Preoperative assessment of hepatic function: Utility of a new convenient two-compartment model analysis using galactosyl human serum albumin scintigraphy

BACKGROUND AND AIM: Preoperative hepatic function was evaluated using technetium-99 m-diethylenetriaminepenta-acetic acid-galactosyl-human serum albumin (Tc-GSA) and a scintillation camera to detect hepatic Tc-GSA uptake by the asialoglycoprotein receptor. METHODS: Sixty-two preoperative patients with liver cancer, including hepatocellular and cholangiocellular carcinomas, were studied, using two-parameter two-compartment model analysis. This model is simpler than either the three- or five-compartment model, both of which are accurate but which require complicated analysis and enormous calculation. The parameters k1 and k2 represented the transfer rate constant from the blood to the liver and from the liver to the blood, respectively. We calculated k1, k2, and k1/k2 from time-radioactivity curves of the heart and liver as well as VLmg, which represented the maximal amount of Tc-GSA in the liver. RESULTS: The results were compared to those of conventional liver function analysis using Tc-GSA (the index of blood clearance (HH15) and the receptor index (LHL15)) or indocyanine green (ICGR15). Both HH15 and LHL15 were significantly correlated with k1, k1/k2, and VLmg. In addition, they closely correlated with the results of ICGR15 and some serum hepatic function tests (aspartate aminotransferase, choline esterase, albumin, platelet). The pathological grading for liver cirrhosis also correlated with k1, k1/k2, and VLmg. From a clinical point of view, VLmg had a significant correlation with the Child-Pugh score. CONCLUSIONS: These results suggest that this new compartment analysis will be useful in evaluating liver function, as it is accurate, simple and convenient.     

Evaluation of gallbladder function before and after gastrectomy using a double-isotope method

The motor function of the gallbladder after partial distal gastrectomy for gastric carcinoma (Billroth-I reconstruction) and its relationship to the motor function of the stomach was investigated using a double-isotope method. In this method, [^99mTc]N-54-pyridoxyl-5-methyltryptophan ([^99mTc]PMT) was utilized as a tracer for the biliary tract and [¹¹¹In]diethyl-triaminopontacetic acid ([¹¹¹In]DTPA) mixed with a liquid test meal was used as a tracer for the digestive tract. Gastric emptying half-time (GET1/2) was measured, since this was used historically as the physiologic indicator of gallbladder contractile stimulus. The volume of test meal that emptied from the stomach into the duodenum per minute (VOL/MIN) was measured, as was the gastric emptying duration (GED). A series of gallbladder emptying phenomena were analyzed using three different criteria: gallbladder emptying half-time (GBET1/2), retention rate of bile in the gallbladder (RR), and the start of gallbladder bile ejection into the duodenum after ingestion (TL: time lag). While GET1/2 was reduced (P<0.01) and VOL/MIN was increased (P<0.01) after gastrectomy, GED was shortened remarkably (P<0.01). GBET1/2 showed no significant change, RR increased (P<0.05), and TL was prolonged (P<0.01). The postoperative dysfunction of the gallbladder was caused by the short and intense stimulus on the biliary tract during the duodenal phase and by intraoperative injury to the innervation of the gallbladder. In particular, the hepatic branch of the left vagus nerve was injured during the right paracardiac lymph node dissection performed as a component of the radical gastrectomy.     

Evaluation of myocardial viability in asymptomatic patients early after infarction with perfusion/metabolism single-photon-emission computed tomographic imaging and dobutamine echocardiography

OBJECTIVE: To study the impact of detection of viability of myocardium in asymptomatic patients early (3-10 days) after Q-wave myocardial infarction on segmental recovery of left ventricular function after elective revascularization. METHODS: Patients were studied with low-dose dobutamine echocardiography (LDDE) and single photon-emission computed tomography with 99mTc sestamibi and [18F]-fluorodeoxyglucose (FDG) imaging. Viability of myocardium was defined as detection of improvement in segmental thickening of left ventricle by LDDE (versus baseline echocardiographic data), uptake of 99mTc sestamibi > 50% of maximum counts, uptake of [18F]-FDG > 50% of maximum normal, combined uptake of 99mTc sestamibi or [18F]-FDG > 50% of normal maximum, uptake of [18F]-FDG > 50% or mismatched pattern (uptake of [18F]-FDG greater than that of 99mTc sestamibi). Functional recovery was defined as improvement of segmental thickening of left ventricle detected at follow-up 8 weeks after infarction (versus baseline resting echocardiographic data). Interpretation of the tests was blinded with respect to the angiographic data and the results of the alternative method. RESULTS: In total 18 patients with 133 left-ventricle segments with abnormal contractile function at baseline were analysed; 29% were hypocontractile and 71% were noncontractile. Examination with LDDE showed that 18% of the segments had normal contractility and 26% were hypocontractile; the respective percentages were 29 and 28% according to follow-up resting echocardiography. Radionuclide tests for viability of myocardium gave positive results in 57% (uptake of [18F]-FDG > 50%) and 62% (uptake of 99mTc sestamibi > 50%) of cases. With respect to segmental analysis, there was a 25-27% positive concordance, a 24-27% negative concordance, and a 48-50% discordance between the LDDE and the radionuclide definitions of viability of myocardium. Additionally, there was no significant difference among sensitivities and specificities for the definitions of viability. The sensitivity was 69% for the uptake of 99mTc sestamibi > 50% criterion, and the highest specificity was 66% for the LDDE. Incorporation of imaging with [18F]-FDG into the analysis yielded a marginally higher sensitivity of 71% for the criterion of uptake of [18F]-FDG or 99mTc sestamibi > 50%, versus imaging with the 99mTc sestamibi alone. CONCLUSION: LDDE was more specific and radionuclide imaging more sensitive for detection of viability of myocardium in asymptomatic patients early after infarction. Possibly defective myocardial metabolization of glucose in the period early after infarction and the specific LDDE protocol applied account for the limited benefit of these studies in terms of facilitating prediction of segmental functional recovery after revascularization in this clinical setting.     

Use of scintigraphy with 99mtechnetium galactosyl human serum albumin for staging of primary biliary cirrhosis and assessment of prognosis

BACKGROUND: Conventional models for prediction of survival in patients with primary biliary cirrhosis (PBC) are based on the results of blood tests and on the clinical condition, which may be affected by treatment. We evaluated the usefulness of hepatic receptor imaging with [99mtechnetium]-diethylenetriaminepentaacetic acid galactosyl human serum albumin (GSA) for the staging and prognosis of PBC without the need for reference to laboratory test results. METHODS: The subjects were 45 patients with PBC, 10 healthy subjects, 62 patients with chronic hepatitis and 144 patients with cirrhosis. Computer acquisition of gamma-camera data was started just before the injection of 185 MBq [99mTc]-GSA and was stopped 20 min later. Time-activity curves were generated from regions of interest (ROI) for the heart and liver. A receptor index was calculated by dividing the radioactivity of the liver ROI by that of the liver-plus-heart ROI 15 min after the injection. An index of blood clearance was calculated by dividing the radioactivity of the heart ROI 15 min after the injection by that of the heart ROI 3 min after the injection. RESULTS: The median receptor index was higher in patients with PBC than in those with cirrhosis. Among patients with PBC, the receptor index was lower in those with stage IV disease than in those in stages I, II or III. The index of blood clearance was lower in patients with PBC than in those with cirrhosis. Among patients with PBC, the index of blood clearance was higher in those with stage IV disease than in those in stages I, II or III. The receptor index was correlated significantly both to the risk score of the Mayo model and to the prognostic index of the Japanese model. The index of blood clearance was also correlated significantly to this score and prognostic index. CONCLUSIONS: Hepatic receptor imaging with [99mTc]-GSA is useful for the evaluation of hepatic functional reserve, staging of PBC and assessment of prognosis.     

Analysis of hepatic hemodynamics by a new method of per-rectal portal scintigraphy using 99mTcO4- (direct intramural administration of radioisotope)

To depict of porto-systemic collaterals clearly, and to analyze of hemodynamics of liver, we developed new method of per-rectal portal scintigraphy (direct intramural administration of 99mTcO4- by 23G needle). And we used this method in patient with liver diseases (acute hepatitis: 5, chronic hepatitis: 7, liver cirrhosis: 25 cases). From time activity curve of the liver and the heart, liver/heart ratio; index of porto-systemic shunt via inferior mesenteric vein (IMV) and first flow ratio(k); index of portal blood flow from IMV pathway/index of hepatic total blood flow were calculated. In our method, the images of portal vein, liver, heart, especially porto-systemic collaterals were visualized more clearly than enema methods. The liver/heart ratio was significantly lower in patients with liver cirrhosis than that in non-cirrhotic patients (p less than 0.01), which indicated that patients with liver cirrhosis had more porto-systemic collaterals than non-cirrhotic diseases. The k was more lower in liver cirrhosis than in acute hepatitis (p less than 0.01). And the k was also more lower in chronic hepatitis than in acute hepatitis (p less than 0.1), which indicated that portal blood flow via IMV reduced in early stage of chronic liver diseases. In conclusion, new method of per-rectal portal scintigraphy has more advantage for analysis of hepatic hemodynamics than enema methods.     

Imaging of vascular injury with 99mTc-labeled monoclonal antiplatelet antibody S12. Preliminary experience in human percutaneous transluminal angioplasty.

BACKGROUND. To evaluate the in vivo safety, biodistribution, and diagnostic accuracy of a monoclonal Fab' antibody (S12) that is specific for the platelet membrane glycoprotein (GMP-140) expressed during platelet activation at vascular injury sites, 11 peripheral percutaneous transluminal angioplasty (PTA) patients (age, 61 +/- 8 years) with severe vascular disease had serial 99mTcS12 radionuclide imaging at 5 and 90 minutes, 4-6 hours, and 20-24 hours after a total of 23 angiographically successful PTA procedures. No acute allergic reactions or hematologic toxicity occurred. METHODS AND RESULTS. The average PTA percent angiographic diameter stenosis (DS) at all 23 sites decreased from 85 +/- 12% to 12 +/- 11%, with a mean before-to-after-PTA change of 73 +/- 14% (p less than 0.01). The mean radionuclide image-derived ratio of 99mTc S12 activity in PTA versus contralateral non-PTA arterial segments for all angioplasty sites was 1.6 +/- 0.5. Vascular 99mTc S12 antibody activity was qualitatively evident in the majority (78%) of PTA sites at 4-6 hours after injection. 99mTc S12 target-to-background (muscle) ratio equaled 2.3 +/- 0.6 at PTA sites. Nine PTA sites (39%) had residual 99mTc S12 activity at 24 hours after injection (mean PTA site-to-contralateral artery ratio, 1.5 +/- 0.4). The mean vascular 99mTc S12 activity ratios in 10 procedurally complicated (defined as extensive dilation [greater than 2 cm] or grade I or greater arterial dissection) and 13 uncomplicated PTA segments were 1.9 +/- 0.5 versus 1.2 +/- 0.1, respectively (p less than 0.01). The associated before-to-after-PTA angiographic improvement was significantly less in procedurally complicated PTA sites (66 +/- 12% versus 80 +/- 12% DS; p less than 0.01). CONCLUSIONS. 99mTc S12 activity is significantly increased at angiographically patent PTA sites that are procedurally complicated and are associated with less significant before-to-after-PTA angiographic improvement. 99mTc S12 monoclonal Fab' antibody imaging permits noninvasive identification of local vascular platelet activation resulting from angioplasty balloon injury in humans.     

Transport of 3,5,3'-triiodothyronine into the perfused rat liver and subsequent metabolism are inhibited by fasting.

The effects of 48-h fasting on transport of T3 and subsequent metabolism in the isolated perfused rat liver were investigated. Tracer T3 disappearance curves from the recirculating medium consisted of a fast component (FC) and a slow component (SC). Using a two-compartment model, both transport [expressed as the fractional transport rate constant from medium to liver (k21)] and disposal of T3 were calculated. After fasting, k21, total metabolism, and metabolism corrected for differences in mass transfer were diminished, pointing to both decreased transport and metabolism, presumably caused by depletion of liver ATP. Concerning transport, it was shown that only transport into the intracellular liver compartment and not transport to the extracellular liver compartment was decreased after fasting. As for metabolism, T3 glucuronidation was diminished; T3 sulfation and subsequent deiodination were not affected. All mentioned decreased parameters normalized after the addition of a combination of insulin, cortisol, and/or glucose to the medium, possibly by (partially) restoration of cellular energy stores.     

Single photon emission computed tomography to determine effective hepatic blood flow and intrahepatic shunting

The noninvasive determination of effective hepatic blood flow, intrahepatic shunted blood flow, intrahepatic shunt index, and total hepatic blood flow was investigated by using the sequential single photon emission computed tomography. This method was performed for a period of 10 minutes following an intravenous injection of ^99mTc-(Sn)-N-pyridoxyl-5-methyltryptophan and a venous blood sampling. This study comprised 8 healthy volunteers, 16 patients with chronic hepatitis, and 33 patients with liver cirrhosis. The intrahepatic shunt index measured with this method coincided with the intrahepatic shunt index determined by catheterization, indicating the high reliability of this procedure. The effective hepatic blood flow in patients with liver cirrhosis was significantly lower than that in the healthy controls and the chronic hepatitis group. The intrahepatic shunted blood flow was significantly higher in patients with liver cirrhosis compared with the flow in healthy controls. The intrahepatic shunt index was also significantly higher in patients with liver cirrhosis compared with the index of healthy controls and those with chronic hepatitis. No substantial differences were noted in the total hepatic blood flow among the three groups. The effective hepatic blood flow, the intrahepatic shunted blood flow, and the intrahepatic shunt index, correlated with the serum albumin concentration, the serum cholinesterase level, and the plasma indocyanine green attenuation rate. From these results, it was concluded that the present procedure constitutes a reliable and effective method for the noninvasive determination of hepatic blood flows. Consequently, it will be of high clinical value for assessing the functional and the pathological alterations of the liver.     

Kinetics of lactate transport into rat liver in vivo

Lactate clearance by liver plays an important role in lactate homeostasis and in the development of lactic acidosis. The role of lactate delivery to liver as a limiting factor in hepatic uptake of lactate is unclear. Lactate delivery of mechanisms could be important if rates of lactate transport approximate rates of lactate metabolism by liver. The rates of lactate transport into liver have been determined in vitro with isolated liver cells and the results have been conflicting. Therefore, the present studies measure the rate of transport of [14C]-L-lactate, and its poorly metabolizeable stereoisomer, [14C]-D-lactate, into rat liver in vivo using a portal vein injection technique. The transport of [3H]-water and of [14C]-sucrose, an extracellular reference compound, were also studied. Portal blood flow was determined from the kinetics of [3H]-water efflux in liver and was 1.93 +/- 0.22 mL/min/g. The volumes of distribution of [14C]-L-lactate, and [14C]-sucrose were 1.31 +/- 0.22, 0.71 +/- 0.07, and 0.22 +/- 0.07 mL/g, respectively. The extraction of unidirectional influx of [14C]-L-lactate and [14C]-D-lactate by rat liver was 93% +/- 10% and 91% +/- 9%, respectively. The rate of lactate transport into rat liver in vivo, 1.8 mumols.min-1.g-1, is approximately twofold greater than the rate of lactate metabolism by rat liver reported in the literature. Therefore, lactate uptake by liver may not be limited by transport under normal conditions. However, conditions such as decreased portal blood flow, which slow lactate delivery to liver by 50% or more, could cause lactate uptake by liver to be limited by transport of circulating lactate.     

Separate analysis of asialoglycoprotein receptors in the right and left hepatic lobes using (99m)Tc-GSA SPECT in patients with acute hepatic damage.

The asialoglycoprotein receptor (ASGPR) is abundantly expressed on the sinusoidal surfaces of hepatocytes. However, regional expression and clinical significance of the ASGPR in acute hepatic damage is presently unknown. Our aim was to clarify the clinical significance of the regional expression of ASGPR in human livers with acute hepatitis (AH) and fulminant hepatic failure (FHF). Eighteen volunteers, 42 patients with AH and 10 with FHF were studied using a newly developed, conventional (99m)Tc-GSA SPECT analysis. Using Cantlie's line as a guide, ASGPR expression was analyzed separately in the right and left hepatic lobes, as well as in the whole liver, using novel indices (the liver uptake ratio [LUR] and liver uptake density [LUD], which reflect the amount and density of ASGPRs in the liver, respectively). Mean LUR and LUD values for the whole liver and the right and left lobes decreased in accordance with the severity of acute hepatic damage. In the FHF group, the reduction in LUR and LUD values in the right lobes was more significant than in the left lobes. The LUR and LUD values for the whole liver correlated well with hepatic functional reserve and total bilirubin levels. The right LUR and LUD values in particular correlated well with these parameters. A time-course observation of 13 patients with either AH or FHF revealed that the expression of ASGPRs in the right lobe recovered faster than in the left. We first evaluated the regional expression of AGSPRs by (99m)Tc-GSA SPECT analysis in both AH and FHF patients, which is a clinically useful and reliable indicator for assessing the severity of regional hepatic damage and evaluating regional liver regeneration.     

In vivo measurement of hepatic binding protein in chronic liver disease--validation as a measure of hepatic functional reserve]

[Tc-99m] Galactosyl-neoglycoalbumin (TcNGA) is a synthetic radiolabeled ligand specific to the hepatocyte receptor, hepatic binding protein (HBP), a specific receptor to serum asialoglycoprotein. A TcNGA study was performed on 34 humans: normal volunteers (7) chronic hepatitis (6), hepatic cirrhosis (8), and hepatocellular carcinoma superimposed on cirrhosis (13). Heart and liver time activity curves were obtained following intravenous injection of TcNGA (5 mCi, 1.82 x 10(-9) mol/kg). HBP concentration ([HBP]) was calculated by curve-fitting techniques using the nonlinear three compartment model, which includes biomolecular reaction between HBP and TcNGA. [HBP] values were compared with conventional liver function tests. [HBP] had a good correlation with prothrombin time (n = 34, r = 0.694, p = 0.0001) thrombotest (n = 34, r = 0.692, p = 0.0001), hepaplastin test (n = 26, r = 0.787, p = 0.0001), albumin (n = 34, r = 0.712, p = 0.0001), cholinesterase (n = 34, r = 0.801, p = 0.0001), ICGR15 (n = 33, r = 0.761, p = 0.0001), KICG (n = 30, r = 0.709, p = 0.0001), ICG Rmax (n = 12, r = 0.735, p = 0.0064) and Child-Turcotte classification score (n = 34, r = 0.819, p = 0.0001). We concluded that excellent correlations of [HBP] to conventional liver function tests suggest that in vivo receptor measurement via TcNGA kinetic analysis is a sensitive and promising method in the estimation of hepatic functional reserve in patients with chronic liver disease.     

Usefulness of [99mTC]MIBI and [18F]fluorodeoxyglucose for imaging recurrent medullary thyroid cancer and hyperparathyroidism in MEN 2a syndrome

We report the case of a MEN 2a patient with a history of medullary thyroid cancer (MTC) treated by total thyroidectomy, who presented an increasing calcitonin level, suggesting tumor recurrence. Conventional radiographic and radionuclide imaging failed to localize the responsible lesions. A planar and tomographic (SPECT) [99mTc]MIBI scan, performed in order to investigate a recent hyperparathyroidism localized a parathyroid adenoma and revealed an abnormal uptake in the left lateral neck region, corresponding to apparently banal lymph nodes on MRI. This abnormal uptake was also observed on a [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) study and was proven to be an uptake in MTC lymph nodes metastases as confirmed by histopathologic analysis. We conclude that, using an adequate acquisition protocol (i.e. SPECT), [99mTc]MIBI scan is potentially able to localize both parathyroid adenoma and recurrent MTC at one and the same time, particularly in case of non-diagnostic conventional imaging techniques. In this setting, the potential usefulness of FDG-PET is also discussed.     

Stereospecificity of triiodothyronine transport into brain, liver, and salivary gland: role of carrier- and plasma protein-mediated transport

The stereospecificity of T3 transport through the walls of the brain capillary, i.e. the blood-brain barrier (BBB), and the salivary gland capillary and through the hepatocyte plasma membrane was studied with a tissue-sampling single injection technique in rats. In the absence of plasma proteins, the ED50 of inhibition of the saturable transport of [125I]L-T3 through the BBB was 1 microM for unlabeled L-T3 and 9 microM for unlabeled D-T3. The brain extraction of [125I]D-T3, 5.9 +/- 0.1% (+/- SE), was about one third that of [125I]L-T3. Conversely, no saturable and no stereospecific T3 transport was observed for the salivary gland capillary, which, unlike the brain capillary, is porous. The hepatic extraction of T3 was minimally stereospecific in the absence of plasma proteins. In the presence of 5 g/dl bovine albumin, the fraction of circulating D- or L-T3 that was available for transport into liver (50-100%) was many-fold greater than the fraction that was free in vitro (approximately 2%); therefore, both D-T3 and L-T3 were available for uptake by liver from the circulating albumin-bound pool. This plasma protein-mediated transport of T3 is believed to represent a process of enhanced dissociation of T3 from the albumin-binding site, since the plasma protein per se is not significantly taken up by liver on a single pass. However, in the presence of 5 g/dl bovine albumin, the extravascular hepatic extraction of [125I]D-T3 (50 +/- 2%) was nearly half that for [125I]T3 (93 +/- 12%), although no significant difference in the in vitro binding of [125I]D-T3 and [125I]L-T3 to 5 g/dl bovine albumin was found with equilibrium dialysis. In addition, the isoelectric point of bovine albumin bound to [125I] L-T3 (5.1) was higher than that of bovine albumin bound to [125I] D-T3 (5.0), as determined by isoelectric focusing, which indicates that the surface of the bovine albumin molecule is slightly more positive when the protein binds L-T3 as opposed to D-T3. The isoelectric focusing and in vivo transport data together suggest that the interaction between the surfaces of the plasma protein and the hepatic microcirculation that is presumed to cause enhanced hormone dissociation from the protein-binding site is electrostatic in nature. These studies (1) show that the BBB thyroid hormone transport system is sharply stereospecific, and this property is probably a major factor underlying the low biological potency of D-T3 in brain.(ABSTRACT TRUNCATED AT 400 WORDS)     

In Vivo Estimates of Hepatic Binding Protein Concentration: Correlation with Classical Indicators of Hepatic Functional Reserve

Hepatic binding protein (HBP) is a hepatic cell surface receptor specific for asialoglycoprotein. In vivo estimates of HBP concentration ([HBP]) were compared to classical indicators for hepatic functional reserve to clarify the validity of [HBP] in estimating the hepatic functional reserve in 30 humans. Estimates of [HBP] were obtained based on kinetic analysis of liver and blood time-activity data resulting from the hepatic clearance of a single injection of technetium-99m galactosyl-neoglycoalbumin, which is a synthetic analog radioligand specific to HBP. Estimates of [HBP] ranged 0.054 to 0.720 microM. Estimates of [HBP] in normal volunteers were 0.668 +/- 0.050 microM, whereas that in liver cirrhosis were 0.188 +/- 0.112 microM. The difference between the mean values of [HBP] estimates was statistically significant (p = 0.0001). Good correlations were observed between [HBP] and prothrombin time (r = 0.625, p = 0.0002), serum albumin level (r = 0.687, p = 0.0001), serum cholinesterase level (r = 0.764, p = 0.0001), indocyanine green plasma disappearance rate (r = 0.602, p = 0.0024), and Child-Turcotte classification score (Pugh's modification) (r = -0.797, p = 0.0001). We concluded that excellent correlations of [HBP] with classical indicators for hepatic functional reserve suggest potential value of [HBP] as a sensitive measure of functioning hepatocyte mass.     

Intestinal permeability in gastrointestinal disorders

This study examined intestinal permeability in gastrointestinal disorders by measuring urinary recovery following oral administration of [99mTc]DTPA in 117 subjects. The mean percent of the ingested dose excreted in a 24-hr urine sample was 2.8 +/- 1.6% in 11 healthy controls, 10.8 +/- 10.2% (P less than 0.001) in 21 ulcerative colitis patients, 8.0 +/- 4.7% (P less than 0.001) in 35 Crohn's disease patients, 5.1 +/- 2.9% (P less than 0.01) in 17 patients with heterogeneous digestive disease diagnoses, and 3.2 +/- 4.7% (P greater than 0.05) in 33 patients with hepatobiliary diagnoses. Among ambulatory patients, Crohn's disease subjects, but not ulcerative colitis patients, had greater urinary recovery than the controls (P less than 0.05). The Crohn's disease activity index correlated positively with the radionuclide recovery in Crohn's subjects (r = 0.455, P less than 0.02). In a heterogeneous sample of subjects simultaneous ingestion of [99mTc]DTPA and [51Cr]EDTA produced urinary levels that were correlated positively (r = 0.556, P less than 0.001). Increased absorption of [99mTc]DTPA relative to [51Cr]EDTA, however, was noted in ulcerative colitis patients (P less than 0.05). In conclusion, increased intestinal permeability has been demonstrated by utilizing [99mTc]DTPA in Crohn's disease and ulcerative colitis patients. Although this observation appears to be a nonspecific indicator of injury, the test provides a simple objective means of establishing disease activity, which possibly may be utilized for therapeutic and investigative studies.     

Dual pathway clearance of 99mTc-DTPA from the bronchial mucosa

Many studies have reported clearance rates of 99mTc-DTPA from the alveolar epithelial surface, but few have measured clearance of this solute from the bronchial mucosa. Those that have attempted such measurements have discounted the possibility that 99mTc-DTPA may be removed from the bronchial airways by mucocilliary transport as well as by absorption through the epithelium. This study was designed to better approximate the rate of 99mTc-DTPA absorption across the bronchial epithelium by correcting the measurements of total 99mTc-DTPA clearance for mucus transport. On two separate study days, each normal, nonsmoking subject (n = 8) breathed an aqueous aerosol (2.0 microns MMAD, sigma g = 2.0) containing 99mTc bound to DTPA or human serum ablumin (HSA) (a relatively nonpermeable solute that is cleared only by mucus transport over the period of measured clearance) while seated in front of a gamma camera. Breathing pattern was standardized to produce a similar central deposition of particles on both study days. From measurements of retention versus time over a 1-h period, exponential rate constants (Ktot and Km) were determined for the clearance of 99mTc-DTPA and 99mTc-HSA, respectively. By modeling the airways as a single compartment with two possible routes of clearance, we determined the permeability rate constant, Kp, as Ktot minus Km. Results showed that mucus clearance (Km) accounted for two thirds of the total rate of 99mTc-DTPA clearance (Ktot) (mean Ktot = 0.00985, Km = 0.00698, and Kp = 0.00287/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Direct measurement of hepatic indocyanine green clearance with near-infrared spectroscopy: Separate evaluation of uptake and removal

We continuously measured hepatic absorbance of indocyanine green (ICG) using near-infrared (NIR) spectroscopy after intravenous bolus injection in rabbits. Hepatic ICG concentration was obtained by subtracting out the absorbance of hemoglobin and other pigments within the liver. Two exponential rate constants, the first reflecting the dye uptake from plasma to the hepatocytes, and the second representing the dye removal from the liver by cytoplasmic transport and biliary excretion, were determined by fitting the time-course curve of hepatic ICG concentration to a two-compartment model with irreversible transfer between the two compartments, as defined by the double-exponential equation: [ICG]_liver(t) = -A exp(-alpha t) + B exp(-beta t). The results showed that treatment with bilirubin, a competitive inhibitor of ICG uptake, caused a decrease in alpha. Treatment with either colchicine, which is toxic to microtubules, or with ouabain, an inhibitor of Na⁺,K⁺-ATPase, caused a decrease in beta. These results were compatible with the kinetic model. This new method was then used in liver-injured rabbits inflicted with hemorrhagic shock and ischemia-reperfusion, to show that the first rate constant is primarily affected by hepatic microcirculatory condition, and the second refers closely to parenchymal liver damage. In another series of partial liver ischemia- reperfusions, it was possible to simultaneously and separately monitor the ICG profiles of post-ischemic and nonischemic areas. Thus, the kinetic analysis of hepatic ICG concentration curves, as directly measured by NIR spectroscopy, led to the separate evaluation of different clearance process of ICG in the liver, suggesting the advanced utility as a comprehensive liver function test. (Hepatology 1996 Jan;23(1):137-44)     

Kinetic analysis of hepatobiliary transport of vincristine in perfused rat liver. Possible roles of P-glycoprotein in biliary excretion of vincristine.

Recent studies using bile canalicular membrane vesicles have suggested that P-glycoprotein may play a role in excreting some anticancer drugs from the liver to the bile. At steady state after a continuous single-pass perfusion of a tracer concentration of [3H]vincristine in the rat liver, the extraction ratio was approximately 0.6, and 70% of the extracted drug was excreted into the bile mostly in unchanged form. The liver/perfusate and bile/liver unbound concentration ratios obtained after correction for intracellular binding and the inside-negative membrane potentials and/or pH difference between the inside and outside of the cells, were approximately 2-3 and 160-280, respectively, suggesting a highly concentrated biliary excretion process. We also examined the effects of verapamil, a P-glycoprotein-related transport inhibitor in cancer cells, on the hepatobiliary transport of [3H]vincristine. Verapamil 50 microM in the perfusate caused a decrease in the biliary excretion rate of [3H]vincristine, whereas [14C]taurocholate (reference compound) remained constant. In contrast, the hepatic uptake rate of [3H]vincristine exhibited minimum reduction, suggesting that verapamil selectively inhibited the biliary excretion of [3H]vincristine at the canalicular membrane. The fact that verapamil had little effect on the initial velocity of [3H]vincristine uptake by isolated hepatocytes also supports the above findings. Since the effect of 150 microM verapamil in the perfusate was not selective for vincristine, the biliary excretion rates of both compounds ([3H]vincristine, [14C]taurocholate) were reduced by this concentration of verapamil. In conclusion, the concentrative excretion of vincristine into the bile and its selective inhibition by a moderate concentration of verapamil provide indirect evidence for the contribution of P-glycoprotein to the biliary excretion of vincristine in a perfused rat liver system.     

The glycogenic effects of placental lactogen and growth hormone in ovine fetal liver are mediated through binding to specific fetal ovine placental lactogen receptors

To examine the relative roles of placental lactogen (PL) and GH in fetal metabolism, we have examined the effects of ovine PL (oPL), ovine GH (oGH), and ovine PRL (oPRL) on glycogen metabolism in cultured ovine fetal hepatocytes and have examined the binding of these hormones to hepatic membranes from fetal and neonatal lambs. In ovine fetal hepatocytes, oPL (150 ng/ml-20 micrograms/ml) stimulated dose-dependent increases in [14C]glucose incorporation into glycogen (18-167%) and total cellular glycogen content (10-69%). oGH and oPRL also stimulated glycogen synthesis in fetal hepatocytes, but the potencies of these hormones were only 12% and 4% that of oPL. The dose-response curves of the three hormones were parallel, and their maximal effects were identical, suggesting a common mechanism of action. In hepatic membranes from fetal lambs, the maximal specific binding of [125I]oPL was 26.3% while the maximal specific binding of [125I]oGH was only 0.9-1.5%. The binding of [125I]oPL was saturable and reversible and varied with incubation time and temperature. Unlabeled oPL (1 ng/ml-5 micrograms/ml) caused a dose-dependent inhibition of the binding of [125I]oPL to fetal hepatic membranes, with half-maximal displacement of [125I]oPL by 5-7 ng unlabeled oPL/ml. oGH and oPRL caused parallel displacement of [125I]oPL, but with potencies only 2% and 0.1% that of oPL. Scatchard analysis of oPL dose-response curves indicated that the hormone bound to a single class of receptors with a dissociation constant of 1.1 X 10(-10) M. The maximal specific binding of [125I]oGH to hepatic membranes of neonatal lambs (20.1%) greatly exceeded the binding of oGH to fetal hepatic membranes. In addition, the potency of oGH in competing for [125I]oPL binding sites in neonatal liver greatly exceeded the potency of oGH in competing for [125I]oPL binding sites in fetal liver. Although the biological effects of both oPL and oGH in postnatal subprimate tissues may be mediated through binding to nonprimate GH receptors, the results of these studies suggest that the glycogenic effects of oPL in ovine fetal liver are mediated through binding to specific fetal oPL receptors. The relatively weak biological effects of oGH and oPRL in ovine fetal liver appear to be mediated through the binding of the hormones to fetal oPL receptors. The presence of specific, high affinity PL receptors in ovine fetal tissues provides a mechanism whereby oPL may function as a GH in the ovine fetus.     

Hepatic trapping of red cells in canine endotoxin shock: a variable phenomenon after splenectomy

We studied in 20 splenectomised dogs the incidence of early intravascular hepatic pooling after administration of E. coli endotoxin. Autologous red cells were labelled in vitro with 99mTc. Bloodpool imaging and haemodynamic measurements were performed simultaneously. Changes in hepatic red cell volume were estimated from alterations in hepatic activity. In 10 dogs, hepatic red cell activity increased considerably (156 to 359% of the basal value). In the remaining animals the hepatic activity did not change markedly or even decreased. The decline in arterial pressure and cardiac output seemed more pronounced in dogs with clear evidence of hepatic pooling. However no significant differences in absolute haemodynamic values could be demonstrated between dogs with and without pooling. It is concluded that an hepatic outflow block is not a constant feature of canine endotoxin shock. Absolute haemodynamic values do not depend on the presence of an outflow block. Thus the presence of hepatic pooling need not make the canine model inappropriate for studies on human sepsis.