Hepatic clearance ofd-sorbitol

The hepatic clearance ofd-sorbitol, a natural polyol which is metabolized by the liver, was studied in normal and cirrhotic subjects after bolus intravenous injection (2 g) and during constant infusion (54 mg/min) with the aim of providing a noninvasive and simple measure of functional liver plasma flow. The high hepatic extraction ofd-sorbitol and the dose-independence of its clearance pointed to a flow-dependent clearance regimen. The renal excretion was taken into account when computing the hepatic clearance. Day-today reproducibility of the test was good. No significant difference was found when the hepatic clearance was measured by bolus injection or constant infusion methods. As measured by the bolus injection method, the mean (±sd) hepatic clearance in the normal subjects (911±137 ml/min) was significantly greater (P<0.001) than that of the cirrhotics (456±181 ml/min).This study was partially supported by grants from Consiglio Nazionale Ricerche (84.01760.04) and Ministero Pubblica Istruzione (2.12.2).     

Impaired elimination of caffeine in cirrhosis

The effect of cirrhosis on the disposition and elimination of caffeine was examined. Caffeine (250 mg) was administered orally to 15 healthy controls and eight patients with cirrhosis. The elimination half-life was prolonged from 5.2±2.4 hr (mean±sd) in controls to 6.1±1.9 hr in cirrhotics, although this did not reach statistical significance. The plasma clearance, however, was significantly higher (1.4±0.5 ml/min/kg) in controls as compared to cirrhotics (0.9±0.3 ml/min/kg) (P<0.05). The plasma binding of caffeine was also lower in cirrhotics (31.3±1.8% vs 25.5±4.0%,P<0.01). The plasma clearance of unbound caffeine therefore was reduced from 2.0±0.8 ml/min/kg in controls to 1.2±0.4 ml/min/kg (P<0.01) in cirrhotics, demonstrating impaired elimination of caffeine in cirrhosis.Supported by the Medical Research Service of the Veterans Administration and NIH Grant AA00267.     

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.     

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。     

Effects of ranitidine on plasma clearance of indocyanine green in patients with liver cirrhosis

The effects of ranitidine on plasma clearance of ICG were investigated in 68 cirrhotic patients (9 were positive for HBsAg, 33 were alcoholics and 26 had cryptogenic cirrhosis). The ICG clearance test was performed before and after ranitidine administration. In 31 patients treated with ranitidine (150 mg perorally), the plasma ICG clearance were 233.6 +/- 20.4 ml/min (mean +/- S.E.) and 239.2 +/- 20.5 ml/min before and after ranitidine, respectively. In the 37 treated with intravenous ranitidine 50 mg, the corresponding values were 205.4 +/- 17.7 ml/min and 206.4 +/- 17.9 ml/min. There was no significant change in the plasma clearance of ICG or the elimination rate constant after ranitidine administration. Even in patients with decompensated liver cirrhosis, no significant change was demonstrated in the plasma ICG clearance after ranitidine. These results led to the conclusions that ranitidine does not reduce the hepatic blood flow and that it is a safe and useful drug for the treatment of gastrointestinal tract bleeding in patients with liver cirrhosis.     

Visual attention orienting in liver cirrhosis without overt hepatic encephalopathy

The attention system in patients with liver cirrhosis has not yet been fully investigated. We therefore studied visual attention orienting in cirrhotic patients without overt hepatic encephalopathy. Seventy cirrhotic patients without overt hepatic encephalopathy (aged 57±10 yr., mean±s.d.) and 55 controls (aged 49±12 yr.) were enrolled. Visual attention orienting was evaluated by a computerized neuropsychological test. The Reitan A test, commonly used to detect subclinical hepatic encephalopathy, was used to evaluate mental performance. Psychometric test scores were reduced in cirrhotics compared to controls (attention test: neutral condition =495±149 vs. 401±98 msec; valid condition =434±110 vs. 398±84 msec; invalid condition =485±146 vs. 392±110 msec; p<0.001; Reitan A test =52±20 vs. 35±11 sec., p<0.001). The attention effect of the cue was found both in controls and cirrhotics; however, it was significantly higher in cirrhotics than in controls (61±111 vs. 33±41 msec; p<0.002). The attention effect was directly correlated with Reitan A test (r=0.23, p=0.05) in cirrhotics. In conclusion, in cirrhotic patients without overt hepatic encephalopathy, visual attention orienting was present and focusing to an indexed location had a higher effect on reaction time compared to controls, possibly because of reduced basal arousal.     

Glucagon metabolism in normal subjects and in cirrhotic patients before and after portasystemic venous shunt surgery

The effect of portasystemic shunt surgery on basal immunoreactive glucagon (IRG) levels, metabolic clearance rate (MCR) and t 1/2 for glucagon decay, and basal systemic delivery rate (BSDR) of glucagon was investigated in paired studies in ten cirrhotic subjects. The degree of hepatocellular dysfunction and extent of portasystemic venous shunting was also recorded. Basal IRG levels were highest in the post-shunt (mean +/- SEM, 382 +/- 73 pg/ml) as compared to the pre-shunt (213 +/- 27 pg/ml; P less than 0.05) cirrhotic and control (53 +/- 13 pg/ml; P less than 0.005) groups. The MCR of glucagon was similar in control (13.0 +/- 1.3 ml/kg/min) and pre-shunt cirrhotic patients (13.3 +/- 1.7 ml/kg/min) but was significantly (P less than 0.02) decreased in the post-shunt cirrhotics (7.6 +/- 1.3 ml/kg/min). The t 1/2 for glucagon decay was similar in the control and cirrhotic groups. The BSDR, an estimate of pancreatic A cell secretion, was increased four-fold (P less than 0.01) in the pre-shunt (3042 +/- 454 pg/kg/min) and post-shunt (2518 +/- 535 pg/kg/min) cirrhotic groups, as compared to controls (750 +/- 244 pg/kg/min). It is concluded that (a) in the presence of cirrhosis, the magnitude of portasystemic shunting is important in determining the degree of hyperglucagonaemia; (b) in preshunt cirrhotics raised basal IRG levels are principally due to A cell hypersecretion of glucagon whereas in post-shunt cirrhotics riased IRG levels reflect both A cell hypersecretion and delayed clearance of glucagon; and (c) acute shunting of splanchnic venous blood away from the liver reduces the clearance of glucagon, suggesting that, in man, the liver contributes to the clearance of circulating glucagon.     

Antipyrine,Oxazepam, and Indocyanine Green Clearance in Patients with Chronic Pancreatitis and Healthy Subjects

Background: Hepatic drug metabolism was examined in patients with chronic pancreatitis and healthy controls by using a cocktail design with three different model compounds: antipyrine to express phase-I oxidation, oxazepam to express phase-II conjugation, and indocyanine green (ICG), a high-clearance compound. Methods: Eight patients with chronic pancreatitis and seven healthy controls participated. Patients were diagnosed by the presence of typical morphologic changes of the pancreas on imaging and had a moderately but significantly reduced exocrine function and no or only slight impairment of the glucose tolerance. No one had a history or clinical signs of liver disease. Clearance of the three model compounds was estimated after the administration of 1 g antipyrine and 15 mg oxazepam orally and a bolus of indocyanine green, 0.5 mg/kg body weight, intravenously. Results: The antipyrine clearance and ICG clearance were significantly decreased in the patients compared with the controls (mean, 27.2 ml/min; 95% confidence interval (CI), 19.4-35; versus 46.2 ml/min; 34.7-58.7, and 501 ml/min; 401-601, versus 771 ml/min; 677-865 (P &lt; 0.05), respectively). The oxazepam clearance did not differ significantly between the two groups (181 ml/min (145-217) versus 178 ml/min (152-204)). The model drug clearance ratios between the patient and control clearances showed decreased values for antipyrine and ICG compared with the oxazepam data (0.59 and 0.65 versus 1.02, respectively). Patients and controls were characterized by a body weight of 58.2 kg (53.1-63.3) and 83.4 kg (72.7-94.1), respectively, and a body mass index (BMI) of 19.6 kg/m² (17.9-21.3) versus 25.9 kg/m² (23.4-28.4) (P &lt; 0.05 for both). Conclusions: Patients with chronic pancreatitis characterized by a moderately reduced exocrine function and absence of diabetes mellitus and overt liver disease had a decreased antipyrine oxidation and ICG clearance, whereas no difference was seen in oxazepam conjugation when compared with healthy volunteers. In chronic pancreatitis the hepatic phase-I oxidation is reduced compared with the phase-II conjugation, as shown by the model drug clearance ratios. The clearance of ICG was also affected, pointing at a reduced hepatic plasma flow, provided that the hepatic extraction fraction is normal for these patients.     

Hemodynamic characterization in experimental liver cirrhosis induced by thioacetamide administration

Systemic and splanchnic hemodynamics in experimental liver cirrhosis in rats induced by thioacetamide were evaluated by the radioactive microsphere method. Cardiac output and regional blood flow were measured in conscious and anesthetized control and cirrhotic rats. The conscious thioacetamide-treatment rats had hyperdynamic circulation with an increased cardiac index (300±10 vs 258±3 ml/min/kg body weight,P<0.001) and increased portal venous inflow compared with the controls (64.60±2.4 vs 48.39±0.88 ml/min/kg body weight,P<0.001). Under pentobarbital anesthesia, the hyperdynamic circulation of the cirrhotic rats was maintained, with an increased cardiac index (276±7 vs 229±5 ml/min/kg body weight,P<0.001) and increased portal venous inflow compared with the controls (72.47±3.0 vs 54.08±1.2 ml/min/kg body weight,P<0.001). Portal pressure, portal venous resistance, and portal systemic shunting increased significantly while splanchnic arterial resistance decreased significantly in cirrhotic rats. Thioacetamide-induced cirrhosis is a useful model for the hemodynamic study of portal hypertension and remains useful in hemodynamic studies in the basal state under pentobarbital anesthesia.     

The Portal Component of Hepatic Perfusion Measured by Dynamic CT (An Indicator of Hepatic Parenchymal Damage)

CT can measure absolute hepatic arterial andportal venous perfusion; pilot data suggests these areraised and lowered, respectively, in cirrhosis. Thisstudy examined the value of functional CT in assessing cirrhosis, using the prothrombin ratio (PTR) asa marker for hepatic parenchymal damage. Twenty subjectswith viral-induced cirrhosis (11 men and 9 women; 55.41± 7.86 years) and 14 controls (8 men and 6 women; 48.36 ± 17.67 years) werestudied. A single section through the liver was scannedafter bolus intravenous injection of 40 ml ioversol 320mgI/ml. Hepatic arterial and portal perfusion wasmeasured using a previously described technique. Hepaticportal perfusion was decreased in patients (0.66± 0.21 ml/min/ml) compared with controls (1.11± 0.23 ml/min/ml; P < 0.0001). A strongcorrelation was seen between PTR and portal perfusion (r =0.662, P = 0.0038) in cirrhotics. Hepatic arterialperfusion did not differ between patients (0.088± 0.082 ml/min/ml) and controls (0.091 ±0.067), and did not correlate with PTR. In conclusion,portal perfusion is reduced in cirrhosis, and thisreduction correlates with PTR. It could thus be used asa marker of hepatic parenchymal damage. This technique may be useful in the follow-up of chronic liverdisease, potentially reducing the need for serial liverbiopsy.     

A comparison between antipyrine and aminopyrine blood clearances.

The purpose of this study was to investigate the relationship between two quantitative liver functions, that is, antipyrine blood clearance and aminopyrine blood clearance, in normal subjects and in patients with liver cirrhosis. The mean blood clearances of antipyrine and aminopyrine in cirrhotic patients (0.220 +/- 0.085 ml/min/kg and 1.13 +/- 0.56 ml/min/kg; n = 64) was 50% and 38% of that of normal subjects (0.440 +/- 0.110 ml/min/kg and 2.95 +/- 0.59 ml/min/kg; n = 11). While no significant correlation was demonstrated between these two values in normal subjects (n = 11, r = -0.107, p greater than 0.10), a strong positive correlation was observed between antipyrine and aminopyrine blood clearances in cirrhotic patients (n = 64, r = 0.846, p less than 0.001). These results suggest that both antipyrine and aminopyrine blood clearances may be valuable indicators for assessing the total hepatic functioning mass in cirrhotics.     

Effects of transjugular intrahepatic portasystemic shunt (TIPS) on splanchnic and systemic hemodynamics,and hepatic function in patients with portal hypertension

The purpose of this study was to evaluate the short-term splanchnic and systemic hemodynamics and hepatic function after TIPS creation. Fifteen cirrhotics with portal hypertension underwent TIPS placement for treatment of variceal hemorrhage, and extensive hemodynamic studies including right heart catheterization, portal pressure measurement, hepatic blood flow, and indocyanine green (ICG) clearance were performed before and 1 month after the procedure. Self-expandable metal stents (Strecker 11 mm diameter) were placed in all cases. Portasystemic gradient significantly diminished (18.3±4.2 vs 8±2.8; 54%±18 mm Hg) after the technique, mainly due to a decrease in portal pressure, and remained stable in the final study. Cardiac output and mean arterial pressure increased (6.2±1.4 vs 8.2±1.8 liters/min, 80.1±10.1 vs 91±11.2 mm Hg, respectively), and a decrease in systemic vascular resistance was registered (1018±211 vs 872±168 dyne/sec/cm⁵); the hepatic blood flow and ICG clearance also decreased significantly (1.5±0.7 vs 0.68±0.2 liters/min, 0.4±0.2 vs 0.24 ±0.06 liters/min, respectively). There was an increase in the preload at the final study, as evidenced by a marked increase in right atrial (3.1±1.6 vs 4.35±2.2 mm Hg, +15%,P<0.05), pulmonary arterial (12.2±2.4 vs 15.9±3.2 mm hg, +31.8%,P<0.001), and wedge pulmonary arterial pressures (6.9±2.4 vs 9.8±3.1 mm Hg, +53%,P<0.001). These results suggest that TIPS worsens the hyperdynamic syndrome associated to portal hypertension. Therefore, in patients with cardiac insufficiency, this procedure should be evaluated. TIPS also decreases the hepatic blood flow, inducing a mild worsening in liver function.Funded in part by the Fondo de Investigaciones Sanitarias de la Seguridad Social, grant 94/0240.     

The implication of hyperglucagonemia and -insulinemia in liver cirrhotics

Glucagon and insulin metabolism was studied in 9 cirrhotic patients and 4 non-cirrhotic controls. Net output of glucagon and insulin into portal circulation was calculated from difference between portal venous and systemic arterial concentrations multiplied by portal plasma flow. Metabolic clearance rate was also calculated as the ratio of the output to systemic concentration. Portal blood flow was measured by the continuous local thermodilution method. The results were as follows: 1) Arterial glucagon concentration was elevated in liver cirrhotics compared with non-cirrhotic-controls. Glucagon output in cirrhotics was higher than in controls [46.3 +/- 11.8 vs. 13.2 +/- 2.5 ng/min (mean +/- SEM), p less than 0.05]. Metabolic clearance rate of glucagon was not significantly different between the two groups. 2) There was a significant correlation between glucagon output and portal venous concentration of norepinephrine (r = 0.625, p less than 0.05). 3) Insulin levels in systemic arterial blood were higher in cirrhotic patients than non-cirrhotic subjects. Insulin output was not significantly different between the two groups, however, metabolic clearance rate of insulin in cirrhotics was reduced in comparison with the controls (274.5 +/- 44.3 vs. 557.7 +/- 108.6 ml/min, p less than 0.05).     

Antipyrine, oxazepam, and indocyanine green clearance in patients with chronic pancreatitis and healthy subjects.

BACKGROUND: Hepatic drug metabolism was examined in patients with chronic pancreatitis and healthy controls by using a cocktail design with three different model compounds: antipyrine to express phase-I oxidation, oxazepam to express phase-II conjugation, and indocyanine green (ICG), a high-clearance compound. METHODS: Eight patients with chronic pancreatitis and seven healthy controls participated. Patients were diagnosed by the presence of typical morphologic changes of the pancreas on imaging and had a moderately but significantly reduced exocrine function and no or only slight impairment of the glucose tolerance. No one had a history or clinical signs of liver disease. Clearance of the three model compounds was estimated after the administration of 1 g antipyrine and 15 mg oxazepam orally and a bolus of indocyanine green, 0.5 mg/kg body weight, intravenously. RESULTS: The antipyrine clearance and ICG clearance were significantly decreased in the patients compared with the controls (mean, 27.2 ml/min; 95% confidence interval (CI), 19.4-35; versus 46.2 ml/min; 34.7-58.7, and 501 ml/min; 4014601, versus 771 mU/min; 677-865 (P < 0.05), respectively). The oxazepam clearance did not differ significantly between the two groups (181 ml/min (145-217) versus 178 ml/min (152-204)). The model drug clearance ratios between the patient and control clearances showed decreased values for antipyrine and ICG compared with the oxazepam data (0.59 and 0.65 versus 1.02, respectively). Patients and controls were characterized by a body weight of 58.2 kg (53.1-63.3) and 83.4 kg (72.7-94.1), respectively, and a body mass index (BMI) of 19.6 kg/m2 (17.9-21.3) versus 25.9 kg/m2 (23.4-28.4) (P < 0.05 for both). CONCLUSIONS: Patients with chronic pancreatitis characterized by a moderately reduced exocrine function and absence of diabetes mellitus and overt liver disease had a decreased antipyrine oxidation and ICG clearance, whereas no difference was seen in oxazepam conjugation when compared with healthy volunteers. In chronic pancreatitis the hepatic phase-I oxidation is reduced compared with the phase-II conjugation, as shown by the model drug clearance ratios. The clearance of ICG was also affected, pointing at a reduced hepatic plasma flow, provided that the hepatic extraction fraction is normal for these patients.     

Nitric oxide in ischaemic acute renal failure of streptozotocin diabetic rats

Summary Changes in nitric oxide (NO) levels were determined in ischaemic acute renal failure in streptozotocin-induced diabetes mellitus rats. Two weeks after streptozotocin administration and immediately after right nephrectomy, the left renal artery was occluded for 60 min. Similar procedures were carried out in non-diabetic rats. The nitrite (NO₂) + nitrate (NO₃) levels were measured in plasma and urine. The effects of chronic oral supplementation with l-arginine and an NO synthase inhibitor (N-omega-nitro-l-arginine) were also studied in both diabetic and non-diabetic rats before and after renal artery clamping. The rats with diabetic acute renal failure had a much lower creatinine clearance (90±22 l · min^–1 · 100 g body weight^–1, p<0.005), and higher fractional excretion of sodium (FENa)% (10.90±4.2, p<0.001) and protein excretion (2078±69 g/ml creatinine clearance, p<0.001) compared with the respective values in the non-diabetic groups (163±30; 1.46±86; 453.3±31). The plasma and urine NO₂ + NO₃ levels were significantly higher in the untreated diabetic rats compared with the untreated normal rats before ischaemia (p<0.001). The ischaemic acute renal failure in non-diabetic rats increased the plasma and urinary NO₂ + NO₃ excretion after ischaemia. The urinary excretion of these metabolites decreased significantly and their plasma levels remained unchanged in the ischaemic diabetic rats. The l-arginine administration resulted in a small but significantly higher creatinine clearance after clamping in the non-diabetic rats. The NO synthase inhibitor caused deterioration in renal function in all ischaemic and non-ischaemic groups. In summary, the greater vulnerability to ischaemia of the diabetic kidney seems to be associated with both impaired response to and impaired production of NO.Abbreviations IARF Ischaemic acute renal failure - STZ streptozotocin - NOSi nitric oxide synthase inhibitor - ARF acute renal failure - Ccr creatinine clearance - FENa% fractional excretion of sodium     

Inhibition of liver metastasis in mice by blocking hepatocyte lectins with arabinogalactan infusions and d-galactose

Summary According to our hypothesis, organ-specific lectins (e.g., the d-galactose-specific hepatic binding protein) play an important role in the organ location of metastatic malignant cells. The rapid clearance and uptake by the liver of tritiated -acid-(asialo)glycoprotein from the circulation of Balb/c mice was markedly delayed after preinjection of d-galactose or arabinogalactan. The preinjection (1h) and regular application (for 3 days after tumor cell inoculation in Balb/c mice) of the receptor blocking agents d-galactose and arabinogalactan prevented the settling of sarcoma L-1 tumor in the liver completely, but did not influence the settling in the lung. Other galactans, dextrans, and phosphate-buffered saline showed no effect. Therefore, when lectins were blocked with competitive-specific glycoconjugates, colonization was prevented.     

Clinical applicability of shortenedd-Xylose breath test for diagnosis of intestinal malabsorption

Urinary and/or plasmaticd-xylose tests are broadly used in clinical practice for the diagnosis of intestinal malabsorption. A 5-hr hydrogen breath test (H₂ BT) has also proven useful. Our goal was to determine whether a shorter, hence more efficient, 3-hr test would perform as well as the 5-hr test. We studied 33 patients with proven malabsorption, 44 patients with irritable bowel syndrome (IBS), and 27 healthy subjects. Each individual ingested 25 g ofd-xylose, and alveolar breath samples were obtained thereafter at 30 min intervals for 5 hr. Breath samples were analyzed for H₂ by gas chromatography. Individual peak delta changes and area under the curve (AUC) were calculated. Simultaneously, the 5-hr cumulative urinary excretion ofd-xylose was measured by colorimetry. Results of 5-hr tests were compared with those of the first 3 hrs. In the malabsorption group, the 5-hr test showed a markedly enhanced production of H₂ relative to healthy controls (delta: 60.7±6.4 vs 7.7±1.5 and AUC: 8465.0±985.4 vs 393.2±232.6,P<0.001 for both) and a reduced urinary excretion ofd-xylose (2.8±0.3 g/5 hr vs 6.3±0.2,P<0.001). Results in IBS patients did not differ from those in healthy controls. Three-hour analysis also reflected an enhanced production of H₂ in the malabsorption group (delta: 45.4±6.4 and AUC: 3700.0±545.6,P<0.001 vs healthy controls). Correlation between 3-hr and 5-hr tests was significant in healthy controls (r=0.9), IBS (r=0.9), and malabsorption (r=0.8). The sensitivity of the 3-hr test was lower than of the 5-hr test (0.72 vs 0.91). The loss of sensitivity of the 3-hr test was attributed to a delayed appearance of the delta peak in the malabsorption group. In conclusion, the H₂ breath test withd-xylose is a useful test for the diagnosis of the intestinal malabsorption, but requires a 5-hr monitoring period to be reliable.     

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)     

Plasma osteocalcin levels in liver cirrhosis.

Osteocalcin, a recently identified protein, is produced by osteoblasts in the bone tissue. Its plasma level is a good marker of bone metabolism and is reduced in the presence of 'osteodystrophia', commonly found in cholostatic liver diseases. We assayed plasma osteocalcin levels in 20 cirrhotic patients and compared the values with those of 22 healthy controls. In the same patients we also measured the liver function, clotting and mineral metabolism indexes and calcitonin plasma levels. Osteocalcin levels were significantly lower in liver disease patients than in controls (5.53 ng/ml S.D. 2.57 vs 7.79 ng/ml S.D. 2.23; p less than 0.01) and calcitonin plasma levels were much higher in cirrhotics (130.18 pg/ml S.D. 212.30 vs 28.9 pg/ml S.D. 13.09; p less than 0.05). We think that the low osteocalcin levels observed in cirrhotics may be a consequence of "hepatic osteodystrophy" due to low vitamin D and calcium plasma levels.     

Arterial hypertension in cirrhosis: arterial compliance, volume distribution, and central haemodynamics

BACKGROUND AND AIMS: Arterial hypertension is a common disorder. Hyperkinetic circulation and reduced effective volaemia are central elements in the haemodynamic dysfunction in cirrhosis. The aim of the present study was to investigate whether cirrhotic patients with arterial hypertension are normokinetic and normovolaemic or whether they reveal the same circulatory dysfunction as their normotensive counterparts. MATERIAL AND METHODS: Thirty three patients with arterial hypertension were identified among 648 patients with cirrhosis: 14 in Child class A, 12 in class B, and seven in class C. Controls were 130 normotensive cirrhotic patients, 19 controls with normal arterial blood pressure and without liver disease, and 16 patients with essential arterial hypertension. All groups underwent haemodynamic investigation with determination of cardiac output (CO), plasma volume (PV), central blood volume (CBV), hepatic venous pressure gradient (HVPG), hepatic blood flow (HBF), arterial compliance (AC), and systemic vascular resistance (SVR) in the supine position. RESULTS: Liver function, as evaluated by galactose elimination capacity, indocyanine green clearance, HBF, and Child score, was significantly better in hypertensive cirrhotics than in their normotensive counterparts (p<0.05-0.01) but portal pressure was similar (HVPG 13 v 15 mm Hg; NS). AC was significantly lower and normal in the arterial hypertensive cirrhotic group (1.07 v 1.39 mm Hg/ml; p<0.02) and SVR was significantly higher and normal (1475 v 1020 dynxs/cm5; p<0.01). Arterial hypertensive cirrhotic patients were hyperdynamic (CO 6.80 v 7.14 l/min; NS) and central hypovolaemic (CBV 19.8 v 20.6 ml/kg; NS), as were normotensive patients, but differences were found in relation to arterial blood pressure. Whereas arterial pressure was inversely correlated with CO, PV, and Child score in the normotensive group (p< 0.01), the same correlations were either direct or insignificant in arterial hypertensive cirrhotics. CONCLUSION: Arterial hypertensive cirrhotic patients are hyperkinetic and central hypovolaemic, in common with their normotensive counterparts, but vasodilatation is reduced and regulation of arterial blood pressure may be less deranged.