Assessment of liver function by the aminopyrine breath test

The aminopyrine breath-test (ABT) has been proposed as a non-invasive quantitative test of liver function and reserve. To evaluate its usefulness, we compared the ABT with standard liver function tests, Child's classification of liver disease and ICG clearance, as means of assessing liver function in 30 patients with cirrhosis. The cumulative output of 14CO2 in breath during the 6 h following [14C]aminopyrine administration was significantly decreased in the cirrhotic group as compared with control subjects. The severity of liver dysfunction, as assessed by Child's classification, was associated with a progressive and statistically significant impairment of the ABT. There was a good correlation between the ABT and ICG systemic clearance (r = 0.770, P less than 0.001) and also between the ABT and ICG intrinsic clearance (r = 0.885, P less than 0.001), a measure which is independent of hepatic blood flow variations. These results further strengthen the concept that the ABT is a simple non-invasive method to assess quantitatively liver function and reserve, and could be useful in following the evolution of patients with liver disease.     

D-Sorbitol plasma disappearance rate: An index to evaluate changes in liver circulation

The hepatic clearance of D-sorbitol was proven to be a reliable parameter for evaluating the functional liver plasma flow. Twenty-five normal subjects and 50 cirrhotic patients were studied in order to assess if the measure of the plasma disappearance rate of sorbitol can be used as a simpler procedure to evaluate changes in liver perfusion and to predict modifications of drug bioavailability due to circulatory events. The plasma disappearance rate was calculated between 10 and 20 min after intravenous administration of a 2-g dose because in this time interval plasma levels were in the optimum range for the chemical assay, and the plasma concentration/time curve fitted a decreasing exponential function. Plasma disappearance rate values were found to correlate significantly (r = 0.666, p<0.001) with sorbitol hepatic clearance, as calculated after the 2-h test. The test had a good day-to-day reproducibility both in normal subjects and cirrhotic patients. In 5 patients submitted to surgical side-to-side portacaval shunt, decreases of plasma disappearance rate and sorbitol hepatic clearance showed no significant difference. Mean values (± SD) of D-sorbitol plasma disappearance rate were 0.048 ± 0.014 min^-1 in cirrhotic patients, and 0.081 ± 0.014 min-¹ in normal subjects (p<0.001).     

Clearance of Antipyrine-Dependence of Quantitative Liver Function

Abstract. The purpose of the present study was to assess tile influence of liver disease on the hepatic drug-metabolizing enzyme systems. The clearance of antipyrine was found to be significantly decreased in 13 patients with liver disease compared with 9 control patients (18.5 and 58.6 ml/min. respectively). Among the patients with liver disease, those with a severely reduced capacity for work had significantly lower clearance of antipyrine than non incapacitated patients (12.5 and 25.4 ml/min. respectively). The clearance of anti pyrine was significantly correlated with the galactose elimination capacity, the serum albumin and the prothrombin values. The results indicate that the drug-metabolizing capacity of the liver changes in parallel with the other metabolic functions, and the use of the clearance of antipyrine as a quantitative test of liver function is suggested.     

Clearance of antipyrine-dependence of quantitative liver function

Abstract. The purpose of the present study was to assess the influence of liver disease on the hepatic drug-metabolizing enzyme systems. The clearance of antipyrine was found to be significantly decreased in 13 patients with liver disease compared with 9 control patients (18.5 and 58.6 ml/min. respectively). Among the patients with liver disease, those with a severely reduced capacity for work had significantly lower clearance of antipyrine than non incapacitated patients (12.5 and 25.4 ml/min. respectively). The clearance of antipyrine was significantly correlated with the galactose elimination capacity, the serum albumin and the prothrombin values. The results indicate that the drug-metabolizing capacity of the liver changes in parallel with the other metabolic functions, and the use of the clearance of antipyrine as a quantitative test of liver function is suggested.     

Citrate pharmacokinetics and metabolism in cirrhotic and noncirrhotic critically ill patients

OBJECTIVES: To investigate pharmacokinetics and metabolism of sodium citrate in critically ill patients. To determine the risk of citrate accumulation in the setting of liver dysfunction (cirrhosis, hepatorenal syndrome). DESIGN: Prospective cohort study. SETTING: Intensive Care Unit, Department of Medicine IV, University Hospital Vienna. PATIENTS: Consecutive critically ill cirrhotic (n = 16) and noncirrhotic patients (n = 16). INTERVENTIONS: Infusion of sodium citrate (0.5 mmol.kg-1.hr-1) and calcium chloride (0.17 mmol.kg-1.hr-1) for 2 hrs. Analysis of serial arterial blood samples. MEASUREMENTS AND MAIN RESULTS: Total body clearance of citrate was normal in noncirrhotic critically ill patients but significantly reduced in cirrhotic patients (710 vs. 340 mL/min, p =.008). Citrate peak concentrations and concentration over time were increased by 65% and 114% in cirrhotic patients (p <.001), respectively; volumes of distribution were similar. Net metabolic changes were quantitatively similar, with pH and plasma bicarbonate concentrations increasing more slowly in cirrhotic patients. No citrate-related side effects were noted. Citrate clearance could not be predicted by standard liver function tests and was not appreciably influenced by renal function and Acute Physiology and Chronic Health Evaluation II scores. CONCLUSIONS: This first systematic study on citrate pharmacokinetics and metabolism in critically ill patients confirms a major role of hepatic citrate metabolism by demonstrating reduced citrate clearance in cirrhotic patients. Pharmacokinetic data could provide a basis for the clinical use of citrate anticoagulation in critically ill patients. Provided dose adaptation and monitoring of ionized calcium, citrate anticoagulation seems feasible even in patients with decompensated cirrhosis. Metabolic consequences of citrate infusion were not different between groups in this study but may be more pronounced in prolonged infusion.     

Ultrasonographic follow-up of liver cirrhosis

Ultrasonography and upper gastrointestinal endoscopy were prospectively used to study 100 consecutive patients with liver cirrhosis. After a period of 20 months to 55 months, 21 patients had died, 23 were lost at follow-up, and 56 patients were reevaluated. In the patients who died during follow-up, the entry liver volume, measured by means of the hepatic volumetric index, was lower as compared to the 56 cirrhotics who survived. During the study period, liver volume significantly decreased to values similar to those observed, at entry, in patients who died. Moreover, esophageal varices increased in size, and the splanchnic veins enlarged. Abdominal ultrasonography provides data regarding the natural history of liver cirrhosis, which might be used, in addition to tests of liver function and endoscopy, as prognostic factors in cirrhotic patients.     

Determinants of hepatic function in liver cirrhosis in the rat. Multivariate analysis.

We investigated the determinants of hepatic clearance functions in a rat model of liver cirrhosis induced by phenobarbital/CCl4. Aminopyrine N-demethylation (ABT), galactose elimination (GBT), and serum bile acids (SBA) were determined in vivo. The livers were then characterized hemodynamically: intrahepatic shunting (IHS) was determined by microspheres and sinusoidal capillarization by measuring the extravascular albumin space (EVA) by a multiple indicator dilution technique. The intrinsic clearance was determined by assaying the activity of the rate-limiting enzymes in vitro. Hepatocellular volume (HCV) was measured by morphometry. ABT and SBA, but not GBT, differentiated cirrhotic from normal liver. IHS ranged from normal to 10%; all cirrhotic livers showed evidence of sinusoidal capillarization (reduced EVA). The cirrhotic livers showed a bimodal distribution of HCV, HCV being decreased in 50% of the cirrhotic livers. Multivariate analysis showed EVA and portal flow to be the main determinants of microsomal (ABT) and cytosolic (GBT) clearance function; SBA, by contrast, were determined solely by IHS. We conclude that sinusoidal capillarization is the main determinant of hepatic clearance, while serum bile acids reflect intrahepatic shunting. These findings emphasize the importance of alterations of hepatic nutritional flow to explain reduced clearance function in cirrhosis of the liver.     

The effect of hepatic cirrhosis on the pharmacokinetics and blood pressure response to nicardipine

The present study was designed to compare the pharmacokinetic handling of a single oral dose of nicardipine in normal subjects and in patients with hepatic cirrhosis and to compare the sensitivity of the two groups to its hypotensive effect. Nicardipine plasma concentrations were substantially higher in the subjects with hepatic cirrhosis with impaired antipyrine clearance, as shown by a significantly higher average Cmax and AUC. The terminal elimination half-life in this group varied from 0.8 to 60.2 hours (median, 11.7 hours), compared with 0.6 to 4.1 hours (median, 1.4 hours) in the group of eight subjects with normal liver function. In the cirrhotic patients with impaired antipyrine clearance, the AUC of the pyridine metabolite averaged 10% of that of the parent drug, whereas in normal subjects the ratio averaged 48%. This finding suggests less conversion of nicardipine to this metabolite in subjects with impaired hepatic function. Peak blood pressure decreases were greater in the cirrhotic group, which was in keeping with the higher plasma levels in these subjects.     

Influence of hypoxia on mitochondrial function and energy status in CCl4-induced cirrhotic rat liver

The influence of hypoxia on hepatic mitochondrial function and energy status was studied in normal and carbon tetrachloride (CCl4)-induced cirrhotic rats. Under hypoxemia of 50 mm Hg-PaO2, hepatic energy status was suppressed both in normal and cirrhotic rats. After the reversal of hypoxia, it was completely restored in normal rats concomitant with a rapid elevation of hepatic mitochondrial redox state (overshoot phenomenon) and increase in the mitochondrial oxidative phosphorylative activity. By contrast, in cirrhotic rats, such an enhancement of mitochondrial function was not observed. It was clarified that cirrhotic liver mitochondrial function was not observed. It was clarified that cirrhotic liver mitochondria have little capacity to respond to the hypoxic stress. A lower resistance to hypoxic episode in cirrhotics might be attributable to the absence of mitochondrial enhancement which is a compensatory mechanism for the deranged energy metabolism of the liver.     

Oral disposition kinetics of ofloxacin in patients with compensated liver cirrhosis.

The disposition kinetics of ofloxacin, a quinolone antibacterial agent excreted essentially unmodified by the kidney, was studied after single oral administration in 8 patients with compensated liver cirrhosis and in 8 control subjects. Mean elimination half-life and apparent volume of distribution were significantly increased in the cirrhotic group (7.6 vs. 4.9 h and 1.6 vs. 1.2 liters kg-1, respectively). A reduction in the renal clearance of ofloxacin was also observed in the cirrhotic patients, in spite of an apparently normal renal function. These observations indicate that also the pharmacokinetics of unmetabolized drugs may be altered in compensated liver cirrhosis. The serum concentration-time profiles of nearly all subjects exhibited a secondary peak 4-6 h after dosing. This double-peak behavior was interpreted as either enterohepatic circulation or biphasic gastric emptying of ofloxacin.     

肝硬化患者肝脏R2值与血清铁蛋白含量的相关性研究

目的：应用磁共振多回波T2*扫描定量计算肝硬化患者肝脏R2*值,并与血清铁蛋白含量进行相关性分析。材料和方法：对32例健康人和42例临床诊断为乙型肝炎后肝硬化和酒精性肝硬化患者行磁共振多回波T2*序列扫描,并采集静脉血样本测量血清铁蛋白浓度。应用SPIN软件分别测量健康人和肝硬化患者肝脏右叶前段和右叶后段R2*值,取其平均值与血清铁蛋白浓度进行Pearson相关性分析。结果：32例健康人和42例肝硬化患者肝脏R2*值分别为（67.02±12.32） Hz和（85.30±28.48） Hz,经两独立样本t检验,显示二者有显著差异,t=3.335,P=0.001。42例肝硬化患者血清铁蛋白浓度为（165.5±104.4） ng/mL（均值±标准差）,R2*值与血清铁蛋白浓度的相关性分别为r=0.710,P=0.000。结论：肝硬化患者肝脏R2*值明显高于健康人,证明肝硬化患者肝脏铁浓度明显高于健康人。肝硬化患者肝脏R2*值与血清铁蛋白浓度有很好的相关性,证明R2*可以用于无创活体定量测量乙型肝炎后肝硬化和酒精性肝硬化患者肝脏内铁浓度。     

Effect of Levovist on splanchnic hemodynamics in cirrhotic patients

This study was aimed to assess the effect of Levovist on Doppler parameters of splanchnic hemodynamics. A total of 12 patients with cirrhosis and 12 healthy subjects underwent Doppler ultrasound (US) examination of the portal vein and of the hepatic, splenic and superior mesenteric arteries before, 5 to 8 and 12 to 15 min after the start of an 8-min long IV infusion of 2.5 g of Levovist. Mean velocity and mean diameter were calculated for the portal vein. Resistance index was determined for the arteries. A significant increase of resistance index was observed in the hepatic (0.80 +/- 0.07 vs. 0.71 +/- 0.06; p < 0.01) and splenic arteries (0.72 +/- 0.06 vs. 0.64 +/- 0.06; p < 0.01) 5 to 8 min after contrast agent injection in patients with cirrhosis, but not in controls. Neither portal vein diameter nor portal flow mean velocity changed during the test in both controls and cirrhotic patients. This effect might be related to a selective trapping of microbubbles in the altered hepatic and splenic microvasculature in patients with cirrhosis rather than being artefactual. It might have implications on harmonic imaging US protocols designed to image the cirrhotic liver in the early arterial phase.     

脉动色素浓度测定法检测吲哚氰绿清除试验在肝储备功能评估中的应用

目的:探讨脉动色素浓度测定法(pulse dye densito graphanalyzer,PDDG)检测吲哚氰绿(ICG)清除试验在肝炎后肝硬化患者术前肝储备功能评估中的作用。方法:用PDDG法进行ICG清除试验,分析其在104例肝炎后肝硬化患者在术后恢复方面与Child-Pugh评分的相关性。结果:吲哚氰绿15min潴留率(ICGR15)在术后腹水、白蛋白用量、利尿剂用量、黄疸等方面与Child-Pugh评分有较好的一致性;同时ICGR15较Child-Pugh评分在术后并发症及治疗方面相关系数更高,相关性更强。结论:PDDG试验是行ICG清除试验检测肝储备功能实用可行的理想方法,能很好地反映肝炎后肝硬化、门脉高压症患者的肝储备功能,对手术后恢复情况有良好的预计性。     

彩色多普勒超声对肝硬化的肾脏血流变化的研究

为研究肝硬化时肾脏血流变化情况。对48例普通肾功能检测正常的肝硬化患者及31例对照组作多普勒超声主肾动脉、段间动脉、叶间动脉阻力指数（RI）测定。结果表明：肝硬化组RI使明显高于对照组（P＜0.01）;Child-pugh计分肝功能B级及C级RI值高于A组（P＜0.01或＜0.05），B级与C级间差别无统计学意义（P＞0.05），与对照组比较，除A级的段间动脉外（P＞0.05），A、B、C级RI值均高于对照组（P＜0.01或0.05）;少量或无腹水组及大量腹水组间RI值无差异（P＞0.05）。上述结果提示普通肾功能正常的肝硬化患者已有了肾脏血流的改变。多普勒超声有可能应用于肝硬化时肾功能损害的病理生理学及临床研究。     

Phenazone Metabolism in Patients with Liver Disease

Phenazone metabolism was studied in 14 patients with liver disease and six normal volunteers. The plasma and renal clearance of phenazone and the 4-hydrozyphenazone excretion in urine was significantly decreased in the patients with liver disease. The urinary excretion of 4-hydroxyphenazone was significantly correlated to the plasma clearance of phenazone (r= + 0.95, P less than 0.001), to quantitative liver function as measured by the galactose elimination capacity (r= + 0.95, P less than 0.001), and to the prothrombin values (r= + 0.82, P less than 0.001). The determination of the 4-hydroxyphenazone excretion in urine may be used as an easy and non-invasive test of quantitative liver function.     

Chronic Liver Disease Impairs Bacterial Clearance in a Human Model of Induced Bacteremia

Sepsis often causes impaired hepatic function. Patients with liver disease have an increased risk of bacteremia. This is thought to be secondary to impaired reticuloendothelial system function. However, this has not been demonstrated clinically. Since transient bacteremia occurs following toothbrushing, we hypothesized that subjects with cirrhosis would have impaired bacterial clearance following toothbrushing compared with subjects with pulmonary disease and healthy controls. After baseline blood was drawn, the subjects underwent a dental examination to determine plaque index and gingival index. Following toothbrushing, blood was drawn at 30 seconds, 5 minutes, and 15 minutes. Bacteremia was measured using quantitative real‐time PCR with primers that amplify all known bacteria. We found greater than 75% incidence of bacteremia following toothbrushing. While control and pulmonary subjects were able to clear this bacteremia, subjects with cirrhosis had prolonged bacteremia. Baseline and peak bacterial load correlated with plaque index, suggesting that dental hygiene predicts the degree of bacteremia. However, only the severity of cirrhosis was predictive of bacterial clearance at 15 minutes, suggesting that liver function is important in clearing bacteremia. In this study, we demonstrate clinically that cirrhosis results in impaired bacterial clearance. This suggests that cirrhotic patients may be more susceptible to sepsis because of ineffective bacterial clearance.     

The simultaneous investigation of liver and kidney function in the presence of dopamine (author's transl)]

The effect of dopamine on liver function and on renal blood flow and the glomerular filtration rate was studied in 13 patients suffering from liver cirrhosis. Hence, the BSP retention and 131I BSP clearance was determined and also the clearance of 99mTc DTPA and of 125I hippuran in decreasing concentrations, as well as under steady state conditions. Methodological problems arising from the application of the slope clearance technique in cirrhotic patients are discussed. Dopamine did not affect the BSP clearance and BSP retention, but a significant increase in renal plasma flow was observed. The glomerular filtration rate was not significant altered.     

Novel computerized psychometric tests as primary screening tools for the diagnosis of minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is a critical neurocognitive complication of decompensated liver cirrhosis and portosystemic shunting, which results in a wide range of cognitive deficits including impairments in working attention, psychomotor speed, and executive function. Current guidelines have recommended paper-and-pencil psychometric tests for the diagnosis of MHE. Most high-risk cirrhotic patients are required to be examined; however, paper-and-pencil psychometric tests are neither convenient nor rapid to perform in the clinic. Recently, novel computerized psychometric tests, including the inhibitory control test, EncephalApp Stroop App, and critical flicker frequency, have been proven to be rapid, effective, and convenient methods for screening MHE in clinical practice and for identifying high-risk cirrhotic patients for further validation using rigid neuropsychometric examinations. However, diagnostic accuracy of these tests is influenced by educational background, age, and cultural differences. This review summarizes clinical evidence of the application of novel computerized psychometric tests for screening MHE.     

围手术期血清胆碱酯酶评估肝硬化肝脏储备功能的临床意义

目的　分析围手术期血清胆碱酯酶评估肝硬化肝脏储备功能的临床意义。方法　对吉林大学中日联谊医院 1996年～ 2 0 0 3年间肝硬化患者 2 4 8例、门奇静脉断流术 113例的病人进行回顾性分析。结果　随着肝脏功能的下降 ,血清胆碱酯酶活性也出现相应的降低。术前血清胆碱酯酶活性低于 190 0u/L时 ,有 5例患者术后出现肝昏迷。结论　血清胆碱酯酶活性与慢性肝病肝脏的严重程度相一致 ,因其具有受肝脏以外因素影响小、半衰期短 (仅为 11天 )、检测方法简单等优点 ,可以作为临床评价肝储备功能的手段之一。通过检测血清胆碱酯酶活性来评估肝脏储备功能可弥补传统的Child分级的不足。当血清胆碱酯酶小于 190 0u/L时手术后出现肝功能衰竭的可能性较大。     

Hepatic artery flow and propranolol metabolism in perfused cirrhotic rat liver.

The oxygen limitation theory states that capillarization of the sinusoidal endothelium in cirrhosis impairs hepatocellular oxygen uptake manifesting as a reduction in oxygen-dependent enzyme activity including phase 1 drug metabolism. The hepatic artery supplies highly oxygenated blood to the liver. Therefore, we tested whether augmentation of hepatic arterial blood flow could improve hepatic oxygenation and function in cirrhosis. Rats were treated with carbon tetrachloride and phenobarbitone to induce hepatic cirrhosis or fibrosis. We used a bivascular rat liver perfusion model to examine the effects of increased hepatic artery flow on propranolol clearance and oxygen consumption. Each liver was perfused at three hepatic artery flow rates, 1 to 3, 4 to 6, and 7 to 9 ml/min with a constant portal venous flow of 7 to 9 ml/min. Increasing the hepatic artery flow led to improvement in propranolol clearance in control (n = 7, P <.001), fibrotic (n = 8, P <.001), and cirrhotic (n = 6, P <.001) livers. Intrinsic clearance of propranolol increased only in the cirrhotic livers (P =.01), indicating an improvement in enzyme activity. Regression analysis indicated that this improvement was mediated by change in oxygen delivery alone (P =.001). The results confirm that propranolol metabolizing enzyme activity in cirrhosis can be improved by increasing oxygen delivery by increasing hepatic arterial blood flow. These findings suggest that increasing hepatic arterial blood flow may be an important therapeutic strategy for improving global liver function in cirrhosis.