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.     

Hepatic phenylalanine metabolism measured by the [13C]phenylalanine breath test

BACKGROUND: The amino acid clearance test including phenylalanine is known to reflect liver functional reserve, which correlates with surgical outcome; however, the procedure is not clinically useful because of its laborious and time-consuming nature. This study evaluates whether phenylalanine oxidation capacity measured by a breath test could reflect liver functional reserve. DESIGN: We determined phenylalanine oxidation capacity in 42 subjects using the L-[1-13C]phenylalanine breath test (PBT). The 13CO2 breath enrichment was measured at 10-min intervals for 120 min after oral administration of 100 mg of L-[1-13C]phenylalanine. Subjects were divided into the following three groups according to their plasma retention rate of indocyanine green at 15 min (ICG R15): Group I (ICG R15 < 10%), Group II (ICG R15 10--20%), and Group III (ICG R15 > 20%). First, we determined the parameters of the phenylalanine oxidation capacity that differentiated these groups and then, using these parameters, we compared the PBT with the ICG clearance test, Child-Pugh classification score and standard liver blood tests. RESULTS: The %13C dose h(-1) at 30 min and cumulative excretion at 80 min were significantly different among the three groups (P < 0.05). These two parameters significantly correlated with the ICG R15, Child-Pugh classification score (P < 0.0001) and results of standard liver blood tests (P < 0.05). CONCLUSIONS: Phenylalanine oxidation capacity measured by the PBT was reduced according to the severity of liver injury assessed by the ICG clearance test, Child-Pugh classification, and standard liver blood tests. These results indicate that the PBT can be used as a noninvasive method to determine liver functional reserve.     

Significance of aminopyrine breath test as a parameter of hepatic functional reserve in 40% partial hepatectomy of rats with CCl4-induced liver injury

Rats with CCl₄-induced liver injury underwent partial (40%) hepatectomy. The [¹⁴C]aminopyrine breath test (ABT) values in rats with CCl₄-induced liver injury were reduced by 34% compared with those in rats with normal liver. Preoperative ABT values clearly discriminated between survivors and those that died following 40% partial hepatectomy in rats CCl₄-induced liver injury (P<0.05). Hepatic protein synthesis was remarkably enhanced in CCl₄-induced liver injury compared with normal liver (P<0.001), and this was inversely correlated with ABT values (P<0.001). These data show that the enhanced hepatic protein synthesis could induce a decrease of hepatic functional reserve. ABT seems to be a useful preoperative test for predicting surgical mortality following hepatectomy.     

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。     

声辐射力脉冲弹性成像技术评估肝占位患者肝脏储备功能的临床价值

目的探讨声辐射力脉冲弹性成像（ARFI）技术评估肝占位患者肝脏储备功能的临床价值。方法选择2011年9月至2012年8月解放军总医院86例肝占位患者。其中肝功能Child-PughA级54例,B级18例,C级14例;70例患者进行手术治疗,16例患者采用非手术治疗。采用ARFI技术测量患者肝脏剪切波速度值（SWV）;同时对患者进行吲哚氰绿（ICG）排泄实验,记录ICG血浆清除速率及ICG 15min滞留率。SWV值与ICG血浆清除速率、ICG 15min滞留率的相关性采用Pearson相关分析;SWV值与Child．Pugh分级的相关性采用Spearman等级相关分析。手术治疗患者与非手术治疗患者SWV值比较采用独立样本t检验以患者的临床决策作为金标准,采用受试者操作特性（ROC）曲线评价ARFI技术判断肝占位患者手术可行性的应用价值。结果SWV值与ICG 15min滞留率、ICG血浆清除速率、Child．Pugh分级有相关性（r=0．764,P〈0．001;P0．686,P=-0．000：r=0．864,P=-0．000）。手术治疗患者SWV值为（2．46±0．45）m／s,非手术治疗患者SwV值为（1．54±0．36）m／s,差异有统计学意义（t=-0．80,P=0．000）。ROC曲线显示,当诊断界值为2．06m／s时,约登指数最高为0．775,其相对应的ARFI技术判断肝占位患者手术可行性的敏感度为87．5％,特异度为90．0％。结论ARFI技术可有效评估肝占位患者肝脏储备功能,为临床治疗方式的决策提供帮助。     

Influence of hepatic reserve and cause of esophageal varices on survival and rebleeding before and after the introduction of sclerotherapy: a retrospective analysis

Esophageal variceal sclerotherapy has been enthusiastically accepted as the procedure of choice for patients with variceal hemorrhage. Because the relationships among liver function, different causes of varices, survival, and rebleeding rates have not been well established in sclerotherapy trials, this enthusiasm may be unjustified. We studied these relationships in 80 patients with bleeding esophageal varices who were admitted to hospitals affiliated with our clinic between 1978 and 1980 and who did not receive sclerotherapy and in 162 patients admitted between 1980 and 1982 who received sclerotherapy with ethanolamine oleate. In both groups of patients, survival and bleeding-free intervals were significantly related (P less than 0.005 and P less than 0.01, respectively) to hepatic reserve (Child's class). In addition, patients with nonalcohol-related liver disease and poor hepatic reserve (Child's class C) had reduced survival and bleeding-free intervals compared with patients in class C with alcohol-related liver disease. Similar probabilities of survival and bleeding-free intervals were noted for Child's class subgroups and etiologic subgroups in the sclerotherapy and nonsclerotherapy groups, although a formal comparison was not made because of the retrospective nature of this study. Indications that sclerotherapy increases survival and reduces rebleeding may be due to different distributions of Child's classes and causes of varices within sclerotherapy and nonsclerotherapy groups in published control trials.     

Altered liver function in diabetes: model experiments with aminopyrine in the rat

The aminopyrine breath test is a valuable quantitative liver function test. However, it may be influenced by factors not related primarily to liver disease. For instance, it has been published that diabetes affects microsomal demethylation of aminopyrine in vitro. The relevance of these findings for the in vivo situation, however, is ill defined. Aminopyrine disposition was evaluated, therefore, by performing an in vivo-in vitro comparison of its kinetics in control, diabetic and insulin-treated diabetic rats. Diabetes was induced by streptozotocin (75 mg/kg i.v.). A tracer dose of [14C]aminopyrine was injected i.p. (40 mu Ci/kg, 0.7 mg/kg) and the kinetics of 14CO2 in breath as well as disappearance of aminopyrine in blood were followed simultaneously for 2 hr. Diabetes increased the 14CO2 elimination rate constant in breath by 90%, whereas total recovery of 14CO2 in breath was decreased by 30% (P less than .001). Aminopyrine clearance in blood was doubled in diabetic rats compared to control (48.9 +/- 11.3 vs. 21.4 +/- 3.3 ml/min X kg, P less than .001). This was due to an increased volume of distribution (1.99 +/- 0.31 in diabetic rats vs. 0.96 +/- 0.11 liters/kg in control). In vitro aminopyrine kinetics in hepatic microsomal preparations showed a 52% higher Vmax of aminopyrine demethylase in D (P less than .001), whereas Km remained unchanged. The diabetes-induced changes were reversible by insulin. It is concluded that diabetes alters the aminopyrine breath test by interfering with demethylation rate and distribution of aminopyrine, and by changing the fate of the cleaved C1-fragments.     

Abnormal vitamin D metabolism in patients with cirrhosis.

To assess the role of hepatic function and alcohol on vitamin D metabolism, serum 25-hydroxyvitamin D (25-OHD) levels were measured in 20 healthy nonalcoholic control subjects, 31 "inactive" cirrhotics whose alcoholism was in remission, 8 alcoholic cirrhotics, and 15 alcoholics with normal liver function. Cirrhosis but not alcoholism, was assoicated with low serum 25-OHD levels. The aminopyrine breath test (ABT) was performed because aminopyrine, like vitamin D3, is metabolized by hepatic microsomes; the ABT correlated highly (r = 0.74, rho less than 0.01) with serum 25-OHD in the inactive cirrhotics. After an intravenous injection of 120 mug vitamin D3, serum 25-OHD rose significantly within 24 hr in 6 healthy controls and 2 patients with celiac disease but not in 6 inactive cirrhotics. The data suggest impaired 25-hydroxylation of vitamin-D impaired in patients with cirrhosis, related predominantly to the degree of hepatic dysfunction.     

Changes in antipyrine and indocyanine green kinetics during nifedipine, verapamil, and diltiazem therapy

Ten healthy subjects received oral antipyrine and intravenous indocyanine green (ICG) alone and after 5 days of oral nifedipine, diltiazem, and verapamil. Antipyrine clearance decreased during verapamil (range 4% to 26%) and diltiazem (6% to 24%) therapy (P less than 0.001) but did not change during nifedipine treatment. Antipyrine t1/2 also increased during verapamil and diltiazem treatment (P less than 0.001). ICG clearance did not change during diltiazem therapy but increased during dosing with nifedipine and verapamil (P less than 0.05). Estimated liver blood flow (derived from ICG clearance and hematocrit) also increased during verapamil (mean 33%) and nifedipine (mean 27%) treatment (P less than 0.05). Drug interactions with other liver-metabolized drugs may occur during therapy with these calcium antagonists. Nifedipine appears to increase liver blood flow whereas diltiazem inhibits oxidative drug metabolism. Drug interactions with verapamil could involve both mechanisms.     

Decreased hepatic microsomal reserve in patients with cirrhosis. Studies using aminopyrine as model drug.

It is unclear whether hepatic drug metabolism which is decreased in patients with liver disease, can be stimulated by enzyme-inducing drugs. Hepatic microsomal reserve, defined as the difference between the basal and phenobarbital-stimulated ABT, was therefore studied in eight healthy control subjects and 12 patients with stable alcoholic cirrhosis. The ABT increased significantly (p less than 0.01) from a basal value of 6.1% +/- 0.8 (mean +/- S.D.) to 8.9% +/- 0.8 in the eight control subjects after phenobarbital ingestion. In the 12 patients with alcoholic cirrhosis the basal ABT was 2.9% +/- 1.5 and did not change significantly after phenobarbital ingestion, when the value was 3.0% +/- 1.6. A small increase in the ABT occurred after phenobarbital ingestion in five of the patients with alcoholic cirrhosis, but in no patient did this increase bring the ABT within normal limits. We conclude that in many patients with stable alcoholic cirrhosis aminopyrine metabolism is decreased and cannot be corrected by treatment with phenobarbital.     

Noninvasive assessment of liver function reserve with fluorescent dosimetry of indocyanine green

Using in vivo multiphoton fluorescent dosimetry, we demonstrate that the clearance dynamics of Indocyanine Green (ICG) in the blood can quickly reveal liver function reserve. In normal rats, the ICG retention rate was below 10% at the 15-minute post-administration; While in the rat with severe hepatocellular carcinoma (HCC), the 15-minute retention rate is over 40% due to poor liver metabolism. With a 785 nm CW laser, the fluorescence dosimeter can evaluate the liver function reserve at a 1/10 clinical dosage of ICG without any blood sampling. In the future, this low-dosage ICG 15-minute retention dosimetry can be applied for the preoperative assessment of hepatectomy or timely perioperative examination.     

Intrinsic hepatic clearance of indocyanine green in the pig: Dependence on plasma protein concentration

Intrinsic hepatic clearance (K) of indocyanine green (ICG) is used as a quantitative measure of liver function. ICG is tightly bound to plasma proteins. The purpose of this study was to examine the effect of changes of plasma protein concentration on K in anaesthetized pigs with intact hepatic circulation. In addition, an attempt was made to evaluate the corresponding changes of the unbound intrinsic clearance of ICG. The plasma protein concentration was changed by exchange of plasma with either dextran-70 or donor pig plasma. Plasma albumin concentration was measured in a peripheral artery and changes of the concentrations of other plasma proteins were assumed to parallel those of albumin. ICG was given as a constant infusion and K was calculated from peripheral artery and hepatic vein concentrations of ICG according to the sinusoidal perfusion model. One experimental series comprised 3 measurement periods: From Period 1 to Period 2 (eight animals) albumin concentration was decreased by 36.6 +/- 6.5% (Mean +/- SD). This was associated with an increase of K of 32.8 +/- 28.8% (P = 0.004). From Period 2 to 3 (five animals) albumin was increased by 13.2 +/- 3.2% and K decreased by 18.5 +/- 8.3% (P = 0.03). In the second experimental series (eight animals), albumin concentration was increased by 21.6 +/- 10.3% and K decreased by 20.3 +/- 8.1% (P = 0.001). For both series, changes in albumin concentration were associated with oppositely directed changes of K in 20 out of 21 comparisons (P less than 0.001). Thus K depends not only on hepatocyte function but also on plasma protein concentration. This finding should affect interpretation of K when used as a liver function test. Changes of the unbound intrinsic clearance of ICG were examined indirectly by means of the K.a product (a: albumin concentration). According to the overall evaluation of the data the unbound intrinsic clearance of ICG was not affected by the changes in plasma protein concentration, but the results were internally inconsistent, apparently due to a time-dependency of the K.a product. We suggest this to be due to a slow but steady decrease of the 'background' K. After correction for the average decrease of K of 0.102% per min our data were in accordance with the hypothesis that the unbound clearance of K was enhanced by the binding protein(s) of ICG.     

The disposition of dapsone in cirrhosis.

Acetylation and N-hydroxylation of dapsone were evaluated in drug-free, non-smoking, normal subjects and subjects with cirrhosis (n = 7 for each group) after oral administration of 100 mg dapsone. Acetylation was not correlated with oral dapsone clearance or reduced in cirrhosis (0.37 +/- 0.43 versus 0.52 +/- 0.32). Fractional metabolic clearance of dapsone to its hydroxylamine was associated with dapsone oral clearance (r = 0.96, p less than 0.001, n = 14). In patients with cirrhosis, liver disease was associated with a trend to reduction in oral clearance (22%) and metabolic clearance of dapsone (48%). Protein binding was minimally reduced by cirrhosis (73% +/- 1% versus 69% +/- 3% in patients with cirrhosis (p less than 0.02). The dapsone recovery ratio was validated as a phenotypic index of the metabolic clearance of dapsone (r = 0.74, p less than 0.05). In an extended comparison of 14 patients with cirrhosis to 70 control subjects, cirrhosis was associated with reductions of 28% in dapsone recovery ratio (p less than 0.001), and 37% in acetylation ratio (p less than 0.01). Neither dapsone recovery ratio nor acetylation ratio correlated with Pugh Score, conventional liver function tests, indocyanine green clearance, or phenotypic measures of S-mephenytoin hydroxylase or debrisoquin hydroxylase activity. We conclude that cirrhosis is associated with minor changes in dapsone disposition and that dosage modification is not required. In addition, there is evidence that cirrhosis has a selective influence on activity of individual isozymes of cytochrome P450.     

Inhibition of drug metabolism by cimetidine in man: dependence on pretreatment microsomal liver function

The effect of cimetidine on hepatic microsomal drug metabolism was studied in six patients with normal liver and eleven patients with chronic liver disease using the aminopyrine breath test. Before administration of cimetidine, the elimination rate constant of 14CO2 from breath (Kb) was 28.3 +/- SD 1.3%/h in patients with normal liver and 13.5 +/- 7.7%/h in patients with liver disease (P less than 0.001). After 7 days of cimetidine therapy (1 g/day) Kb decreased to 23.3 +/- 5.2%/h (19.0 +/- 13.8% decrease; P less than 0.05) and 7.4 +/- 5.8%/h (50.5 +/- 14.4% decrease; P less than 0.001), respectively. Plasma levels of cimetidine were not significantly different (1.05 +/- 0.14% micrograms/ml v. 0.88 +/- 0.41; P greater than 0.05). The findings indicate that therapeutic doses of cimetidine lead to an inhibition of drug metabolism which is more pronounced in patients with impaired liver function than in liver normals. Therefore, patients with chronic liver disease may be at increased risk with respect to interactions between cimetidine and other drugs which are demethylated by the liver.     

Effects of dietary protein on theophylline pharmacokinetics and caffeine and aminopyrine breath tests

The effects of low- and high-protein diets on theophylline kinetics and the time course of changes in 13C-labeled caffeine and aminopyrine CO2 breath tests were examined in six young men. With a low-protein diet, mean theophylline clearance fell 21% (P less than 0.04) and the t1/2 rose from 8.0 to 10.6 hours (P less than 0.02). With a high-protein diet, mean theophylline clearance rose 26% (P less than 0.004) and the t1/2 shortened to 7.4 hours (P less than 0.03). Theophylline volume of distribution and protein binding did not change. Renal clearance of theophylline was lowered during the low-protein diet. Theophylline clearance correlated with caffeine breath test values during the low- (r = 0.73) and high- (r = 0.70) protein diets. Theophylline clearance correlated less well with the aminopyrine breath test values during the low- (r = 0.47) and high- (r = 0.55) protein diets. Thus dietary protein significantly influenced theophylline clearance, but the caffeine and aminopyrine breath tests showed a differential response to this important environmental factor.     

Effect of aging and cigarette smoking on antipyrine and indocyanine green elimination.

The plasma clearances of antipyrine (AP) and indocyanine green (ICG) have been measured after intravenous administration in each of 20 normal male subjects aged 22 to 72 yr. An additional 4 subjects aged 65 to 73 yr received only ICG. AP clearance fell with age in the group as a whole (r = 0.56; p less than 0.01), but when cigarette smoking habits were considered the relationship was apparent only in smokers (r = 0.68; p less than 0.02). In the under 40 yr group. AP clearance was higher in smokers than nonsmokers (p less than 0.02). There was no such difference in men over 40 yr of age. These observations suggest that the enzyme-inducing effect of smoking diminishes with advancing years. In contrast, and consistent with a reduction in liver blood flow, the clearance of the highly extracted ICG fell with age, irrespective of smoking habits (r = 0.57; p less than 0.004). These findings suggest that while hepatic drug clearance may be impaired in elderly people, the outcome depends not only on the effects of the aging process on the physiologic determinants of hepatic clearance (liver blood flow and the activity of the drug-metabolizing enzymes) but also on the effects of environmental factors, such as smoking.     

The Influence of Dye Infusion Rate and Hepatic Plasma Flow on Indocyanine Green Clearance

The plasma clearance and extraction ratio of indocyanine green (ICG) were followed in cats anesthetized with chloralose. In one series of experiments the ICG infusion rate was raised stepwise and in another the hepatic plasma flow was changed by replacing part of the blood volume with erythrocytes, plasma, or dextran (Macrodex®). For unknown reasons blood replacement with Macrodex increased the ICG elimination. Both plasma clearance and extraction ratio were independent of ICG infusion rate but dependent on hepatic plasma flow. In contrast, a clearance calculated from the dye elimination rate and the estimated average hepatic plasma concentration of ICG was independent of changes in hepatic plasma flow. In conclusion, plasma clearance and extraction ratio of indocyanine green are not ideal for estimation of liver function. However, when clearance is calculated from the average hepatic plasma concentration of the dye, it becomes independent of hepatic plasma flow and thus a more reliable index of liver function.     

无创肝血流测定在麻醉监护中的应用

目的：采用无创的脉搏色素浓度测定（DDG）技术研究麻醉期间肝脏血流和代谢变化。方法：利用DDG技术测定吲哚菁绿（ICG）的代谢速率,研究10例美国麻醉医师协会麻醉风险分类ASAⅠ～Ⅱ级全身麻醉患者麻醉前后肝脏血流和排泄功能的变化。结果：麻醉诱导后ICG血浆清除率从（0．29±0．07）明显下降到（0．19±0．04）（P〈0．01）;5、10、15min的滞留率相应有所增加;代谢半衰期从（2．50±0．61）min延长到（3．74±0．91）min（P％0．01）。有效肝脏血流量和心脏指数均有所下降,分别从（1．41±0．40）L·min^-1。下降到（0．95±0．20）L·min^-1（P〈0．05）和从（4．07±1．08）L·min^-1·m^-2下降到（2．47±0．69）L·min^-1·m。（P〈0．01）。结论：麻醉能够减少肝脏血流,并降低ICG的排泄率。     

临床与CT形态和肝容积测量相结合评估肝癌介入患者肝储备功能的价值

目的 探讨将传统的肝储备功能Child-Pugh(C-P)分级方法指标体系与CT肝硬化分级和CT保留肝容积率相结合,形成新的肝储备功能评估方法(改良C-P分级),在评估肝癌介入患者肝储备功能中的价值.方法 对60例行肝动脉化疗栓塞术(TACE)的原发性肝癌患者开展前瞻性研究.分别于术前和术后以C-P与改良C-P评分系统...     

功能影像学评估肝脏储备功能研究进展

评估肝脏储备功能具有重要的临床意义,可确定肝切除的安全范围,早期识别潜在的肝损伤,评价中晚期肝病的治疗效果并判断预后等。评估肝脏储备功能的方法多样,吲哚菁绿（ICG）清除试验是目前临床较常用的方法,其应用价值已得到广泛认可。随着功能影像学的发展,无创或微创,更便捷、准确、全面地评估肝脏储备功能成为可能。本文对影像学评估肝脏储备功能的研究进展及其与ICG清除试验的关系进行综述。