Portacaval Shunt Research Articles

A case report of budd-chiari syndrome during puerperium requiring two liver transplants

Budd-Chiari syndrome is a rare and serious condition characterised by obstruction to the outflow of hepatic venous blood. Thrombophilias, malignancies, infections and pregnancy have been implicated as causes. Anticoagulation, portacaval...

Observation and nursing of patients undergoing percutaneous transhepatic portacaval shunt

目的 探讨经颈静脉肝内门腔静脉分流术的观察和护理效果.方法 2010年7月至2011年1月对因肝硬化失代偿期食管胃底静脉曲张破裂出血而入院的4例患者施行了经颈静脉肝内门腔静脉分流术(11Ps),并进行有针对性的护理.结果 4例患者TIPs术均成功,成功率100%,3例患者术后病情得到控制,护理效果满意,无并发症的发生,好转出院;1例因凝血功能差,腹腔出血,经止血、输血等抢救失败于术后7 h死亡.结论 做好术前准备及心理护理,术中密切观察患者生命体征,术后严格按医嘱用药,做好出院指导,可有效防止并发症,提高治疗效果。

Brain biomolecules oxidation in portacaval-shunted rats

Oxidative stress induced by a high ammonia concentration has been suggested to be implicated in the pathophysiology of hepatic encephalopathy (HE). Therefore, oxidative damage of brain biomolecules could contribute towards explaining the neurological and motor alterations observed in HE. Portacaval-shunted (PCS) rats (n = 5) were used as an animal model of chronic HE. Plasma and brain ammonia were measured by the l-glutamate dehydrogenase method. Reactive oxygen species was measured by the dichlorodihydrofluorescein diacetate method. Lipid peroxidation was measured as thiobarbituric acid-reactive substances (TBARS) by a colorimetric method; malondialdehyde (MDA) and 4-hydroxy-2-noneal (HNE) were measured by HPLC and an immunological method respectively. Protein oxidation (carbonylation) was measured as total carbonyl after labelling with 2,4-dinitrophenyl hydrazine (DNPH) using a spectrophotometric method. Individual protein oxidation was studied, after labelling with DNPH and its separation by one-dimensional (1D) electrophoresis, by an immunological method. Ammonia-induced oxidative stress in PCS rats was associated with increased MDA and HNE, together with increased protein oxidation, evidenced by total carbonyl quantification and by the analysis of individual protein bands separated by 1D electrophoresis. However, lipid peroxidation measured as TBARS did not show differences. Our data show an increased evidence of oxidative stress in PCS rat brain; moreover, PCS rat brain proteins are oxidized (carbonylated), some proteins being more sensitive to oxidation than others. These data also show that at least six specific brain proteins in PCS rats are highly sensitive to carbonylation. Identification of these proteins may be crucial for a better understanding of HE pathophysiology.

Percutaneous bypass creation between hollow organs by modified gun-sight approach

This animal study investigated the feasibility of creating a bypass between two hollow organs, using a modified gun-sight approach with a pull-through string and pull-through tow wire. Ten procedures (femoral arteriovenous shunt, n = 4; portacaval shunt, n = 4; cholangiogastrostomy, n = 2) were performed in six adult swine. Snares were inserted into the two hollow organs through the sheath and deployed at the site of bypass creation. When snares overlapped on fluoroscopy, a needle was inserted to pass through both snares. The string was inserted through the needle, with only the needle then withdrawn. The snare furthest from the skin was closed to capture the string and was then withdrawn. The other snare was withdrawn without closing. The string thus served as a pull-through string penetrating both hollow organs. This string was then attached to a pull-through tow wire, withdrawn, and exchanged for the pull-through tow wire. By withdrawing the pull-through tow wire, the delivery sheath connected to the pull-through tow wire was towed through the site of the bypass, and the stent was placed. In all cases, bypass creation was achieved. Percutaneous bypass creation using a modified gun-sight approach with a pull-through string and pull-through tow wire is feasible between two hollow organs.

Portosystemic hepatic encephalopathy model shows reversal learning impairment and dysfunction of neural activity in the prefrontal cortex and regions involved in motivated behavior

Hepatic encephalopathy (HE) is a neurological complication that affects attention and memory. Experimental animal models have been used to study HE, the most frequent being the portacaval shunt (PCS). In order to investigate learning impairment and brain functional alterations in this model, we assessed reversal learning and neural metabolic activity in a PCS rat model. PCS and sham-operated rats were tested for reversal learning in the Morris water maze. Brains were then processed for cytochrome oxidase (CO) histochemistry. The PCS group had reversal learning impairment and a reduction in CO activity in the prefrontal cortex, ventral tegmental area and accumbens shell nucleus. These results suggest that this model of portosystemic HE shows learning impairments that could be linked to dysfunction in neural activity in the prefrontal cortex and regions involved in motivated behavior.

Transjugular Intrahepatic Portosystemic Shunt: State of the Art

Since the first description of transjugular portal venography and radiologic portacaval shunt placement by Rosch n 19691 and the subsequent introduction of the transjugular intrahepatic portasystemic shunt (TIPS) into clinical medicine by Colapinto in 1982, TIPS has been increasingly adopted as a means of reducing portal pressures in patients with complications related to portal hypertension, such as refractory variceal bleeding. The procedure has also evolved to encompass other indications, such as refractory ascites2,3 and ts related complications, such as hepatorenal syndrome4 and epatic hydrothorax.5,6 In addition TIPS has also been sucessfully applied to patients with Budd–Chiari syndrome,7,8 portal vein occlusion,9 and ectopic variceal bleeding.10 Created with the use of catheters, balloons, and stents inserted under radiologic guidance, TIPS intrinsically functions as a side-to-side porta-caval shunt. The 2 major drawbacks of the TIPS procedure are progressive encephalopathy caused by direct portosystemic shunting and shunt dysfunction. Since the late 1990s the practice of TIPS has been greatly influenced by the introduction of the model for end-stage liver disease (MELD) scoring system for risk assessment of short-term mortality in patients undergoing TIPS and also by the introduction of polytetrafluoroethylene-covered endografts, which achieve durable long-term patency. These endografts and their effect on producing long-term shunt patency are redefining the role of TIPS for treating complications of portal hypertension. In this review article, we describe the common indications of TIPS procedure, the pathophysiology of portal hypertension, and anatomic aspects relevant to the safe creation of a TIPS. We describe the preprocedure evaluation of patients undergoing a TIPS procedure and techniques for step-wise placement of a TIPS as well as monitoring for and management of shunt dysfunction. We also look at newer techniques, such as direct intrahepatic portocaval shunting

Partial IVC Clamping Improves Intraoperative Hemodynamic Parameters in the Rodent Portacaval Anastomosis Model

The mechanisms involved in the development of hepatic encephalopathy still remain uncertain. The rodent portacaval shunt is a model that reproduces many of the pathological features observed in humans (1), but is a technically demanding exercise. While the traditional technique involves complete occlusion of the IVC, a c-clamp was fashioned to partially clamp the IVC thereby sustaining venous return and cardiac output. The aim of this study is to determine if the c-clamp technique provides greater hemodynamic stability and enhances the success rate of the portacaval shunt procedure. To answer this question, two experimental groups, c-clamp (N = 7) and cross-clamp (N = 7), and a sham group (N = 3) were included. Intraoperative hemodynamic parameters were recorded at specific times during the procedure. The c-clamp group showed greater hemodynamic stability when compared to the cross-clamp group. It was manifested by 1) significantly higher mean arterial blood pressure [63 (range, 8) vs 47 (range, 10) mmHg, p < 0.05], 2) faster capillary refill [4 (range, 2) vs 6 (range, 2) seconds, p < 0.05], 3) higher urinary output [0.18 (range, 0.02) vs 0.14 (range, 0.02) ml, p < 0.05], and 4) lower bowel wet-to-dry ratio [4.168 (range, 0.258) vs 4.731 (range, 0.271), p<0.05]. We conclude partial IVC clamping improves hemodynamic stability during the construction of the rat portacaval shunt model.

Reversal of Experimental Posthepatectomy Liver Failure in Pigs: A New Application of Hepatocyte Bioreactors

Postoperative liver failure remains a major cause of morbidity and mortality after extensive hepatectomies. This study aims to evaluate the effectiveness of a hepatocyte bioreactor in the treatment of experimental post-hepatectomy liver failure. Our experimental model included a combination of a side-to-side portacaval shunt, occlusion of the hepatoduodenal ligament for 150 min, 70% hepatectomy, and reperfusion. Following the development of liver failure, 12 pigs were randomized into a control group (n = 6) and a treatment group (n = 6). Both groups underwent extracorporeal perfusion through a plasma separation device, a membrane oxygenator, and two parallel bioreactors. In the latter group, the bioreactors were loaded with 10 billion fresh hepatocytes, isolated from a donor pig. Following hepatocyte treatment, all animals were maintained for 24 h under mechanical ventilation, with intravenous fluid and glucose supplementation. Hemodynamic parameters, intracranial pressure, and biochemical parameters were measured. Liver biopsies were obtained during the 24-h autopsy. The extracorporeal circuit was well-tolerated hemodynamically. Treated animals had lower intracranial pressure compared with controls (at 24 h, 15 ± 3.1 vs. 22 ± 3.5 mm Hg, P = 0.006). Plasma ammonia in treated animals was lower compared with controls at 12 h (100 ± 29 vs. 244 ± 131 µmol, P = 0.026). Liver histological study showed decreased necrosis and increased regeneration activity in treated animals compared with controls. Treatment through an extracorporeal hepatocyte bioreactor attenuates brain edema and improves histological and functional parameters of the liver remnant of pigs with posthepatectomy liver failure.

Experimental study of protective effects of hepatotrophic factors on hepatic functions in rats with portal hypertension after portacaval shunt

To investigate the protective effects of hepatotrophic factors (hepatocyte growth-promoting factor and insulin) on hepatic functions and pathology in rats with portal hypertension after portacaval shunt. The rats of hepatic cirrhosis with portal hypertension were randomly assigned into 1 control group, 1 model group and 4 treatment groups (NS, HGF, INS, HGF + INS). An end-side portacaval shunt was performed in the treatment group. The hepatotrophic factors were respectively injected into portal vein. After treatment, the serum levels of ALT (alanine aminotransferase), AST (aspartate aminotransferase), HA (hyaluronic acid) and LN (laminin) were determined by radioimmunoassay. And then according to the hematoxylin and eosin (H&E) staining results, the tissue slides were prepared. The serum levels of ALT (30.13 ± 4.12 U/L), AST (133.75 ± 21.18 U/L), HA (322.49 ± 52.33 µg/L) and LN (23.89 ± 5.03 µg/L) were lower in the HGF + INS group than those in the NS group (all P < 0.01); the scores of hepatic fibrosis stages (1.63 ± 0.74) and collagen semiquantitative of Masson stain (10.17 ± 1.14 × 10(-2)) were significantly reduced in the HGF + INS group than those in the NS group (all P < 0.01). The injection of hepatotrophic factors through portal vein after portacaval shunt can improve hepatic functions, reduce the damages of hepatocyte and improve the degree of hepatic fibrosis.

Portacaval shunting attenuates portal hypertension and systemic hypotension in rat anaphylactic shock

Anaphylactic shock in rats is characterized by antigen-induced hepatic venoconstriction and the resultant portal hypertension. We determined the role of portal hypertension in anaphylactic hypotension by using the side-to-side portacaval shunt- and sham-operated rats sensitized with ovalbumin (1mg). We measured the mean arterial blood pressure (MAP), portal venous pressure (PVP), and central venous pressure (CVP) under pentobarbital anesthesia and spontaneous breathing. Anaphylactic hypotension was induced by an intravenous injection of ovalbumin (0.6mg). In sham rats, the antigen caused not only an increase in PVP from 11.3cmH(2)O to the peak of 27.9cmH(2)O but also a decrease in MAP from 103mmHg to the lowest value of 41mmHg. CVP also decreased significantly after the antigen. In the portacaval shunt rats, in response to the antigen, PVP increased slightly, but significantly, to the peak of 17.5cmH(2)O, CVP did not decrease, and MAP decreased to a lesser degree with the lowest value being 60mmHg. These results suggest that the portacaval shunt attenuated anaphylactic portal hypertension and venous return decrease, partially preventing anaphylactic hypotension. In conclusion, portal hypertension is involved in rat anaphylactic hypotension presumably via splanchnic congestion resulting in decreased venous return and thus systemic arterial hypotension.

Alcoholic Versus Nonalcoholic Cirrhosis in a Randomized Controlled Trial of Emergency Therapy of Bleeding Varices

It has been proposed that portal-systemic shunts be avoided in alcoholic cirrhotics because survival rate is allegedly lower in alcoholics than in nonalcoholics. We examined this issue in a randomized controlled trial. Two hundred eleven unselected, consecutive patients with cirrhosis and bleeding esophageal varices were randomized to endoscopic sclerotherapy (EST) (n = 106) or emergency portacaval shunt (EPCS) (105). Treatment was initiated within 8 h. EST failure was treated by rescue portacaval shunt (PCS). Ten-year follow-up was 96%. Results strongly favored EPCS over EST (P< 0.001). Among EPCS patients, 83% were alcoholic and 17% nonalcoholic. Outcomes were (1) permanent control of bleeding 100% versus 100%; (2) 5-y survival 71% versus 78%; (3) encephalopathy 14% versus 19%; (4) yearly charges $38,300 versus $43,000. EPCS results were similar in alcoholic and nonalcoholic cirrhotics. EPCS is an effective first line emergency treatment in all forms of cirrhosis, including alcoholic.

Liver Transplantation in a Randomized Controlled Trial of Emergency Treatment of Acutely Bleeding Esophageal Varices in Cirrhosis

Background Bleeding esophageal varices (BEV) in cirrhosis has been considered an indication for liver transplantation (LT). This issue was examined in a randomized controlled trial (RCT) of unselected, consecutive patients with advanced cirrhosis and BEV that compared endoscopic sclerotherapy (EST; n = 106) to emergency direct portacaval shunt (EPCS; n = 105). Methods Diagnostic work-up and treatment were initiated within 8 hours. Patients were evaluated for LT on admission and repeatedly thereafter; 96% underwent over 10 years of regular follow-up. The analysis was supplemented by 1300 unrandomized cirrhotic patients who previously underwent portacaval shunt (PCS) with 100% follow-up. Results In the RCT long-term bleeding control was 100% following EPCS, only 20% following EST. Also, 3-, 5-, 10-, and 15-year survival rates were 75%, 73%, 46%, and 46%, respectively, following EPCS compared with 44%, 21%, 9%, and 9% following EST, respectively ( P < .001). Only 13 RCT patients (6%) were ultimately referred for LT mainly because of progressive liver failure; only 7 (3%) were approved for LT and only 4 (2%) underwent LT. The 1- and 5-year LT survival rates were 0.68% and 0, respectively, compared with 81% and 73%, respectively, after EPCS. In the 1300 unrandomized PCS patients, 50 (3.8%) were referred and 19 (1.5%) underwent LT. The 5-year survival rate was 53% compared with 72% for all 1300 patients. Conclusions If bleeding is permanently controlled, as occurred invariably following EPCS, cirrhotic patients with BEV seldom require LT. PCS is effective first-line and long-term treatment. Should LT be required in patients with PCS, although technically more demanding, numerous studies have shown that PCS does not increase mortality or complications. EST is not effective emergency or long-term therapy.

Long-term survival after 67 hours of anhepatic state due to primary liver allograft nonfunction

Primary liver allograft nonfunction immediately after transplantation poses a life-threatening situation for the recipient. Emergency retransplantation may not be immediately possible due to organ unavailability. Total hepatectomy with temporary portacaval shunt has been described as a bridge to retransplantation when the presence of the graft appears to be harming the recipient. Case reports of retransplantation after total hepatectomy with anhepatic times greater than 48 hours routinely describe poor outcomes. We present a case with excellent patient outcome after 95 hours of clinical anhepatic state, including 67 hours of anatomical anhepatic time, because of primary liver allograft nonfunction. This case report documents the longest anhepatic time with subsequent successful transplant to date.

Astrocyte Glutamine Synthetase: Importance in Hyperammonemic Syndromes and Potential Target for Therapy

Many theories have been advanced to explain the encephalopathy associated with chronic liver disease and with the less common acute form. A major factor contributing to hepatic encephalopathy is hyperammonemia resulting from portacaval shunting and/or liver damage. However, an increasing number of causes of hyperammonemic encephalopathy have been discovered that present with the same clinical and laboratory features found in acute liver failure, but without liver failure. Here, we critically review the physiology, pathology, and biochemistry of ammonia (i.e., NH3 plus NH4+) and show how these elements interact to constitute a syndrome that clinicians refer to as hyperammonemic encephalopathy (i.e., acute liver failure, fulminant hepatic failure, chronic liver disease). Included will be a brief history of the status of ammonia and the centrality of the astrocyte in brain nitrogen metabolism. Ammonia is normally detoxified in the liver and extrahepatic tissues by conversion to urea and glutamine, respectively. In the brain, glutamine synthesis is largely confined to astrocytes, and it is generally accepted that in hyperammonemia excess glutamine compromises astrocyte morphology and function. Mechanisms postulated to account for this toxicity will be examined with emphasis on the osmotic effects of excess glutamine (the osmotic gliopathy theory). Because hyperammonemia causes osmotic stress and encephalopathy in patients with normal or abnormal liver function alike, the term "hyperammonemic encephalopathy" can be broadly applied to encephalopathy resulting from liver disease and from various other diseases that produce hyperammonemia. Finally, the possibility that a brain glutamine synthetase inhibitor may be of therapeutic benefit, especially in the acute form of liver disease, is discussed.

Direct Costs of Care in a Randomized Controlled Trial of Endoscopic Sclerotherapy versus Emergency Portacaval Shunt for Bleeding Esophageal Varices in Cirrhosis—Part 4

BackgroundEmergency treatment of bleeding esophageal varices (BEV) in cirrhotic patients is of prime importance because of the high mortality rate surrounding the episode of acute bleeding. Nevertheless, there is a paucity of randomized controlled trials of emergency surgical therapy and no reports of the costs of any of the widely used forms of emergency treatment. The important issue of direct costs of care was examined in a randomized controlled trial that compared endoscopic sclerotherapy (EST) to emergency portacaval shunt (EPCS). MethodsTwo hundred eleven unselected consecutive patients with ultimately biopsy-proven cirrhosis and endoscopically proven acute BEV were randomized to EST (n = 106) or EPCS (n = 105). Diagnostic workup was completed, and EST or EPCS was initiated within 8 h. Criteria for failure of EST or EPCS were clearly defined, and crossover rescue treatment was applied, when primary therapy failed. Ninety-six percent of patients underwent more than 10 years follow-up, or until death. Complete charges for all aspects of care were obtained continuously for more than 10 years. ResultsDirect charges for all aspects of care were significantly lower in patients treated by EPCS than in patients treated by emergency EST followed by long-term repetitive sclerotherapy. Charges per patient, per year of treatment, and per year in each child’s risk class were significantly lower in patients randomized to EPCS. Charges in patients who failed endoscopic sclerotherapy and underwent a rescue portacaval shunt were significantly higher than the charges in both the unshunted sclerotherapy patients and the patients randomized to EPCS. This result was particularly noteworthy given the widespread practice of using surgical portacaval shunt as rescue treatment only when all other forms of therapy have failed. ConclusionsIn this randomized controlled trial of emergency treatment of acute BEV, EPCS was significantly superior to EST with regard to direct costs of care as reflected in charges for care as well as in survival rate, control of bleeding, and incidence of portal-systemic encephalopathy. These results provide support for the use of EPCS as a first line of emergency treatment of BEV in cirrhosis (clinicaltrials.gov #NCT00690027).

Ultrasonography-guided percutaneous transhepatic portacaval shunt creation

We successfully created a percutaneous transhepatic portacaval shunt under ultrasonography (US) guidance in a 46-year-old man with refractory ascites. The shunt was created to salvage an attempt to create a transjugular intrahepatic portosystemic shunt (TIPS) that failed because of the elevated level of portal vein bifurcation due to alcoholic liver cirrhosis. Under US guidance, we simultaneously punctured the right branch of the portal vein and the inferior vena cava (IVC) using a two-step biliary drainage set. An Amplatz gooseneck snare was introduced transjugularly to retrieve the percutaneously inserted guidewire. The intrahepatic tract between the portal vein and the IVC was dilated using a balloon catheter, and a stent was placed in the tract. The patient showed complete resolution of ascites at discharge. We assume that our method is an alternative method for TIPS creation in patients with inadequate anatomical relations between the portal vein branches and the hepatic veins. This approach is thought to be feasible for patients with occluded or small hepatic veins.

Emergency Portacaval Shunt Versus Rescue Portacaval Shunt in a Randomized Controlled Trial of Emergency Treatment of Acutely Bleeding Esophageal Varices in Cirrhosis—Part 3

BackgroundEmergency treatment of bleeding esophageal varices in cirrhosis is of singular importance because of the high mortality rate. Emergency portacaval shunt is rarely used today because of the belief, unsubstantiated by long-term randomized trials, that it causes frequent portal-systemic encephalopathy and liver failure. Consequently, portacaval shunt has been relegated solely to salvage therapy when endoscopic and pharmacologic therapies have failed. Question: Is the regimen of endoscopic sclerotherapy with rescue portacaval shunt for failure to control bleeding varices superior to emergency portacaval shunt? A unique opportunity to answer this question was provided by a randomized controlled trial of endoscopic sclerotherapy versus emergency portacaval shunt conducted from 1988 to 2005. MethodsUnselected consecutive cirrhotic patients with acute bleeding esophageal varices were randomized to endoscopic sclerotherapy (n = 106) or emergency portacaval shunt (n = 105). Diagnostic workup was completed and treatment was initiated within 8 h. Failure of endoscopic sclerotherapy was defined by strict criteria and treated by rescue portacaval shunt (n = 50) whenever possible. Ninety-six percent of patients had more than 10 years of follow-up or until death. ResultsComparison of emergency portacaval shunt and endoscopic sclerotherapy followed by rescue portacaval shunt showed the following differences in measurements of outcomes: (1) survival after 5 years (72% versus 22%), 10 years (46% versus 16%), and 15 years (46% versus 0%); (2) median post-shunt survival (6.18 versus 1.99 years); (3) mean requirements of packed red blood cell units (17.85 versus 27.80); (4) incidence of recurrent portal-systemic encephalopathy (15% versus 43%); (5) 5-year change in Child’s class showing improvement (59% versus 19%) or worsening (8% versus 44%); (6) mean quality of life points in which lower is better (13.89 versus 27.89); and (7) mean cost of care per year ($39,200 versus $216,700). These differences were highly significant in favor of emergency portacaval shunt (all p < 0.001). ConclusionsEmergency portacaval shunt was strikingly superior to endoscopic sclerotherapy as well as to the combination of endoscopic sclerotherapy and rescue portacaval shunt in regard to all outcome measures, specifically bleeding control, survival, incidence of portal-systemic encephalopathy, improvement in liver function, quality of life, and cost of care. These results strongly support the use of emergency portacaval shunt as the first line of emergency treatment of bleeding esophageal varices in cirrhosis.

Neuropathological changes in the brain of pigs with acute liver failure

Objective. Cerebral edema is a serious complication of acute liver failure (ALF), which may lead to intracranial hypertension and death. An accepted tenet has been that the blood-brain barrier is intact and that brain edema is primarily caused by a cytotoxic etiology due to hyperammonemia. However, the neuropathological changes in ALF have been poorly studied. Using a well characterized porcine model we aimed to investigate ultrastructural changes in the brain from pigs suffering from ALF. Materials and methods. Sixteen female Norwegian Landrace pigs weighing 27–35 kg were randomised into two groups: ALF (n = 8) and sham operated controls (n = 8). ALF was induced with an end-to-side portacaval shunt followed by ligation of the hepatic arteries. Biopsies were harvested from three different areas of the brain (frontal lobe, cerebellum, and brain stem) following eight hours of ALF and analyzed using electron microscopy. Results. Profound perivascular and interstitial edema were found in all three areas. Disruption of pericytic and astrocytic processes were seen, reflecting breakdown/lesion of the blood-brain barrier in animals suffering from ALF. Furthermore, neurons and axons were edematous and surrounded by vesicles. Severe damage to Purkinje neuron (necrosis) and damaged myelin were seen in the cerebellum and brain stem, respectively. Biopsies from sham operated animals were normal. Conclusions. Our data support the concept that vasogenic brain edema plays an important role in the development of intracranial hypertension in pigs with ALF.

985 Emergency Portacaval Shunt Versus Rescue Portacaval Shunt in a Randomized Controlled Trial of Emergency Treatment of Bleeding Esophageal Varices in Cirrhosis

985 Emergency Portacaval Shunt Versus Rescue Portacaval Shunt in a Randomized Controlled Trial of Emergency Treatment of Bleeding Esophageal Varices in Cirrhosis

A Semi-Mechanistic Model to Predict the Effects of Liver Cirrhosis on Drug Clearance

Liver cirrhosis is characterized by a decrease in functional hepatocytes, lowered circulating levels of plasma proteins and alterations in blood flow due to the development of portacaval shunts. Depending on the interplay between these parameters and the characteristics of an administered drug, varying degrees of impaired systemic clearance and first-pass metabolism are anticipated. The Simcyp Population-based ADME Simulator has already been used successfully to incorporate genetic, physiological and demographic attributes of certain subgroups within healthy populations into in vitro-in vivo extrapolation (IVIVE) of xenobiotic clearance. The objective of this study was to extend population models to predict systemic and oral drug clearance in relation to the severity of liver cirrhosis. Information on demographics, changes in hepatic blood flow, cytochrome P450 enzymes, liver size, plasma protein binding and renal function was incorporated into three separate population libraries. The latter corresponded to Child-Pugh scores A (mild), B (moderate) and C (severe) liver cirrhosis. These libraries, together with mechanistic IVIVE within the Simcyp Simulator, were used to predict the clearance of intravenous and oral midazolam, oral caffeine, intravenous and oral theophylline, intravenous and oral metoprolol, oral nifedipine, oral quinidine, oral diclofenac, oral sildenafil, and intravenous and oral omeprazole. The simulated patients matched the clinical studies as closely as possible with regard to demographics and Child-Pugh scores. Predicted clearance values in both healthy control and liver cirrhosis populations were compared with observed values, as were the fold increases in clearance values between these populations. There was good agreement (lack of statistically significant difference, two-tailed paired t-test) between observed and predicted clearance ratios, with the exception of those for two studies of intravenous omeprazole. Predicted clearance ratios were within 0.8- to 1.25-fold of observed ratios in 65% of cases (range 0.34- to 2.5-fold). The various drugs that were studied showed different changes in clearance in relation to disease severity, and a 'one size fits all' solution does not exist without considering the multiple sources of the changes. Predictions of the effects of liver cirrhosis on drug clearance are of potential value in the design of clinical studies during drug development and, clinically, in the assessment of likely dosage adjustment.