Extrahepatic Surgery in Cirrhosis Significantly Increases Portal Pressure in Preclinical Animal Models

Background: Liver cirrhosis is a relevant comorbidity with increasing prevalence. Postoperative decompensation and development of complications in patients with cirrhosis remains a frequent clinical problem. Surgery has been discussed as a precipitating event for decompensation and complications of cirrhosis, but the underlying pathomechanisms are still obscure. The aim of this study was to analyze the role of abdominal extrahepatic surgery in cirrhosis on portal pressure and fibrosis in a preclinical model.Methods: Compensated liver cirrhosis was induced using tetrachlormethane (CCL4) inhalation and bile duct ligation (BDL) models in rats, non-cirrhotic portal hypertension by partial portal vein ligation (PPVL). Intestinal manipulation (IM) as a model of extrahepatic abdominal surgery was performed. 2 and 7 days after IM, portal pressure was measured in-vivo. Hydroxyproline measurements, Sirius Red staining and qPCR measurements of the liver were performed for evaluation of fibrosis development and hepatic inflammation. Laboratory parameters of liver function in serum were analyzed.Results: Portal pressure was significantly elevated 2 and 7 days after IM in both models of cirrhosis. In the non-cirrhotic model the trend was the same, while not statistically significant. In both cirrhotic models, IM shows strong effects of decompensation, with significant weight loss, elevation of liver enzymes and hypoalbuminemia. 7 days after IM in the BDL group, Sirius red staining and hydroxyproline levels showed significant progression of fibrosis and significantly elevated mRNA levels of hepatic inflammation compared to the respective control group. A progression of fibrosis was not observed in the CCL4 model.Conclusion: In animal models of cirrhosis with continuous liver injury (BDL), IM increases portal pressure, and development of fibrosis. Perioperative portal pressure and hence inflammation processes may be therapeutic targets to prevent post-operative decompensation in cirrhosis.

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Regulator 1-Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Signaling Pathway in Investigating the Pathological Characteristics and Molecular Mechanism of Liver Cirrhosis Complicated by Acute Kidney Injury

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2022.2859 ◽

2022 ◽

Vol 12 (1) ◽

pp. 112-120

Author(s):

Jieqi Gong ◽

Huanhua Lu

Keyword(s):

Acute Kidney Injury ◽

Liver Cirrhosis ◽

Signaling Pathway ◽

Molecular Mechanism ◽

Kidney Injury ◽

Male Rats ◽

Control Group ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Duct Ligation

The objective of this study was to investigate the molecular mechanism of the histopathological characteristics of liver cirrhosis (LC) complicated with acute kidney injury (AKI) and the signaling pathway of silent information regulator 1 (SIRT1)-peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) during the pathogenesis of LC. 20 healthy male rats with AKI complicated by laparoscopic cholecystectomy were selected and divided randomly into control group (C group), lipopolysaccharide (LPS) group, bile duct ligation (BDL) group, and model group (lipopolysaccharide+BDL) (D group). The indexes of all the rats were determined, including serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), sarcoplasmic enzyme (Scr), and blood urea nitrogen (BUN); the SIRT1 and PGC-1α expressions in renal tissues of rats from each group was detected. Results showed that the AST and ALT levels in BDL group and D group were higher markedly than those before surgery (P < 0.05). The serum levels of Scr and BUN in D group 4 hours after LPS injection increased hugely compared with before injection (P < 0.05). Compared with BDL group, the protein levels of SIRT1 and PGC-1α in renal tissue of group D were decreased sharply (P < 0.05), and the SIRT1 protein expression was positively correlated with PGC-1α (r = 0.836 and P < 0.01). When LC were complicated with AKI, SIRT1 activity was reduced and PGC-1α expression was inhibited. Moreover, SIRT1-PGC-1α signaling pathway played a protective role in pathogenesis of LC complicated with AKI.

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Acute Cholecystitis Reduces Interstitial Cells of Cajal in Porcine Gallbladder Through Decreased mRNA Synthesis

Cellular Physiology and Biochemistry ◽

10.1159/000489987 ◽

2018 ◽

Vol 47 (2) ◽

pp. 535-544 ◽

Cited By ~ 4

Author(s):

Zhen-peng Huang ◽

Hu Qiu ◽

Bao-ping Yu

Keyword(s):

Acute Cholecystitis ◽

Guinea Pigs ◽

Interstitial Cells Of Cajal ◽

Interstitial Cells ◽

Motility Disorder ◽

Gallbladder Motility ◽

Control Group ◽

Mrna Levels ◽

Duct Ligation ◽

Cells Of Cajal

Background/Aims: Acute cholecystitis is a common gastrointestinal disorder, often characterized by acute cholecystitis with gallbladder motility disorder. Interstitial cells of Cajal (ICCs) are the pacemaker cells of gut motility in the gastrointestinal tract. Disruption of ICC function is related to motility disorders. The aim of this study was to explore the cellular and molecular mechanisms of ICCs in acute cholecystitis and after the resolution of acute inflammation. Materials and Methods: Fifty adult guinea pigs were randomly divided into five groups: a sham-administered group (control group); two groups that were intraperitoneally administered an anti-polyclonal neutrophil (PMN) antibody 24 h before common bile duct ligation (CBDL); and two groups of guinea pigs that were subjected to CBDL without receiving the PMN antibody. Guinea pigs that underwent CBDL were held for 24 h or 48 h after surgery before being subjected to laparotomy and cholecystectomy. Immunohistochemistry, TUNEL assays, western blotting, and real-time PCR were performed to determine ICC morphology and density, to detect ICC apoptosis, and to examine stem cell factor (SCF) and c-kit protein expression and SCF and c-kit mRNA levels, respectively. Results: Both hematoxylin-eosin staining and histological inflammation scores in the PMN groups were lower than those in the control groups (P < 0.01). No differences were observed in ICC morphology between groups. During acute cholecystitis, ICCs numbers were reduced. Conversely, the density of ICCs increased after inflammation was relieved (P < 0.01). In addition, SCF and c-kit protein and mRNA expression levels decreased during acute cholecystitis (P < 0.05) and increased after inflammation was relieved (P < 0.05). Furthermore, ICC apoptosis increased during acute cholecystitis and decreased after resolution of acute cholecystitis (P < 0.01). Conclusions: In acute cholecystitis, ICC injury may be related to gallbladder motility disorder.

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Factor VIII expression in liver disease

Thrombosis and Haemostasis ◽

10.1160/th03-05-0310 ◽

2004 ◽

Vol 91 (02) ◽

pp. 267-275 ◽

Cited By ~ 120

Author(s):

Martine Hollestelle ◽

Hendrika Geertzen ◽

Irene Straatsburg ◽

Thomas van Gulik ◽

Jan van Mourik

Keyword(s):

Liver Cirrhosis ◽

Liver Disease ◽

Factor Viii ◽

Rna Extraction ◽

Control Group ◽

Mrna Levels ◽

Protein Distribution ◽

Elevated Plasma ◽

Cirrhotic Tissue ◽

Plasma Factor

SummaryLiver disease is associated with markedly elevated plasma factor VIII (FVIII) levels, whereas the synthesis of many other coagulation factors and proteins is reduced. In order to define the mechanism of FVIII increase, we have determined the expression levels of FVIII, both at mRNA and protein level, in patients with liver disease who underwent partial liver resection. In addition, the expression of von Willebrand factor (VWF) and low density lipoprotein receptor-related protein (LRP), proteins known for their ability to modulate FVIII plasma levels, were examined. Tissue samples for RNA extraction were obtained from 4 patients with cirrhosis, 9 patients with liver failure without cirrhosis and 6 patients with liver metastasis of a colon or rectum carcinoma (control group). In patients with liver cirrhosis hepatic FVIII and LRP mRNA levels were significantly lower than controls (p ≤ 0.010), while VWF mRNA was significantly higher (p ≤ 0.050). Immunohistochemical analysis revealed that cellular VWF protein distribution was also increased in cirrhotic livers compared to liver tissue from patients with non-cirrhotic liver disease. In cirrhotic tissue enlarged portal veins appeared to overgrow FVIII producing sinusoidal endothelial cells. Similarly, the number of LRP-producing cells appeared to be lower in cirrhotic tissue than in controls. The plasma concentration of both FVIII and VWF was significantly higher in patients with cirrhosis than control subjects (p = 0.038 and 0.010 respectively). These results demonstrate that elevated plasma FVIII levels in liver cirrhosis are associated with increased hepatic biosynthesis of VWF and decreased expression of LRP, rather than increased FVIII synthesis.

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Microbiota transplants from feces or gut content attenuated portal hypertension and portosystemic collaterals in cirrhotic rats

Clinical Science ◽

10.1042/cs20210602 ◽

2021 ◽

Author(s):

Hui-Chun Huang ◽

Ming-Hung Tsai ◽

Ching-Chih Chang ◽

Chon Kit Pun ◽

Yi-Hsiang Huang ◽

...

Keyword(s):

Liver Cirrhosis ◽

Portal Hypertension ◽

Liver Injury ◽

Portal Pressure ◽

Vascular Density ◽

Variceal Hemorrhage ◽

Distribution Method ◽

Portosystemic Shunts ◽

Duct Ligation ◽

Portosystemic Collaterals

Liver cirrhosis and portal hypertension is the end of chronic liver injury with hepatic, splanchnic and portosystemic collateral systems dysregulation. Liver injury is accompanied by gut dysbiosis whereas dysbiosis induces liver fibrosis, splanchnic angiogenesis and dysregulated vascular tones vice versa, making portal hypertension aggravated. It has been proved that intestinal microbiota transplantation alleviates dysbiosis. Nevertheless, the influences of microbiota transplantation on cirrhosis related portal hypertension are not so clear. Liver cirrhosis with portal hypertension was induced by bile duct ligation in rats. Sham rats were surgical controls. Rats randomly received vehicle, fecal or gut (terminal ileum) material transplantation. The results showed that microbiota transplantation from feces or gut material significantly reduced portal pressure in cirrhotic rats (P = .010, .044). Hepatic resistance, vascular contractility, fibrosis and relevant protein expressions were not significantly different among cirrhotic rats. However, microbiota transplantation ameliorated splanchnic hyperdynamic flow and vasodilatation. Mesenteric angiogenesis, defined by whole mesenteric window vascular density, decreased in both transplantation groups and phosphorylated eNOS was downregulated. Portosystemic shunts determined by splenorenal shunt flow decreased in both transplantation groups (P = .037, .032). Shunting severity assessed by microsphere distribution method showed consistent results. Compared to sham rats, cirrhotic rats lacked Lachnospiraceae. Both microbiota transplants increased Bifidobacterium. In conclusion, microbiota transplantation in cirrhotic rats reduced portal pressure, alleviated splanchnic hyperdynamic circulation and portosystemic shunts. The main beneficial effects may be focused on portosystemic collaterals-related events, such as hepatic encephalopathy and gastroesophageal variceal hemorrhage. Further clinical investigations are mandatory.

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Bile acids do not mediate the hyperdynamic circulation in portal hypertensive rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1990.259.1.g21 ◽

1990 ◽

Vol 259 (1) ◽

pp. G21-G25 ◽

Cited By ~ 1

Author(s):

P. Genecin ◽

J. Polio ◽

L. A. Colombato ◽

G. Ferraioli ◽

A. Reuben ◽

...

Keyword(s):

Blood Flow ◽

Portal Hypertension ◽

Mean Arterial Pressure ◽

Bile Acids ◽

Portal Pressure ◽

Control Group ◽

Portal Vein Ligation ◽

Hypertensive Rats ◽

Hyperdynamic Circulation ◽

Portosystemic Shunting

Portal hypertension is accompanied by hyperdynamic systemic and splanchnic circulation. Serum bile acids (BAs), which are elevated in portal hypertension and have vasodilatory properties, have been proposed as mediators of this hyperdynamic circulation. In this study, portal hypertensive rats [accomplished by partial portal vein ligation (PVL)] were gavaged with cholestyramine (PVL-CH) to decrease circulating BA levels. A control group of rats was gavaged with an inert suspension of Metamucil (PVL-ME). The following hyperdynamic parameters were found to be similar in PVL-CH and PVL-ME: mean arterial pressure (119 +/- 6 vs. 124 +/- 5 mmHg), portal pressure (13.2 +/- 0.6 vs. 14.5 +/- 0.5 mmHg), cardiac index (0.33 +/- 0.04 vs. 0.34 +/- 0.03 ml.min-1.g body wt-1), splanchnic blood flow (1.4 +/- 0.13 vs. 1.6 +/- 0.1 ml.min-1.g body wt-1), portosystemic shunting (82 +/- 8 vs. 92 +/- 3%), peripheral arteriolar resistances (344 +/- 74 vs. 387 +/- 29 mmHg.min.ml-1.g body wt), and splanchnic arteriolar resistances (75 +/- 14 vs. 72 +/- 6 mmHg.min.ml-1.g splanchnic wt; 1,471 +/- 150 vs. 1,325 +/- 120 mmHg.min.ml-1.g body wt). BA in PVL-ME (84 +/- 9 microM/l) were similar to those previously observed in untreated PVL and significantly greater than those measured in PVL-CH (25 +/- 4 microM/l; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

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Extrahepatic angiogenesis hinders recovery of portal hypertension and collaterals in rats with cirrhosis resolution

Clinical Science ◽

10.1042/cs20171370 ◽

2018 ◽

Vol 132 (6) ◽

pp. 669-683 ◽

Cited By ~ 2

Author(s):

Shao-Jung Hsu ◽

Ming-Hung Tsai ◽

Ching-Chih Chang ◽

Yu-Hsin Hsieh ◽

Hui-Chun Huang ◽

...

Keyword(s):

Portal Hypertension ◽

Portal Pressure ◽

Treatment Strategies ◽

Vascular Complications ◽

Control Group ◽

No Production ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Duct Ligation ◽

Window Area

Liver cirrhosis is characterized by portal hypertension. However, the alteration of portal hypertension-related derangements during cirrhosis resolution is not well known. The present study aimed to establish animal models with cirrhosis resolution and to investigate the relevant changes during this process. Male Sprague–Dawley rats were applied. In reverse thioacetamide (rTAA) model, rats were randomly allocated into four groups with control, thioacetamide (TAA) cirrhosis and rTAA groups that discontinued TAA for 4 or 8 weeks after cirrhosis induction. In reverse bile duct ligation (rBDL) model, rats received choledochoduodenal shunt surgery upon the establishment of cirrhosis and 4, 8, or 16 weeks were allowed after the surgery. At the end, portal hypertension-related parameters were evaluated. Cirrhosis resolution was observed in rTAA groups. Portal pressure (PP) decreased after cirrhosis resolution but remained higher than control group (control, TAA, rTAA4, rTAA8 (mmHg): 5.4 ± 0.3, 12.9 ± 0.3, 8.6 ± 0.4, 7.6 ± 0.6). Further survey found the increased splanchnic blood flow did not reduce during cirrhosis resolution. The extrahepatic pathological angiogenesis was not ameliorated (% of mesenteric window area: 1.2 ± 0.3, 7.3 ± 1.1, 8.3 ± 1.0, 11.3 ± 2.7). In collateral system, the shunting degree reduced while the vessels structure remained. The vascular contractility of all systems and nitric oxide (NO) production were normalized. In rBDL series, PP decreased in rBDL16 groups but the extrahepatic angiogenesis persisted. In conclusion, cirrhosis resolution attenuates but not completely normalizes portal hypertension because of persistently high splanchnic inflow and angiogenesis. In clinical setting, vascular complications such as varices could persist after cirrhosis resolution and further investigation to define the follow-up and treatment strategies is anticipated.

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Activation of the EGFR-PI3K-CaM Pathway by PRL-1 Ameliorates Liver Cirrhosis via ER Stress-dependent Calcium

10.21203/rs.3.rs-710155/v1 ◽

2021 ◽

Author(s):

Se Ho Kim ◽

Jae Yeon Kim ◽

Soo Young Park ◽

Won Tae Jeong ◽

Jin Man Kim ◽

...

Keyword(s):

Liver Cirrhosis ◽

Er Stress ◽

Rat Model ◽

Mitochondrial Dynamics ◽

Control Group ◽

Therapeutic Effects ◽

Sprague Dawley ◽

Stress Markers ◽

Duct Ligation ◽

Stress Dependent

Abstract Background: Accumulation of cholesterol and depletion of calcium induce hepatic injury through the endoplasmic reticulum (ER) stress response. ER stress regulates the calcium imbalance between the ER and mitochondria. Previously, we reported that phosphatase of regenerating liver-1 (PRL-1)-overexpressing placenta-derived mesenchymal stem cells (PD-MSCsPRL-1) promoted liver regeneration through mitochondrial dynamics in a cirrhotic rat model. However, whether PRL-1 is involved in ER stress-dependent calcium is unclear. So, we demonstrated that PD-MSCsPRL-1 improves hepatic functions by regulating ER stress and calcium channels in a rat model of bile duct ligation (BDL). Methods: Liver cirrhosis was induced in Sprague-Dawley (SD) rats using surgically induced BDL for 10 days. PD-MSCs and PD-MSCsPRL-1 (2x106 cells) were intravenously administered to animals, and their therapeutic effects were analyzed. WB-F344 cells exposed to thapsigargin (TG) were cocultured with PD-MSCs or PD-MSCsPRL-1. Results: ER stress markers (e.g., eIF2α, ATF4, and CHOP) were increased in the non-transplantation group (NTx) compared with the control group. PD-MSCsPRL-1 significantly decreased ER stress markers compared to NTx and induced dynamic changes in calcium channel markers (e.g., SERCA2b, IP3R, MCU, and VDAC1) (*p<0.05). In TG-treated WB-F344 cells, cocultivation with PD-MSCsPRL-1 decreased cytosolic CaM expression and cytosolic and mitochondrial Ca2+ concentrations; however, the ER Ca2+ concentration was increased compared to that in PD-MSCs (*p<0.05). Additionally, PRL-1 through epidermal growth factor receptor (EGFR) activated phosphatidylinositol-3-kinase (PI3K) signaling, resulting in calcium increases via CaM expression. Conclusions: These findings suggest that PD-MSCsPRL-1 improved hepatic functions through calcium changes and attenuated ER stress in a BDL-injured rat model. Therefore, these results provide useful data for the development of next-generation MSC-based stem cell therapy for regenerative medicine in chronic liver disease.

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Glucobrassicin Metabolites Ameliorate the Development of Portal Hypertension and Cirrhosis in Bile Duct-Ligated Rats

International Journal of Molecular Sciences ◽

10.3390/ijms20174161 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4161

Author(s):

Ting Chang ◽

Hsin-Ling Ho ◽

Shao-Jung Hsu ◽

Ching-Chih Chang ◽

Ming-Hung Tsai ◽

...

Keyword(s):

Liver Cirrhosis ◽

Portal Hypertension ◽

Bile Duct ◽

Portal Pressure ◽

Sham Operation ◽

Duct Ligation ◽

Phosphorylated Akt ◽

Protein Expressions ◽

Portosystemic Shunting ◽

Portosystemic Collaterals

Patients suffering from liver cirrhosis are often complicated with the formation of portosystemic collateral vessels, which is associated with the progression of a splanchnic hyperdynamic circulatory state. Alleviating pathological angiogenesis has thus been proposed to be a feasible treatment strategy. Indole-3-carbinol (C9H9NO, I3C) and 3,3′-diindolymethane (DIM), formed by the breakdown of glucosinolate glucobrassicin, are prevalent in cruciferous vegetables and have anti-angiogenesis properties. We aimed to evaluate their influences on portal hypertension, the severity of mesenteric angiogenesis, and portosystemic collaterals in cirrhosis. Sprague-Dawley rats with common bile duct ligation (CBDL)-induced liver cirrhosis or sham operation (surgical control) were randomly allocated to receive I3C (20 mg/kg/3 day), DIM (5 mg/kg/day) or vehicle for 28 days. The systemic and portal hemodynamics, severity of portosystemic shunting, mesenteric angiogenesis, and mesenteric proangiogenic factors protein expressions were evaluated. Compared to vehicle, both DIM and I3C significantly reduced portal pressure, ameliorated liver fibrosis, and down-regulated mesenteric protein expressions of vascular endothelial growth factor and phosphorylated Akt. DIM significantly down-regulated pErk, and I3C down-regulated NFκB, pIκBα protein expressions, and reduced portosystemic shunting degree. The cruciferous vegetable byproducts I3C and DIM not only exerted a portal hypotensive effect but also ameliorated abnormal angiogenesis and portosystemic collaterals in cirrhotic rats.

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The beneficial effects of curcumin in cirrhotic rats with portal hypertension

Bioscience Reports ◽

10.1042/bsr20171015 ◽

2017 ◽

Vol 37 (6) ◽

Cited By ~ 7

Author(s):

Shao-Jung Hsu ◽

Jing-Yi Lee ◽

Te-Yueh Lin ◽

Yu-Hsin Hsieh ◽

Hui-Chun Huang ◽

...

Keyword(s):

Liver Cirrhosis ◽

Portal Hypertension ◽

Vascular Resistance ◽

Portal Pressure ◽

Acute Administration ◽

Vegf Receptor ◽

Variceal Hemorrhage ◽

Common Bile Duct Ligation ◽

Duct Ligation ◽

Portosystemic Collaterals

In liver cirrhosis with portal hypertension, the uneven distribution of vasoactive substances leads to increased intrahepatic vascular resistance and splanchnic vasodilatation. Angiogenesis also induces increased portal inflow and portosystemic collaterals. The collaterals may induce lethal complications such as gastroesophageal variceal hemorrhage, but the therapeutic effect of vasoconstrictors is still suboptimal due to poor collateral vasoresponsivenss. Curcumin has aroused much attention for its antifibrosis, vasoactive, and anti-angiogenesis actions. However, whether it affects the aforementioned aspects is unknown. Liver cirrhosis was induced by common bile duct ligation (CBDL) in Sprague–Dawley rats. Sham-operated rats were controls. CBDL and sham rats were randomly allocated to receive curcumin (600 mg/kg per day) or vehicle since the 15th day after BDL. On the 29th day, portal hypertension related parameters were surveyed. Portosystemic collateral in situ perfusion was performed to evaluate vascular activity. Chronic curcumin treatment decreased portal pressure (PP), cardiac index (CI) and increased systemic vascular resistance (SVR) in cirrhotic rats. In splanchnic system, curcumin decreased superior mesenteric artery (SMA) flow and increased SMA resistance. Mesenteric angiogenesis was attenuated by curcumin. Acute administration of curcumin significantly induced splanchnic vasoconstriction. The mesenteric protein expressions of p-endothelial nitric oxide synthase (eNOS), cyclooxygenase (COX) 2 (COX2), vascular endothelial growth factor (VEGF), p-VEGF receptor 2 (VEGFR2), and p-Erk were down-regulated. In collateral system, curcumin decreased portosystemic shunting and induced vasoconstriction. In conclusion, chronic curcumin administration in cirrhotic rats ameliorated portal hypertension related hemodynamic derangements and portosystemic collaterals. Curcumin also attenuated splanchnic hyperdynamic circulation by inducing vasoconstriction through inhibition of eNOS activation and by decreasing mesenteric angiogenesis via VEGF pathway blockade.

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A Novel Method of Determining Portal Systemic Shunting using Biodegradable 99TCm Labelled Albumin Microspheres

HPB Surgery ◽

10.1155/1995/31761 ◽

1995 ◽

Vol 8 (4) ◽

pp. 223-229 ◽

Cited By ~ 2

Author(s):

J. Yates ◽

D. M. Nott ◽

P. J. Maltby ◽

D. Billington ◽

J. N. Baxter ◽

...

Keyword(s):

Portal Hypertension ◽

Portal Vein ◽

Portal Pressure ◽

Repeated Measurements ◽

Control Group ◽

Portal Vein Ligation ◽

Hypertensive Rats ◽

Albumin Microspheres ◽

Novel Method

Portal systemic shunting (PSS) and portal pressure were measured in control rats and in animals with portal hypertension induced by partial portal vein ligation (PPVL). The portal pressure in rats with partial portal vein ligation (13.4 ± 0.5 mm.Hg.) was significantly higher (p < 0.005) than in the control group (9.6 ± 0.6 mm.Hg.). Portal systemic shunting measured by consecutive injections of radiolabelled methylene diphosphonate (MDP), a non-diffusable marker and albumin microspheres directly into the splenic pulp was significantly increased (P < 0.005) in the portal hypertensive animals (30.8 ± 2.5%) compared to sham operated rats (2.6 ± 1.5%). Similarly, in portal hypertensive rats portal systemic shunting measured by intrasplenic injections of radiolabelled cobalt microspheres (37.1 ± 3.9%) was significantly greater (p < 0.005) than in control animals. There was a good correlation and agreement (r = 00.97) between the two methods of measuring portal systemic shunting. However because the 99Tcm-albumin microspheres are biodegradable the method allows portal systemic shunting to be measured in man. Furthermore since the computer adjusts the baseline to zero after each determination of portal systemic shunting the methodology allows repeated measurements to be made.

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