Total and functional hepatic blood flow decrease in parallel with ageing

OBJECTIVES: To study changes in hepatic blood flow with age. DESIGN: Functional hepatic flow (FHF) and total hepatic flow (THF) were determined by non-invasive methods in 40 normal subjects in four age groups (<45, 45-60, 61-75 and >75 years). All subjects had normal routine liver function tests and no history of liver disease. RESULTS: THF was measured by pulsed echo-Doppler, as the sum of portal and hepatic artery blood flow; FHF was measured by the hepatic clearance of D-sorbitol. THF significantly decreased with age, particularly in subjects over 75 (from 1445+/-220 ml/min to 1020+/-148; P<0.001), and a similar reduction was observed in FHF (from 1514+/-250 ml/min to 1015+/-163; P<0.001). THF and FHF were strictly correlated in the whole population (r = 0.871; P<0.001) and both correlated with age (r = -0.510 and r = -0.596; P<0.005). CONCLUSION: With ageing there is a reduction of hepatic blood flow without any additional intrahepatic shunting.     

联合测定吲哚箐绿和D-山梨醇评价肝储备功能

目的 利用高效液相法(HPLC)测定正常肝脏和肝硬化肝脏的吲哚箐绿(ICG)肝固有代谢容量,并结合D-山梨醇无创测量肝功能性血流量、肝内分流率,全面评价肝储备功能。方法 制作大鼠肝硬化模型和肝脏隔离灌注模型,据HPLC法和Bergmeyer酶分光光度法分别测量ICG和D-山梨醇的药代动力学参数。结果 (1)HPLC证实ICG包括ICG原形(ICGg)和ICG降解产物(ICGdp)两种成分,保留时间分别为8.9min和24.2min,两种成分光谱相似,但体内代谢不同。(2)据ICGg计算的肝固有代谢容量(Q_(INT,I))在对照组和肝硬化组分别为(36.57±13.03)ml/min和(14.39±5.13)ml/min,肝硬化组Q_(INT,I)明显下降(t=7.08,P<0.01)。(3)肝功能性血流量(Q_(FUNC)),肝内分流率(Q_(IHS))在对照组和肝硬化组分别为:(34.06±5.12)ml/min和(17.54±7.02)ml/min,(9.9±1.4)％和(47.5±20.9)％,肝硬化组Q_(FUNC)显著下降(t=8.41,P<0.01),Q_(IHS)显著增加(t=8.35,P<0.01)。结论(1)HPLC法可避免ICGdp的干扰,优于传统的分光光度法,能用于肝固有代谢容量测定。(2)D-山梨醇肝清除率,是无创测定正常肝脏的总血流量,和肝硬化肝脏的肝功能性血流量、肝内分流率的实用可靠方法。(3)ICG与D-山梨醇联合使用,有助于全面评价肝脏功能状态。     

Evaluation of liver functional reserve by combining D-sorbitol clearance rate and CT measured liver volume

AIM: Our research attempted to evaluate the overall functional reserve of cirrhotic liver by combination of hepatic functional blood flow, liver volume, and ChildPugh′s classification, and to discuss its value of clinical application.METHODS: Ninety two patients with portal hypertension due to hepatic cirrhosis were investigated. All had a historyof haematemesis and hematochezia, esophageal and gastric fundus varices, splenomegaly and hypersplenia.A 2-year follow-up was routinely performed and no one was lost. Twenty two healthy volunteers were used as control group. Blood and urine samples were collected 4times before and after intravenous D-sorbitol infusion.The hepatic clearance (CLH) of D-sorbitol was then calculated according to enzymatic spectrophotometric method while the total blood flow (QToTAL) and intrahepatic shunt (RINs) were detected by multicolor Doppler ultrasound, and the liver volume was measured by spiral CT. Data were estimated by t-test, variance calculation and chi-squared test. The relationships between all these parameters and different groups were investigated according to Child-Pugh classification and postoperative complications respectively.RESULTS: Steady blood concentration was achieved 120 mins after D-sorbitol intravenous infusion, which was (0.358±0.064) mmoⅠ@L-1 in cirrhotic group and (0.189±0.05)mmol@L-1 in control group (P＜0.01). CLH=(812.7±112.4) ml@min-1,QTOTAL=(1280.6±131.4) ml@min-1, and RINS=(36.54±10.65)%in cirrhotic group and CLH=(1248.3±210.5) ml.min-1, QTOTAL=(1362.4-±126.9) ml@min-1, and RINS=(8.37±3.32) % in control group (P＜0.01). The liver volume of cirrhotic group was 1057±249 cm3, 851±148 cm3 and 663±77 cm3 in Child A, B and C group respectively with significant difference (P＜0.001).The average volume of cirrhotic liver in Child B, C group was significantly reduced in comparison with that in control group (P＜0.001). The patient, whose liver volume decreased by 40 % with the CLH below 600 ml@min-1, would have a higher incidence of postoperative complications. There was no strict correspondent relationship between CLH, liver volume and Child-Pugh′s classification.CONCLUSION: The hepatic clearance of D-sorbitol, CT measured liver volume can be reliably used for the evaluation of hepatic functional blood flow and liver metabolic volume. Combined with the Child-Pugh′s classification, it could be very useful for further understanding the liver functional reserve, therefore help determine reasonable therapeutic plan, choose surgical procedures and operating time.     

Hepatic arterial pulsatility index in cirrhosis: correlation with portal pressure.

BACKGROUND/AIMS: Determination of the pulsatility index by means of duplex sonography provides the opportunity to evaluate the vascular resistance of the hepatic artery noninvasively. The aim of this study was to investigate the relationship between the hepatic arterial pulsatility index and the hepatic venous pressure gradient in cirrhosis. METHODS: In 50 patients with cirrhosis, hepatic venous pressure gradient was determined in the fasting state. Immediately thereafter, hepatic arterial pulsatility index and portal blood flow velocity were measured by duplex sonography with no knowledge of hepatic venous pressure values. In addition, the duplex parameters were determined in 20 controls. RESULTS: Hepatic arterial pulsatility index was significantly higher in patients with cirrhosis than in controls (0.92+/-0.1 vs. 1.14+/-0.18; p<0.001) and directly correlated with the hepatic venous pressure gradient (r = 0.7; p<0.001). Furthermore, weak correlations were found between hepatic arterial pulsatility index and Child-Pugh score (r = 0.49; p<0.01) and between portal blood flow velocity and hepatic venous pressure gradient (r = -0.48; p<0.01). CONCLUSION: In cirrhosis the hepatic arterial vascular resistance seems to increase parallel to the rise of the portal pressure. Therefore, duplex sonographic determination of the hepatic arterial pulsatility index may contribute to the noninvasive evaluation of portal hypertension.     

Impact of antithrombin Ⅲ on hepatic and intestinal microcirculation in experimental liver cirrhosis and bowel inflammation： An in vivo analysis

AIM: To analyze the hepatic and intestinal microcirculation in an animal model of liver cirrhosis and inflammatory bowel disease (IBD) and to characterize the anti-inflammatory action of antithrombin III (ATIII) on leukocyte kinetics and liver damage. METHODS: Hepatic and intestinal microcirculation was investigated by intravital videomicroscopy. Standardized models of experimental chronic liver cirrhosis and bowel inflammation were employed. Animals were divided into four groups (n = 6/group): controls, animals with cirrhosis, animals with cirrhosis and IBD, animals with cirrhosis and IBD treated with ATIII. RESULTS: Cirrhosis facilitated leukocyte rolling and sticking in hepatic sinusoids (1.91+/-0.28 sticker/microm vs 0.5+/-0.5 sticker/microm in controls, P<0.05). The effect enhanced in animals with cirrhosis and IBD (5.4+/-1.65 sticker/microm), but reversed after ATIII application (3.97+/-1.04 sticker/microm, P<0.05). Mucosal blood flow showed no differences in cirrhotic animals and controls (5.3+/-0.31 nL/min vs 5.4+/-0.25 nL/min) and was attenuated in animals with cirrhosis and IBD significantly (3.49+/-0.6 nL/min). This effect was normalized in the treatment group (5.13+/-0.4 nL/min, P<0.05). Enzyme values rose during development of cirrhosis and bowel inflammation, and reduced after ATIII application (P<0.05). CONCLUSION: Liver cirrhosis in the presence of IBD leads to a significant reduction in mucosal blood flow and an increase in hepatic leukocyte adherence with consecutive liver injury, which can be prevented by administration of ATIII.     

Hepatic-Intestinal Disposal of Endogenous Human Alpha Atrial Natriuretic Factor99-126 in Patients with Cirrhosis

Hepatic-intestinal disposal of endogenous human alpha atrial natriuretic factor99-126 (ANF) was assessed in 13 patients with cirrhosis (six Child-Turcotte class A, five class B, and two class C) and eight control subjects. The Fick principle was applied during hepatic vein catheterization. Arterial ANF concentration in patients with cirrhosis [11.1 +/- 1.6 (SEM) pmol/L] was not significantly different from that of the control subjects (14.9 +/- 4.2 pmol/L, NS). Arteriohepatic venous extraction ratio of ANF (0.43 +/- 0.05 in cirrhosis vs 0.37 +/- 0.09 in controls, NS), hepatic-intestinal clearance (274 +/- 46 vs 237 +/- 46 ml/min, NS) and removal rate (2.9 +/- 0.88 vs 3.1 +/- 0.77 pmol/min, NS) were closely similar in patients and controls. The present results give no indication that significantly reduced hepatic-intestinal disposal of ANF has a role in causing altered circulating plasma levels of this peptide in cirrhosis. This is in keeping with the presence of vascular clearance receptors and peptidases for ANF degradation independent of hepatocellular function.     

Quinidine pharmacokinetics in patients with cirrhosis or receiving propranolol.

Quinidine pharmacokinetics (half-life, volume of distribution, and clearance) as well as protein binding were evaluated following a single 200 mg. oral dose of quinidine sulfate in eight control patients, in eight patients with moderate to severe cirrhosis, and in seven patients receiving 40 to 400 mg./day of propranolol. Patients with cirrhosis had a significantly longer quinidine half-life (9 +/- 1 hr; p less than .01) when compared to control patients (6 +/- 0.5h). This was not related to a reduced quinidine clearance rate but rather to an increase in quinidine volume of distribution (4.1 +/- .4 L./Kg. in cirrhotic patients vs 2.6 +/- 1 L./Kg. in control patients; p less than .01). Abnormal quinidine binding (greater than 25 per cent unbound fraction) was noted in seven of the eight cirrhotic patients. In contrast, patients receiving propranolol had a normal quinidine half-life of 6 +/- 0.5 hr. However, these patients had a significantly reduced quinidine clearance (3.3 +/- .7 ml./min./Kg. vs. 5.3 +/- .5 ml./min./Kg. in controls; p less than .05) and higher peak concentrations (1.25 +/- .20 micrograms/ml. vs. .80 +/- .5 micrograms/ml. in controls; p less than .05). Therefore in patients receiving propranolol, quinidine levels may be higher than expected shortly after dosage, and therefore a potential for transient toxicity exists in these patients. Maintenance quinidine dosage may have to be reduced in patients with moderate to severe hepatic cirrhosis, but not in patients receiving propranolol. Total quinidine concentration measurement underestimate free quinidine concentrations in most cirrhotic patients.     

Increased turnover of Gc-globulin in patients with hepatic encephalopathy

BACKGROUND: A low serum level (< 100 mg/L) of the actin-scavenger Gc-globulin is a prognostic marker of non-survival in fulminant hepatic failure (FHF). It is unknown whether decreased production or increased consumption (or both) is responsible for the low Gc-globulin levels. METHODS: Ten patients with FHF and four patients with acute or chronic liver disease (AOCLD) with hepatic encephalopathy (HE) grades II-IV were included. Eight patients with cirrhosis (chronic liver disease, CLD) without HE served as controls. Total, free, and actin-bound Gc-globulin were measured in samples from an artery, a central vein, and a hepatic vein. In 12 patients (9 FHF, 3 AOCLD), concentrations were measured before and after high volume plasmapheresis (HVP). RESULTS: Total Gc-globulin was reduced to 21%, 40%, and 43% of the normal level in the FHF, AOCLD, and CLD groups, respectively, whereas bound Gc-globulin was within normal range in all patients. The Gc:actin complex ratio was increased 3.8, 2.5, and 1.9-fold compared with normal levels. Total, free, and bound serum Gc-globulin levels did not differ among arterial, systemic venous, or hepatic venous blood. Total Gc-globulin rose to >100 mg/L in all patients after HVP, whereas bound Gc-globulin remained unchanged. The Gc-globulin production rate in FHF and AOCLD patients was increased to 4.1 +/- 1.3 mg/min compared to literature values of 0.6 mg/min in healthy individuals. The estimated half-life of total Gc-globulin was shorter in the patients compared to healthy individuals (127 +/- 56 min and 870 min, respectively). CONCLUSIONS: Gc-globulin levels were reduced in patients with FHF and AOCLD because a 7-fold increase of Gc-globulin production rate could not compensate for the accelerated clearance. Bound Gc-globulin was maintained within normal levels in all circumstances studied, indicating a possible regulatory role of this parameter in the clearance of actin.     

Remethylation and transsulfuration of methionine in cirrhosis: studies with L-[H3-methyl-1-C]methionine

Disturbances of the methionine cycle may result in liver injury. Patients with alcohol-induced liver disease often exhibit hypermethioninemia and a delayed clearance (CL) of methionine, but the extent to which transsulfuration and remethylation pathways of the cyclic methionine metabolism are affected is unknown. Methionine turnover was determined in 7 healthy volunteers and 6 patients with alcohol-induced cirrhosis after oral administration of 2 mg/kg [(2)H(3)-methyl-1-(13)C]methionine, which permitted us to follow transsulfuration by its decarboxylation to (13)CO(2) and remethylation by replacement of the labeled methyl group by an unlabeled one. Basal plasma concentrations of endogenous methionine (50 +/- 5 vs. 25 +/- 2 micromol/L, mean +/- SEM, P <.001) were significantly higher in patients with cirrhosis and its CL was significantly decreased (774 +/- 103 vs. 2,050 +/- 141 mL/min, P <.001). Methionine turnover amounted to 42 +/- 4 vs. 27 +/- 3 micromol/kg/h (P <.05) in controls and patients with cirrhosis, respectively. The fraction of administered methionine undergoing remethylation was lower in patients with cirrhosis (7.6 +/- 1.5 vs. 14.1 +/- 1.1%, P <.005). However, because of the larger pool of circulating methionine, the total flux of methionine through the remethylation pathway was similar in both groups. A significantly lower fraction of the administered dose appeared in the form of (13)CO(2) in breath in patients with cirrhosis (2.2 +/- 0.4 vs. 11.0 +/- 0.8%, P <.001). In conclusion, the data indicate that the liver with cirrhosis compensates for a decreased activity of remethylating enzymes by operating at higher concentrations of methionine. In contrast, transsulfuration is impaired in patients with alcohol-induced cirrhosis such that an assessment of transsulfuration by a simple breath test may provide a clinically useful estimate of hepatic function.     

Sorbitol removal by the metastatic liver: a predictor of systemic toxicity of intra-arterial chemotherapy in patients with liver metastases

BACKGROUND/AIM: Hepatic arteriovenous shunting in the metastatic liver reduces the advantages of intraarterial infusion of chemotherapeutic agents because of the passage of drugs into the systemic circulation. The aim of this study was to quantitatively assess spontaneous functional hepatic arteriovenous shunting in patients with liver metastases and to determine its implication in the increase in systemic toxic effects of intra-arterial infusion chemotherapy with floxuridine. METHODS: Twenty-five patients who underwent implantation of arterial ports for regional chemotherapy of liver metastases were studied. Functional hepatic arterio-venous shunting was evaluated through the bioavailability of intra-arterially administered D-sorbitol, a safe, natural compound whose kinetic features make its hepatic clearance flow dependent. In addition, D-sorbitol hepatic clearance (a parameter reflecting functional liver blood flow) and common liver function tests were evaluated for each studied patient. Patients were then grouped with respect to the percentage of medically-assessed liver occupation by metastases and with respect to systemic toxicity of the chemotherapeutic treatment. Both univariate and multivariate analyses by Student's t-test and stepwise logistic regression, respectively, were performed in both groups for each of the evaluated parameters (age, liver function tests, D-sorbitol hepatic clearance and arterial bioavailability). RESULTS: Arterial bioavailability of D-sorbitol ranged between 0.05 and 0.72 and was significantly greater in patients with more than 50% liver occupation (0.39+/-0.19) compared with those with minor liver involvement (0.17+/-0.13; p = 0.003); it was also significantly greater in patients experiencing high-grade systemic toxicity (0.40+/-0.19) compared with those with low-grade toxicity (0.16+/-0.11; p<0.001). Multivariate analysis showed that arterial bioavailability of D-sorbitol was the only parameter among those evaluated which was able to predict systemic toxicity of this kind of chemotherapy. CONCLUSIONS: Our results show that, in the metastatic liver, arterial bioavailability of D-sorbitol, an index of functional arteriovenous shunting, varies widely, is significantly greater in patients with massive liver occupation and it is a good predictor of systemic toxicity of intra-arterial regional chemotherapy with floxuridine.     

Verapamil has no effect on porto-hepatic pressure gradient, hepatic blood flow and elimination function of the liver in patients with liver cirrhosis

This study aimed to assess the effects of verapamil, a calcium-channel blocker, on porto-hepatic pressure gradient and on hepatic function as measured by the intrinsic hepatic clearance of indocyanine green (ICG) in patients with biopsy proven alcoholic cirrhosis. Hepatic venous pressures and hepatic extraction of ICG were measured before and 60 min after intravenous injection of 10 mg of verapamil in 19 consecutive patients. Hepatic blood flow and intrinsic hepatic clearance of ICG were calculated in the 10 patients whose hepatic extraction fraction was higher than 10%. No significant difference was observed when comparing porto-hepatic pressure gradient (17.72 +/- 4.79 vs. 17.77 +/- 4.43 mmHg), hepatic blood flow (13.47 +/- 4.75 vs. 16.13 +/- 7.88 ml.min-1.kg-1) and intrinsic hepatic clearance of ICG (1.99 +/- 0.54 vs. 1.97 +/- 0.45 ml.min-1.kg-1) before and after verapamil injection. We conclude that verapamil has no beneficial effect in patients with alcoholic cirrhosis.     

Effects of verapamil on hepatic and systemic hemodynamics and liver function in patients with cirrhosis and portal hypertension

The effects of verapamil on hepatic and systemic hemodynamics and on liver function were investigated in 10 patients with portal hypertension due to advanced micronodular cirrhosis to verify whether, as it has been suggested, this calcium channel blocker may improve liver function and reduce portal pressure in these patients. The oral administration of 100 mg of verapamil caused systemic vasodilation, evidenced by a significant reduction in mean arterial pressure (-8.1 +/- 7.6%, p less than 0.025) and systemic vascular resistance (-12.5 +/- 9.5%, p less than 0.001), and increased heart rate (+13.9 +/- 10.4%, p less than 0.01). However, no beneficial effect was noted on portal pressure evaluated by hepatic vein catheterization (baseline 19.8 +/- 4.0, verapamil 20.2 +/- 3.6 mmHg, NS), hepatic blood flow (1.45 +/- 0.64 vs. 1.47 +/- 0.62 liters per min, NS) and hepatic vascular resistance (1.314 +/- 611 vs. 1,266 +/- 513 dyn per sec per cm-5, NS). Similarly, no change was observed in portal blood flow, measured in six patients by pulsed Doppler flowmeter (0.94 +/- 0.30 vs. 0.89 +/- 0.35 liter per min, NS). In addition, verapamil did not increase the hepatic intrinsic clearance of these patients (0.20 +/- 0.07 vs. 0.19 +/- 0.06 liter per min, NS). This study suggests that verapamil is of no beneficial effect in patients with advanced cirrhosis of the liver.     

Systemic Availability of Propionate and Acetate in Liver Cirrhosis

In 15 patients with cirrhosis of the liver and 10 control subjects, 7.5 mmol sodium propionate and 7.5 mmol sodium acetate were instilled endoscopically into the duodenum. Venous concentrations of propionate and acetate were measured for 90 min after administration of the enteral dose by gas-liquid chromatography. In patients with liver cirrhosis, propionate rose from a basal value of 6.1 +/- 4.7 (SD) microM to a peak concentration of 50.1 +/- 25.6 microM, whereas, in controls, it rose only from 1.4 +/- 1.6 to 10.3 +/- 7.6 microM. The oral propionate clearance was significantly lower in patients with cirrhosis (4.51 +/- 1.63 L/min) than in controls (118.47 +/- 154.79 L/min). Acetate went up from 39.5 +/- 16.3 to 134.1 +/- 62.7 microM in patients with cirrhosis and from 60.9 +/- 19.0 to 102.0 +/- 44.0 microM in controls. The oral acetate clearance was lower in patients with liver cirrhosis (2.80 +/- 2.17 L/min) than in control persons (10.86 +2- 5.72 L/min). The differences between the groups were more striking for propionate than for acetate values. It is concluded that the systemic availability of propionate and acetate is higher in patients with liver cirrhosis than in controls. This may be due to portosystemic shunting and/or diminished hepatic and extrahepatic extraction of the acids.     

Relationship between hepatic blood flow,liver tests,haemodynamic values and clinical characteristics in patients with chronic liver disease*

Although hepatic blood flow (HBF) has been measured in patients with liver disease for many years, the results of these studies have not provided clear information concerning the usefulness of this measurement. Hepatic blood flow was measured in 392 patients with either cirrhosis (n= 356) or hepatic fibrosis (n= 36). The control group included 59 subjects with normal liver architecture. Hepatic clearance of indocyanine green (ICG) was markedly reduced in patients with cirrhosis and hepatic fibrosis compared with controls (182±5, 276±22 and 421±25 mL/min, respectively). In patients with cirrhosis, ICG clearance and extraction were significantly correlated, but were not correlated to HBF. Although HBF did not differ between patients with cirrhosis and controls (1.26±0.04 vs 1.35±0.07 L/min, respectively), patients with hepatic fibrosis had lower HBF (1.04±0.07 L/min; P< 0.05). In patients with cirrhosis, no correlation was observed between HBF and cardiac output, mean arterial pressure, azygos blood flow, the hepatic venous pressure gradient or Pugh's score. However, a significant difference in HBF was observed in patients with and without hepatic encephalopathy (1.00±0.09 vs 1.28±0.03 L/min, respectively; P<0.05). In conclusion, the present study shows that, in patients with cirrhosis, HBF is normal and is not related to other haemodynamic values or liver tests. These results discourage the measurement of HBF in the evaluation of patients with cirrhosis.     

Endothelin-1 and -3 plasma concentrations in patients with cirrhosis: Role of splanchnic and renal passage and liver function

Increased as well as decreased plasma concentrations of the endothelins, endogenous vasoactive peptides, have been reported in cirrhosis. This might be caused by alterations of hepatic or renal clearance or release. Therefore, the aim of the current study was to investigate the influence of splanchnic and renal passage and of liver function on plasma concentrations of endothelin-1 (ET-1) and endothelin-3 (ET-3) in patients with cirrhosis compared with controls. Eighteen patients with cirrhosis and 8 normotensive controls of similar age were investigated. Arterial and venous plasma samples were obtained simultaneously, and ET-1 and ET-3 concentrations were determined in extracted plasma by two separate radioimmunoassays. Arterial as well as hepatic and renal venous concentrations of ET-1 in cirrhosis (17.8 ± 0.8 pg/mL, 19.1 ± 0.9 pg/mL, and 16.8 ± 0.8 pg/mL) were significantly (P < .001) higher than in controls (9.2 ± 1.7 pg/mL, 9.0 ± 2.0 pg/mL, and 8.4 ± 1.9 pg/mL, respectively). The same held true for the corresponding ET-3 plasma concentrations in cirrhosis (19.3 ± 1.6 pg/mL, 20.5 ± 1.5 pg/mL, and 18.4 ± 1.5 pg/mL, respectively) compared with controls (11.1 ± 1.8 pg/mL, 11.3 ± 1.5 pg/mL, and 10.1 ± 1.7 pg/mL, respectively; P < .01). There was a significant (P < .05) renal net extraction of ET-1 and ET-3 in cirrhosis. In contrast, a significant (P < .05) net release of ET-1 and ET-3 (2.40 ± 0.80 ng/min and 1.75 ± 1.16 ng/ min) during splanchnic passage was observed in cirrhosis, but not in controls (−0.24 ± 0.51 ng/min, and −0.46 ± 0.64 ng/min). Plasma concentrations of ET-3 in cirrhosis were correlated to the Child-Turcotte score (r = .66, P < .01) and inversely to the functional liver cell mass, determined by the galactose elimination capacity (r = −.72, P < .01). Hepatic venous ET-1 concentrations correlated to the hepatic blood flow assessed by the indocyanine green clearance (r = .48; P < .05). Net splanchnic release may contribute to elevated ET-1 and ET-3 plasma concentrations in patients with cirrhosis. Splanchnic ET-1 and ET-3 handling in cirrhosis may be influenced by different mechanisms.     

Serum and urinary zinc in fulminant hepatic failure

Patients with chronic hepatic encephalopathy have been shown to have low serum zinc levels. Moreover, in a controlled study, significant improvement was seen in these patients on oral zinc supplementation. Information on zinc status in fulminant hepatic failure is insufficient. Serum and urinary zinc abnormalities were studied in 22 patients with fulminant hepatic failure (FHF) and they were compared with age- and sex-matched controls. The mean serum zinc values were significantly less in patients with FHF (72.7 +/- 3.7 micrograms/100 mL versus 107.9 +/- 6.2 micrograms/mL) while the urinary zinc values were significantly higher compared with controls (603.5 +/- 9.3 micrograms/24 h versus 334.4 +/- 10 micrograms/24 h). The serum zinc levels significantly and progressively decreased, while urinary zinc significantly increased after admission in patients with FHF. The serum zinc values in the group that survived were significantly higher than those in the group of patients who died. Correspondingly, urinary zinc was lower in survivors than in the group that expired. This study indicates that serum and urinary zinc levels could be used as a prognostic indicator in FHF. A therapeutic trial with zinc supplementation is justified in this group of patients.     

Effect of cirrhosis on sulphation by the isolated perfused rat liver

BACKGROUND/AIMS: There is evidence to suggest that not all pathways of drug metabolism are similarly affected in cirrhosis. The effect of cirrhosis on drug oxidation and glucuronidation has been extensively investigated but little is known of the effect of cirrhosis on drug sulphation. The aim of this study was to investigate the effect of cirrhosis on sulphation. METHODS: We investigated the effect of cirrhosis on p-nitrophenol sulphation and compared this with the effect of cirrhosis on p-nitrophenol glucuronidation as well as on d-propranolol oxidation simultaneously in the single-pass isolated perfused rat liver. The perfusate contained added inorganic sulphate to maximise production of p-nitrophenol sulphate. RESULTS: About 77% and 59% of p-nitrophenol was eliminated as the sulphate conjugate by the healthy (n=6) and cirrhotic (n=7) livers, respectively. Mean total p-nitrophenol clearance was decreased in cirrhosis (healthy: 18.5+/-0.2 vs. cirrhotic 15.3+/-4.0 ml/min; p<0.05). The decrease in total clearance of p-nitrophenol was due solely to the decrease in sulphate formation clearance, which was significantly decreased (healthy: 14.1+/-1.9 vs. cirrhotic: 9.27+/-3.33 ml/min; p<0.05). Mean glucuronide formation clearance (healthy: 5.11+/-0.94 vs cirrhotic: 5.79+/-0.85 ml/ min; p>0.05) was not significantly altered. Mean total propranolol clearance was decreased in cirrhosis (healthy: 19.9+/-0.1 vs. cirrhotics: 18.0+/-1.5 ml/min; p<0.05). CONCLUSIONS: We have shown that in cirrhosis there is significant impairment of drug oxidation and sulphation, whilst glucuronidation is spared. The decreased sulphation of p-nitrophenol was most likely due to a decrease in phenol sulphotransferase and/or decrease in cofactor synthesis.     

Effect of portacaval shunt on drug disposition in patients with cirrhosis

To examine the consequences of liver blood flow variations on drug disposition in cirrhosis, we studied the effects of portacaval shunt on drug clearance in 35 cirrhotic patients. Lidocaine clearance and bioavailability, indocyanine green (ICG) clearance, aminopyrine breath test, and hepatic blood flow were measured before and 18 months after surgery. The patients were divided into two groups according to severity of disease: 14 patients (group 1) had slight liver dysfunction (ICG extraction ratio greater than 0.25) and 21 patients (group 2) had severe liver disease (ICG extraction ratio less than 0.25). After portacaval shunt the decrease in hepatic blood flow was similar for both groups (-65%). In group 1, ICG systemic clearance decreased from 9.10 +/- 0.68 to 4.40 +/- 0.34 ml/min . kg (p less than 0.05), whereas ICG intrinsic clearance remained unchanged; lidocaine systemic clearance decreased from 7.93 +/- 0.93 to 5.09 +/- 0.33 ml/min . kg (p less than 0.05), whereas lidocaine intrinsic clearance remained unchanged; bioavailability increased from 0.601 +/- 0.076 to 1, resulting in an abrupt reduction of oral clearance from 18.01 +/- 4.90 to 5.09 +/- 0.33 ml/min . kg (p less than 0.05). In group 2, ICG systemic clearance decreased slightly from 3.90 +/- 0.39 to 2.28 +/- 0.16 ml/min . kg (p less than 0.01) and ICG intrinsic clearance was not modified; lidocaine systemic and intrinsic clearance remained unchanged; and bioavailability increased from 0.779 +/- 0.229 to 1, resulting in a decrease of oral clearance from 7.68 +/- 1.65 to 4.23 +/- 0.37 ml/min X kg (p less than 0.05). The aminopyrine breath test was not affected by surgery in either group. We conclude that reduction of hepatic blood flow after portacaval shunt has only minimal effects on drug disposition in patients with severe liver disease, but results in a notable reduction in the clearance of high-extraction drugs in cirrhotics with mild liver disease.     

Antipyrine clearance in chronic and neoplastic liver diseases: A study of 518 patients

Antipyrine metabolism is widely used as an index of the drug-metabolizing reserve of the liver. It is well known that metabolism of this drug is impaired in subjects with acute hepatitis or cirrhosis, but conflicting data have been reported regarding patients with chronic postinfectious hepatitis or liver cancer. We studied conventional liver-function parameters and antipyrine metabolism (antipyrine per o.s. 18mg/kg) in 518 subjects. One hundred and one patients had liver metastases (various primaries). Based on the number and size of lesions, the hepatic involvement was considered minimal in 47 and massive in 54 (groups B1 and B2, respectively). One hundred and two had chronic active hepatitis (CAH); 51 patients with histological evidence of fibrosis/early cirrhosis and 51 patients were without histological evidence of fibrosis/early cirrhosis. Ninety-two had histologically confirmed cirrhosis (group D), and the remaining 120 had cirrhosis and hepatocellular carcinoma (group E). The control group was composed of 103 subjects with healthy livers (group A). Antipyrine clearance (AP Cl) in CAH patients with fibrosis (0.246 ± 0.98 mL/min per kg) was similar to that observed in patients with cirrhosis (0.223 ± 0.148 mL/min per kg), and both values were significantly lower than that found in CAH patients without fibrosis (0.406 ± 0.159 mL/min per kg, P < 0.01). Antipyrine clearance in patients with liver metastases (0.426 ± 0.174 mL/min per kg) was similar to that of the healthy group (0.489 ± 0.210 mL/min per kg). Cirrhotics and cirrhotics with hepatocellular carcinoma (HCC) presented similar degrees of impairment. Antipyrine clearance was positively correlated with serum albumin (r²= 0.10, P= 0.01) and prothrombin time (r²= 0.129, P < 0.01) in all groups, except those with liver metastases. In patients with CAH, the presence of fibrosis/cirrhosis is associated with impaired antipyrine metabolism. The lack of impairment in groups with liver metastases suggests that the functional hepatic reserve is maintained even in the presence of massive neoplastic invasion.     

Renal sodium retention in cirrhosis: tubular site and relation to hepatic dysfunction

Renal sodium handling, assessed by the response to acute saline loading, was investigated in 14 well-compensated, nonascitic alcoholic cirrhotics and six normal controls. Urinary sodium excretion in cirrhotic patients (199 +/- 141 mumoles per min) was significantly lower than in controls (387 +/- 104 mumoles per min; p less than 0.01) at 3 hr postinfusion. In contrast to controls, renal plasma flow and glomerular filtration rate did not increase in the cirrhotics in response to acute saline loading. Proximal fractional reabsorption of sodium was estimated by clearance techniques in the presence of a hypotonic diuresis. Cirrhotic subjects with impaired functional liver cell mass as assessed by antipyrine clearance were unable to decrease proximal fractional reabsorption of sodium significantly in response to saline loading. Assessment in the cirrhotics included measurement of hepatic vein pressure gradient, indocyanine green extraction ratio, indocyanine green clearance, and antipyrine clearance as indices of portal pressure, intrahepatic shunting, hepatic blood flow and functional hepatocellular mass, respectively. Urinary sodium excretion in the cirrhotics correlated strongly with antipyrine clearance (r = 0.839, p less than 0.0001) and weakly with portal pressure (r = 0.562, p = 0.037). No correlation was seen with the other indices of hepatic blood flow and shunting. The findings of this study suggest that alcoholic cirrhosis is associated with a decline in hepatocellular function which results in either a decreased clearance of a salt-retaining hormone or decreased synthesis of a natriuretic hormone.(ABSTRACT TRUNCATED AT 250 WORDS)