Hepatic Reticuloendothelial Function Research Articles

In vivo imaging of hepatic neutrophil migration in severe alcoholic hepatitis with 111In-radiolabelled leucocytes.

The study’s aim was to image severe alcoholic hepatitis (SAH) using 111In-labelled leucocytes with two objectives in mind: firstly for non-invasive diagnosis and secondly to provide a platform for experimental therapies aiming to inhibit intrahepatic neutrophil migration. 111In-leucocyte scintigraphy was performed 30 min and 24 h post-injection in 19 patients with SAH, 14 abstinent patients with alcohol-related cirrhosis and 11 normal controls. Eleven with SAH and seven with cirrhosis also had 99mTc-nanocolloid scintigraphy. Change in hepatic 111In radioactivity was expressed as decay-corrected 24 h:30 min count ratio and, in SAH, compared with histological grading of steatohepatitis and expression of granulocyte marker, CD15. Hepatic microautoradiography on biopsy specimens obtained 24 h post-injection of 111In-leucocytes was performed in one patient. Median 24 h:30 min hepatic 111In activity ratio was higher in SAH (2.5 (interquartile range (IQR): 1.7–4.0) compared with cirrhotics and normal controls (1.0 (0.8–1.1) and 0.8 (0.7–0.9) respectively, P<0.0001). In SAH, it correlated with CD15 expression (r = 0.62, P=0.023) and was higher in marked compared with mild/moderate steatohepatitis (4.0 (3.0–4.6) compared with 1.8 (1.5–2.6), P=0.006). Hepatic-to-splenic 99mTc count rate ratio was reduced in SAH (0.5 (0.4–1.4)) compared with cirrhotics (2.3( 0.6–3.0)) and three historic normal controls (4.2 (3.8–5.0); P=0.003), consistent with impaired hepatic reticuloendothelial function. Scintigraphic findings in SAH included prominent lung radioactivity at 30 min, likely the result of neutrophil primimg. Microautoradiography demonstrated cell-associated 111In in areas of parenchymal neutrophil infiltration. In conclusion, 111In-leucocyte scintigraphy can non-invasively diagnose SAH and could provide a platform for evaluation of novel treatments aiming to inhibit intrahepatic neutrophil migration.

Prognostic Utility of 90Y Radioembolization Dosimetry Based on Fusion 99mTc-Macroaggregated Albumin–99mTc-Sulfur Colloid SPECT

Planning hepatic (90)Y radioembolization activity requires balancing toxicity with efficacy. We developed a dual-tracer SPECT fusion imaging protocol that merges data on radioactivity distribution with physiologic liver mapping. Twenty-five patients with colorectal carcinoma and bilobar liver metastases received whole-liver radioembolization with resin microspheres prescribed as per convention (mean administered activity, 1.69 GBq). As part of standard treatment planning, all patients underwent SPECT imaging after intraarterial injection of 37 MBq of (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) to simulate subsequent (90)Y distribution. Immediately afterward, patients received 185 MBq of labeled sulfur colloid ((99m)Tc-SC) intravenously as a biomarker for normal hepatic reticuloendothelial function and SPECT was repeated. The SPECT images were coregistered and fused. A region-based method was used to predict the (90)Y radiation absorbed dose to functional liver tissue (DFL) by calculation of (99m)Tc-MAA activity in regions with (99m)Tc-SC uptake. Similarly, the absorbed dose to tumor (DT) was predicted by calculation of (99m)Tc-MAA activity in voxels without (99m)Tc-SC uptake. Laboratory data and radiographic response were measured for 3 mo, and the survival of patients was recorded. SPECT-based DT and DFL were correlated with parameters of toxicity and efficacy. Toxicity, as measured by increase in serum liver enzymes, correlated significantly with SPECT-based calculation of DFL at all time points (P < 0.05) (mean DFL, 27.9 Gy). Broad biochemical toxicity (>50% increase in all liver enzymes) occurred at a DFL of 24.5 Gy and above. In addition, in uni- and multivariate analysis, SPECT-based calculation of DT (mean DT, 44.2 Gy) correlated with radiographic response (P < 0.001), decrease in serum carcinoembryonic antigen (P < 0.05), and overall survival (P < 0.01). The cutoff value of DT for prediction of 1-y survival was 55 Gy (area under the receiver-operating-characteristic curve = 0.86; P < 0.01). Patients who received a DT of more than 55 Gy had a median survival of 32.8 mo, compared with 7.2 mo in patients who received less (P < 0.05). Dual-tracer (99m)Tc-MAA-(99m)Tc-SC fusion SPECT offers a physiology-based imaging tool with significant prognostic power that may lead to improved personalized activity planning.

Choline treatment affects the liver reticuloendothelial system and plasma fatty acid composition in diabetic rats

This study investigated effects of choline treatment on hepatic reticuloendothelial and biliary functions and plasma fatty acid composition in diabetic rats. Diabetes was induced by streptozotocin (STZ). Choline was administered to untreated rats and a portion of STZ-treated rats for two sequences of five consecutive days, separated by a 2-day interval. Hepatic functions were studied using (99m) Tc Tin (II) colloid (TIN) and 99 mTc mebrofenin [bromo-iminodiacetic acid (BrIDA)] imaging. The TIN-uptake ratios (organ/whole body) of heart, liver and spleen, and the BrIDA-uptake ratios (organ or tissue/whole body) of liver, biliary tree and abdomen were obtained following imaging studies. Fatty acids were analysed by GC/MS. Choline treatment did not attenuate hyperglycaemic development. Diabetic rats showed (i) a decreased TIN-uptake ratio in liver with co-increased ratios in heart and spleen; choline treatment diminished these changes, (ii) elevated BrIDA-uptake ratios in biliary tree and abdomen but not in liver; choline treatment did not attenuate the elevations and (iii) decreases in plasma palmitoleic acid and oleic acid, reflecting an impaired stearoyl-CoA desaturase function; choline treatment did not affect the diminutions, but caused a decrease in arachidonic acid with a co-increase in linoleic acid. Some rats developed hypoproteinemia (HPO). HPO rats also exhibited decreases in plasma palmitoleic acid and oleic acid. Diabetes caused almost absence of palmitoleic acid in HPO rats. Choline treatment exerted no effect on the plasma fatty acid composition of diabetic HPO rats. Choline treatment affected hepatic reticuloendothelial function and plasma fatty acid composition, but not hepatobiliary function, in diabetic rats. Whether choline treatment is beneficial requires further studies.

Effects of a somatostatin analogue (SMS 201-995) on hepatic and splenic reticulo-endothelial function in the rat.

The effects of a long acting somatostatin analogue, SMS 201-995, on reticulo-endothelial system (RES) activity were studied in rats. Administration of 2 micrograms SMS 201-995 subcutaneously twice a day for 7 days significantly increased the splenic and hepatic uptake of 99mTc-sulphur colloid and damaged 51mCr-red blood cells. Furthermore, SMS 201-995 administration significantly increased the plasma clearance of colloidal carbon as indicated by a lower area under the curve and an increased elimination constant. SMS 201-995 administration also significantly improved survival after intraperitoneal injection of Escherichia coli endotoxin. These results suggest that SMS 201-995 stimulates RES activity in rats. It is suggested that SMS 201-995 may be of value in stimulating RES activity in patients with cirrhosis and portal hypertension.

Hepatic reticuloendothelial function during parenteral nutrition including an MCT/LCT or LCT emulsion after liver transplantation - a double-blind study

Hepatic reticuloendothelial function during parenteral nutrition including an MCT/LCT or LCT emulsion after liver transplantation - a double-blind study

Small intestinal bacterial overgrowth versus antimicrobial capacity in patients with spontaneous bacterial peritonitis.

Spontaneous bacterial peritonitis (SBP) is a serious infection in cirrhotic patients with ascites. Both defects in the host defense mechanisms and the enhancement of the offensive factor (small intestinal bacterial overgrowth (SIBO)) may contribute to the development of SBP. Therefore, the aim of this study was to evaluate the role of SIBO versus various antimicrobial capacities in the pathogenesis of SBP in cirrhotic patients. Forty-five cirrhotic patients were enrolled in this study. Bacterial overgrowth was evaluated by breath hydrogen test (BH2T). The hepatic reticuloendothelial system phagocytic index (HRESPI) was measured by intravenously injected colloid suspensions. The Child-Pugh scores in the SBP group were higher than in the non-SBP group (10.5 +/- 2.0 versus 8.0 +/- 1.8, P < 0.01). The ascitic protein concentration was significantly lower in the SBP group than in the non-SBP group (897 +/- 425 mg/l versus 1,325 +/- 453 mg/l, P < 0.01). Furthermore, the serum C3 concentration was lower in the SBP group than in the non-SBP group (43.1 +/- 13.6 ng/dl versus 73.2 +/- 26.4 ng/dl, P < 0.01). The serum C4 concentration was also lower in the SBP group than in the non-SBP group (12.4 +/- 4.0 ng/dl versus 16.9 +/- 6.6 ng/dl, P < 0.05). The incidence of SIBO was higher in the SBP group than in the non-SBP group (68.2% versus 17.4%, P < 0.01). HRESPI values were significantly higher in the two groups of cirrhotic patients than in the normal reference. However, there were no statistical differences in HRESPI between the two groups (8.4 +/- 2.8 min in the SBP group versus 7.9 +/- 2.8 min in the non-SBP group). The results of this study showed that the hepatic reticuloendothelial function is impaired in cirrhotic patients, but the degree of impairment does not differ between patients with and without previous history of SBP. Lower ascitic total protein, lower serum C3 and C4 concentrations, and presence of SIBO are all risk factors for SBP. Based on the results of our study, defects in the host defense mechanisms and the enhancement of the offensive factor (SIBO) may act in concert for the development of SBP.

Endotoxemia depresses hepatic reticuloendothelial (RES) function and consequently redistributes the trapping of circulating bacteria to the lung

Endotoxemia depresses hepatic reticuloendothelial (RES) function and consequently redistributes the trapping of circulating bacteria to the lung

Hepatic haemodynamics and reticuloendothelial function in the rat in response to chronic ethanol administration

This study investigated the effects of chronic ethanol intake on hepatic haemodynamics and reticuloendothelial system function in the rat. Comparisons were also made with blood flow to pancreas, kidney, spleen, lung and skin. Male Wistar rats, approximately 0.15 kg initial body weight, were fed a diet containing 35% of the total calories as ethanol. Controls were pair-fed identical amounts of the same diet in which ethanol was replaced by isocaloric glucose. The hepatic perfusion index and reticuloendothelial function was determined with [(99m) Tc]-labelled sulphur colloid [(99m) Tc]-SC) and blood flow with radiolabelled microspheres under anaesthesia. After 4-5 weeks the weights of liver and skin of alcohol fed rats decreased by 10% (p= 0.040) and 23% (p= 0.024), respectively, compared to controls and there was a small increase in kidney weight (15%, p = 0.001). Blood flow to liver, pancreas, kidney, spleen, lung and skin was not altered significantly by chronic alcohol administration, irrespective of whether the data were expressed as a percentage of cardiac output, blood flow per minute per organ or blood flow per minute per g tissue weight (p > 0.113 in all instances). However, there was a significant increase in splenic reticuloendothelial system activity (+ 121%, p = 0.018). Hepatic reticuloendothelial system activity was also increased (+ 22%, p = 0.061). Chronic alcohol administration resulted in significant increases in portal pressure (+ 55%, p = 0.042) and portal venous resistance (+ 66%, p = 0.001), but portal venous inflow and hepatic perfusion index were not altered compared to controls The results of this study indicated that chronic alcohol administration did not alter visceral blood flow significantly, but did increase portal pressure, portal vascular resistance and reticuloendothelial system activity.

Increased incidence of glomerulonephritis following spleno-renal shunt surgery in non-cirrhotic portal fibrosis

In a prospective study of 200 non-cirrhotic portal fibrosis (NCPF) patients, 7% had mild proteinuria and their renal biopsies showed mild mesangial proliferative glomerulonephritis (mes-PGN). The remaining 93% biopsies were normal. However, following the insertion of a spleno-renal shunt (SRS) for portal hypertension 32% of these patients developed nephrotic syndrome in five years. Renal histology revealed mesangiocapillary glomerulonephritis (MCGN) (18.5%), mes-PGN (9%), minimal change nephropathy (3%), and chronic sclerosing GN (1.5%). Immunofluorescence showed granular deposition of IgA and C3. IgA2 was the predominant form of Ig in the glomerular deposits, indicating that IgA in the immune complexes was derived from the gastrointestinal tract. Electron microscopy revealed electron dense deposits in the mesangium. In contrast to the NCPF patients who underwent a SRS for portal hypertension, the 200 patients in our study who underwent spleno-renal shunting because of extra hepatic portal obstruction did not have renal disease, nor did they develop renal disease during the five-year post-operative follow-up. Fifty percent of the glomerulonephritis (GN) in the NCPF group progressed to renal failure in five years; 46.6% continued to have proteinuria. Low serum complement, C3 (40%) and circulating immune complexes (14.8%) were detected in the glomerulonephritis group. Our study shows that: (i) there is a high rate of the occurrence of GN following SRS in NCPF patients, but not in those with normal livers; (ii) the type of GN is primarily IgA nephropathy; and (iii) the GN could be the result of defective hepatic reticuloendothelial function in the NCPF group that is worsened by the shunting procedure.

A study of endotoxaemia in patients with primary biliary cirrhosis.

Hepatic reticuloendothelial function may be diminished in patients with primary biliary cirrhosis. Endotoxin concentrations in peripheral blood and in the superior mesenteric vein were measured, by the beta-glucan sensitive, factor-free, endotoxin-specific limulus assay, in patients with primary biliary cirrhosis and liver cirrhosis (non-PBC cirrhosis). Endotoxaemia was detected in the peripheral blood of seven out of nine patients (78%) with asymptomatic primary biliary cirrhosis, but in only two out of thirteen patients (15%) with non-PBC cirrhosis. The endotoxin level was significantly higher in the earlier stages of primary biliary cirrhosis than in the later stages (P < 0.05). The endotoxin level in superior mesenteric vein blood was significantly lower in patients with primary biliary cirrhosis than in patients with non-PBC cirrhosis. Peripheral endotoxaemia in patients with primary biliary cirrhosis may be due to the diminished capacity of the hepatic reticuloendothelial system, for phagocytosis of endotoxin.

Hepatic reticuloendothelial function following resuscitation with hemoglobin solutions.

Red cell substitutes could lead to depressed reticuloendothelial (RE) particulate clearance function. This hypothesis was tested using an animal model of hypovolemia-resuscitation. Anesthetized male Sprague-Dawley rats were subjected to 50% blood volume hemorrhage followed by isovolumic replacement with stroma-free hemoglobin (SFH, 7 gHb/dl), polyhemoglobin (PHS, 14 gHb/dl), or shed blood (SB). At 30 min post-transfusion, the liver was isolated and perfused with colloidal carbon. Hepatic RE function was assessed from the carbon clearance kinetics. In separate experiments, the hepatic Kupffer cells were isolated and cultured from rats that were previously hemorrhaged and transfused with normal saline solution. The cultured Kupffer cells were incubated with SFH or bovine albumin (ALB) and their phagocytic function assessed in-vitro. The hepatic carbon clearance following exchange transfusion with hemoglobin solutions was not significantly altered as compared to shed blood controls (P greater than 0.05). Similarly, phagocytic function of hemoglobin treated Kupffer cells was not significantly different (P greater than 0.05) from that of ALB treated cells.

Hepatic reticuloendothelial function in rats with various portasystemic shunts and total liver arterialization

Hepatic reticuloendothelial function was measured in 6 experimental groups of rats with various portasystemic shunts or total liver arterialization by computer calculation of the hepatic uptake rate of intravenously injected 99mTc-sulphur colloid. Marked reduction of the hepatic reticuloendothelial system (RES) function was found both 1 and 3 weeks after the construction of a mesentericocaval or conventional end-to-side portacaval shunt. Hepatic RES function was also lowered both 1 and 3 weeks after a modified portacaval shunt, but the reduction was much less pronounced. Total liver arterialization produced a similar mild reduction of hepatic RES function after 1 week; however, there was no longer any significant reduction after 3 weeks. This study concludes that total liver arterialization ameliorates the negative effect that portasystemic shunting has on hepatic RES function.

Studies of hepatic tolerance of polyvinylpyrrolidone in the rat

Intraperitoneal polyvinylpyrrolidone in amounts much larger than used in povidone-iodine for peritonitis or for adhesion prophylaxis was administered to rats. No adverse effects on hepatic reticulo-endothelial function could be detected using dynamic hepatic scintigraphy and fewer histochemical changes occurred than expected.

Quantitative reticuloendothelial function of liver and spleen in man.

A method for separate determinations of liver and spleen reticuloendothelial function, using a small-size 99Tcm -antimony sulphide colloid and gamma camera technique, is described. Several methods for achieving blood-background correction are examined, and it is shown that, by a three-compartment model, the use of a specific blood pool tracer can be dispensed with. Hepatic and splenic uptake of the colloid can be described by first order kinetics, and can be calculated to an error less than 5%. In a reference material (n = 13), hepatic and splenic clearance was 262 ml/min (100-412) and 22 ml/min (0-62), respectively. In cirrhosis (n = 7), hepatic clearance was decreased and splenic clearance increased. The results indicate that this method, which is well suited for clinical studies and which is based on a reasonable physiologic model, in cirrhosis of the liver demonstrates a decreased hepatic reticuloendothelial function with (compensatory?) increase in that of the spleen.

Hepatic reticuloendothelial function in the sub-totally nephrectomized rat model of chronic uremia.

The chronic uremic condition was induced in male Wistar rats by long term maintenance of the animals following sequential sub-total and contralateral nephrectomies. Hepatic reticuloendothelial (RES) activity was estimated by non-invasive measurement of blood clearance rates and hepatic uptake of 99Tcm sulfur colloid administered intravenously. The blood half-time, and the blood clearance rate constants for normals and chronic uremics were 78 +/- 10 s and 49.5 +/- 5 s, and 7.51 +/- 1.04 x 10(-3) s-1 and 10.81 +/- 1.17 x 10(-3) s-1 respectively. The normal hepatic uptake rate constant was 9.03 +/- 1.25 x 10(-3) s-1, compared with a uremic uptake rate constant of 14.34 +/- 1.51 s-1. Measurement of total liver radioactivity upon termination, 15 min after injection, showed significantly increased total uptake in uremia, whereas no change in spleen radioactivity was observed. The clinical implications of these data are discussed.

Correlation of plasma lysosomal enzyme levels with hepatic reticuloendothelial function after trauma.

Plasma lysosomal enzyme levels and hepatic phagocytosis were determined following Noble-Collip drum trauma in the rat. Circulating cathepsin and acid phosphatase activity increased after sublethal trauma (300 rev), reaching maximal levels at 1-3 hr and returning to pretrauma levels at 24 hr after trauma. Hepatic phagocytosis was decreased maximally at 1 hr and recovered to control levels at 24 hr after sublethal trauma. Increasing trauma intensity (100-500 rev) resulted in a progressive failure in hepatic Kupffer cell phagocytosis and a progressive increase in plasma lysosomal enzyme levels when tested at 60-min post-trauma. A significant inverse correlation was found between the plasma lysosomal enzyme levels and Kupffer cell phagocytosis after trauma. The functional significance of the relationship between these two parameters and its importance in shock survival remain to be determined.

Effect of extracorporeal circulation on reticuloendothelial function.

DURING the past decade total or partial extracorporeal circulation has been developed to the extent that it permits repair of most lesions in and around the heart. The knowledge concerning the effect of extracorporeal circulation on the function of individual organs is unfortunately quite limited. Such information is required to understand why certain complications may occur after open-heart surgery. In addition it would provide a basis for future evaluation of technically improved methods of assisted circulation. There are several studies of the effect of extracorporeal circulation on liver function. 1-3 All of them have been directed towards the function of the hepatocytes. No attempts to evaluate the function of the Kupffer cells have been made to our knowledge. In a previous study it was shown that hepatic reticuloendothelial function is impaired following cardiopulmonary bypass in rats. 4 The object of the present study was to explore the possible mechanisms responsible

Localized "radiation hepatitis" as demonstrated by scintillation scanning.

The liver has usually been considered radiation-resistant. Ingold et al. (1) recently summarized the literature on radiation effects on the liver and added some observations of their own. They noted that in 13 of 40 patients receiving radiation to the entire liver evidence of radiation “hepatitis” developed. A relationship was shown between the dose of irradiation and the incidence of radiation effect on the liver, no effect being observed with doses of less than 3,000 rads. Liver dysfunction was seen in 7 of the 17 patients who received doses in the 3,800–4,000-rad range and in 3 of the 4 patients who received doses in excess of 4,000 rads. On the other hand, they noted that “limited portions of the liver can apparently stand doses as high as 5,500 rads without detectable deleterious effects to the individual.” Ingold et al. also demonstrated alteration in some liver function tests in many of the patients in whom treatment was delivered to the entire liver. They stated that the serum alkaline phosphatase was the most reliable laboratory index of radiation damage when the entire liver was irradiated. Evidence concerning serum biochemical alterations following segmental irradiation of the liver was not presented. Usselman (2) demonstrated by photo-scanning alterations in liver function, using both Au198 and rose bengal I131, in patients who had received segmental irradiation of the liver. Johnson et al. (3) believed that they had demonstrated by scintillation scanning radiation-induced suppression of hepatic reticuloendothelial function in 6 patients who had received therapeutic irradiation of the liver. Our observations indicate that scintillation scanning of the liver following intravenous injection of radioactive colloidal gold may be a more sensitive index of localized radiation hepatitis than that provided by clinical and biochemical data. Evidence of a radiation-induced abnormality of the liver was shown by scintillation scanning in 6 patients with neoplastic disease, in whom a segment of the liver was irradiated. A scintillation scan of the liver was obtained shortly after completion of a course of radiation therapy to an upper abdominal portal in 4 patients with a malignant neoplasm of the testis and in 2 young women with Stage II Hodgkin's disease. Liver scans prior to treatment were available for 3 patients and an additional scan was obtained in two others several months after completion of the radiotherapy. Illustrative Cases Case I: E. K., a 37-year-old white male, underwent a left orchiectomy on Dec. 29, 1965, with a histologic diagnosis of mixed seminoma and teratocarcinoma of the testis. Abdominal exploration on Jan. 18, 1966, confirmed the presence of unresectable retroperitoneal disease. Prior to radiation therapy, a scintillation scan of the liver (Jan. 12, 1966) was normal (Fig. 1,A), as were serum values for bilirubin, alkaline phosphatase, glutamic pyruvate transaminase, and Bromsulphalein retention.

RADIATION INDUCED HEPATIC INJURY

1. Radiation induced suppression of hepatic reticuloendothelial function was demonstrated by scintillation scanning in 6 patients undergoing therapeutic irradiation of the liver. In the 1 patient so tested, suppressed hepatocellular function was also demonstrated.2. Evidence of injury to the liver was the de novo appearance of a well defined area of diminished or absent radioactivity on the scintillation scan, corresponding to the position of the radiation portals in each case.3. In 3 patients, reappearance of normal function was observed 84-106 days post irradiation. Follow-up of the remaining patients was limited to shorter periods.4. There were no clinical findings attributable to radiation induced hepatic injury.5. These data are additional evidence that the liver is a relatively radiosensitive organ.