clonidine on such disturbances. DESIGN Cross-sectional physiologic and neurochemical evaluation of patients with cirrhosis and of healthy controls; an uncontrolled trial of intravenous clonidine in the cirrhotic patients. PATIENTS Forty-four hospitalized patients with biopsy-proven alcoholic cirrhosis and 31 healthy controls. INTERVENTIONS Intravenous clonidine. MAIN OUTCOME MEASURES Radiotracer-derived measures of norepinephrine release to plasma, central hemodynamics, wedge hepatic vein pressure, and measures of renal function. MAIN RESULTS In patients with cirrhosis, clonidine reduced previously elevated norepinephrine overflow rates for the whole body, kidneys, and hepatomesenteric circulation. This sympathetic inhibition was accompanied by the following potentially clinically beneficial effects: the lowering of renal vascular resistance (median reduction, 24%; 95% CI, 14% to 31%), the elevation of glomerular filtration rate (median increase, 27%; CI, 14% to 39%), and the reduction of portal venous pressure (median reduction, 25%; CI, 18% to 32%). The norepinephrine and hemodynamic responses to graded clonidine dosing (1, 2, and 3 micrograms/kg body weight intravenously) indicated that the sympathetic outflow to the hepatomesenteric circulation was more sensitive to pharmacologic suppression with clonidine than was the sympathetic outflow to the systemic circulation. CONCLUSIONS The sympathetic nerves to the kidneys, heart, and hepatomesenteric circulation are stimulated in patients with cirrhosis. Clonidine inhibits these activated sympathetic outflows differentially, which could possibly provide a basis for the selective pharmacologic treatment of portal hypertension in patients with cirrhosis.

Hepatic extraction of morphine is impaired in cirrhosis

SummaryUsing hepatic vein catheterization this study has provided the first direct measurement of morphine hepatic extraction in 8 controls and 8 cirrhotics.The extraction ratio was 0.52 in the control group and was reduced by 25% in the cirrhotics. This reduction is due to impaired enzyme capacity rather than reduced blood flow. The effect of cirrhosis is less than that reported in similar studies of high clearance oxidized drugs and this lends support to the concept that glucuronidation may be relatively spared in cirrhosis.A discrepancy between the systemic clearance and the hepatic clearance provides indirect support for extra-hepatic metabolism of morphine.

Glomerular hyperfiltration in patients with well-compensated alcoholic cirrhosis

BACKGROUND Peripheral and splanchnic arteriolar tone is often decreased in patients with cirrhosis. The responsible circulating vasodilator(s) would be expected to also lower renal vascular resistance. To examine this possibility we have undertaken a hemodynamic study of the renal circulation in patients with stable, well characterized, compensated cirrhosis and in healthy controls of similar age and sex. METHODS Clearance techniques were used to assess splanchnic and renal hemodynamics and hepatocellular function. RESULTS Renal vascular resistance was significantly reduced in the cirrhotic patients (P = 0.048) and was accompanied by a significant (P = 0.014) and proportional (r = -0.45; P = 0.016) increase in glomerular filtration rate. The hepatic extraction of indocyanine green, a measure of functional intrahepatic portasystemic shunts, was the only independent predictor of glomerular filtration rate (r = -0.65; P = 0.002). CONCLUSIONS The results support the hypothesis that, in patients with cirrhosis, the presence of portasystemic shunts results in an increased delivery of endogenous vasodilator(s) into the systemic circulation where their principal action on the renal circulation is to preferentially decrease afferent arteriolar tone. The resultant glomerular hyperfiltration may contribute to the pathogenesis of cirrhotic glomerulosclerosis.

Urotensin II: a novel vasoactive mediator linked to chronic liver disease and portal hypertension.

Background/Aims: Urotensin II (UII) is recognised as the most potent human vasoconstrictor; however, its role in chronic liver disease (CLD) is unknown.

Change in serum hyaluronan: A simple index of short-term drug-induced changes in hepatic sinusoidal perfusion

BACKGROUND Hyaluronan is an endogenous polysaccharide whose clearance from the plasma is predominantly by liver sinusoidal cells and is sinusoidal flow dependent. This study was designed to determine if a change in serum hyaluronan might reliably reflect short-term drug-induced changes in sinusoidal perfusion. METHODS Hemodynamic changes following an oral dose of ketanserin were compared with changes in serum hyaluronan levels in 12 patients with alcoholic liver disease and portal hypertension. Indices determined comprised heart rate, mean arterial pressure (MAP), cardiac output (CO), systemic vascular resistance, hepatic venous pressure gradient (HVPG), indocyanine green (ICG) clearance and extraction, and total hepatic blood flow. Measurements were made in a basal state 1 hour after ketanserin ingestion and expressed as a ratio of values post- to pre-ketanserin administration. RESULTS Ketanserin had variable effects comprising both increases and decreases in all indices. On univariate and multivariate analysis, changes in serum hyaluronan concentration (1.05 +/- 0.13, mean +/- SD) significantly correlated with only one index: changes in ICG clearance (0.93 +/- 0.17, r = -0.65, P = 0.02). CONCLUSIONS Changes in serum hyaluronan levels reflect short-term drug-induced changes in sinusoidal perfusion in patients with alcoholic liver disease and portal hypertension. Serial measurement of serum hyaluronan levels may offer a simple method of screening vasoactive drugs for their short-term effects on sinusoidal perfusion.

Norfloxacin treatment for clinically significant portal hypertension: results of a randomised double-blind placebo-controlled crossover trial.

Background: While selective intestinal decontamination (SID) can alter the hyperdynamic circulatory state of cirrhosis, the impact of SID on portal pressure remains unclear especially in the setting of clinically significant portal hypertension.

Liver stiffness and the prediction of clinically significant portal hypertension and portal hypertensive complications

Abstract Objective. Clinically significant portal hypertension (CSPH) is associated with increased risk of liver disease complications, but its identification requires invasive methods. Liver stiffness (LS) measurement via transient elastography correlates with the presence of CSPH. We, therefore, evaluated LS as a noninvasive tool in the prediction of CSPH and portal hypertensive complications. Material and methods. Ninety-five consecutive patients successfully underwent measurement of hepatic venous pressure gradient (HVPG) and LS on the same day. Recent laboratory tests were correlated. Patients were followed up for development of portal hypertensive complications. Predictors of CSPH and complications were identified. Results. Seventy-six (80%) were male and mean age was 56.8 ± 9.3 years. Ninety-three percent and 72% of patients had cirrhosis and esophageal varices, respectively. Only LS (r2 = 0.38; p < 0.0001) and international normalized ratio (r2 = 0.21; p = 0.02) were independently associated with HVPG. An LS >29.0 kilopascal (kPa) predicted CSPH with 71.9% sensitivity, 100% specificity, 100% positive predictive value (PPV), and 56.0% negative predictive value (NPV). An LS <25.0 kPa in those with platelet count >150 × 109/L excluded CSPH with 91.7% sensitivity, 100% specificity, 100% PPV, and 90% NPV. Ninety patients were followed up for a median duration of 15.1 months. CSPH and LS >34.5 kPa predicted portal hypertensive complications with 100% and 75.0% sensitivity, 40.3% and 69.4% specificity, 43.1% and 52.5% PPV, and 100% and 86.2% NPV, respectively. Conclusion. LS shows promise as a noninvasive marker of CSPH and portal hypertensive complications. Combining LS with platelet count improves diagnostic accuracy in the exclusion of CSPH.

A comparison of Doppler flowmetry with conventional assessment of acute changes in hepatic blood flow

The validity and clinical relevance of Doppler flowmetry in measuring changes in regional blood flow are uncertain. In the present study we compared changes induced by ketanserin in regional splanchnic blood flow as measured by Doppler flowmetry with changes in conventionally measured systemic and in hepatic haemodynamic indices estimated pharmacokinetically using indocyanine green. Fourteen patients with alcoholic cirrhosis and portal hypertension were evaluated. On multivariate analyses, significant associations were noted for only three indices: changes in estimated hepatic blood flow were predicted jointly by changes in flow in the main and right portal veins and hepatic artery (R2= 0.80); changes in intrahepatic shunting (indocyanine green extraction) were predicted by changes in flow in the main and right portal veins (R2= 0.55); and changes in sinusoidal perfusion (indocyanine green clearance) were significantly predicted by changes in main portal vein flow alone (R2= 0.76). These data support the validity of Doppler flowmetry in quantifying change in regional blood flow, but highlight the limitations in its clinical application and interpretation. The association of changes in main portal vein flow with changes in sinusoidal perfusion has clinical potential but requires confirmation using other modulating drugs.

Non-cirrhotic portal hypertension in HIV mono-infected patients

Background and Aim:  Unexplained liver injury including fibrosis and portal hypertension has rarely been reported among patients with HIV in the absence of co‐infection with hepatitis B (HBV) or hepatitis C (HCV). We describe a series of HIV mono‐infected patients with evidence of non‐cirrhotic portal hypertension.