Improved survival after liver transplantation in patients with hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) is present in 10-32% of chronic liver disease patients, carries a poor prognosis and is treatable by liver transplantation (LT). Previous reports have shown high LT mortality in HPS and severe HPS (arterial oxygen (PaO(2)) < or =50 mmHg). We reviewed outcomes in HPS patients who received LT between 2002 and 2008 at two transplant centers supported by a dedicated HPS clinic. We assessed mortality, complications and gas exchange in 21 HPS patients (mean age 51 years, MELD score 14), including 11/21 (52%) with severe HPS and 5/21 (24%) with living donor LT (median follow-up 20.2 months after LT). Overall mortality was 1/21 (5%); mortality in severe HPS was 1/11 (9%). Peritransplant hypoxemic respiratory failure occurred in 5/21 (24%), biliary complications in 8/21 (38%) and bleeding or vascular complications in 6/21 (29%). Oxygenation improved in all 19 patients in whom PaO(2) or SaO(2) were recorded. PaO(2) increased from 52.2 +/- 13.2 to 90.3 +/- 11.5 mmHg (room air) (p < 0.0001) (12 patients); a higher baseline macroaggregated albumin shunt fraction predicted a lower rate of postoperative improvement (p = 0.045) (7 patients). Liver transplant survival in HPS and severe HPS was higher than previously demonstrated. Severity of HPS should not be the basis for transplant refusal.

Neuroactive steroids and fatigue severity in patients with primary biliary cirrhosis and hepatitis C.

Fatigue is one of the most common non-specific symptoms associated with several disease states including liver diseases. Recently, it was reported that levels of progesterone metabolites such as allopregnanolone (3alpha,5alpha-tetrahydroprogesterone; 3alpha,5alpha-THP) and isopregnanolone (3beta,5alpha-THP) were increased in plasma of patients with chronic fatigue syndrome. We hypothesize that THP metabolites might be associated with fatigue commonly observed in chronic liver diseases. We evaluated fatigue scores and plasma levels of five progesterone metabolites in 16 patients with primary biliary cirrhosis (PBC), 12 patients with chronic hepatitis C (CHC) and 11 age-matched controls. The fatigue impact scale (FIS) ratio was significantly increased (P < 0.01) in patients with PBC and CHC compared to controls. Plasma levels of 3alpha,5alpha-THP and pregnanolone (3alpha,5beta-THP) were significantly increased in PBC and CHC patients. The other progesterone metabolites, i.e. 3beta,5alpha-THP, 3beta,5beta-THP and 3alpha,5alpha-tetrahydrodeoxycorticosterone were either undetectable or detected only in some patients. Plasma levels of 3alpha,5alpha-THP and 3alpha,5beta-THP were found to be significantly higher in patients with fatigue (P < 0.05), while those of patients without fatigue were not significantly different from controls. Both 3alpha,5alpha-THP and 3alpha,5beta-THP are positive allosteric modulators of the gamma-aminobutyric acid type A (GABA-A) receptor and readily cross the blood-brain barrier. The present preliminary findings suggest that increased inhibition through GABA-A receptors due to the accumulation of neuroinhibitory steroids may represent an important pathophysiological mechanism of fatigue in chronic liver diseases.

Usefulness of transjugular intrahepatic portosystemic shunt in the management of bleeding ectopic varices in cirrhotic patients.

PURPOSE: To evaluate the safety and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) in the control of bleeding from ectopic varices. METHODS: From 1995 to 2004, 24 cirrhotic patients, bleeding from ectopic varices, mean age 54.5 years (range 15-76 years), were treated by TIPS. The etiology of cirrhosis was alcoholic in 13 patients and nonalcoholic in 11 patients. The location of the varices was duodenal (n = 5), stomal (n = 8), ileocolic (n = 6), anorectal (n = 3), umbilical (n = 1), and peritoneal (n = 1). RESULTS: TIPS controlled the bleeding in all patients and induced a decrease in the portacaval gradient from 19.7 +/- 5.4 to 6.4 +/- 3.1 mmHg. Postoperative complications included self-limited intra-abdominal bleeding (n = 2), self-limited hemobilia (n = 1), acute thrombosis of the shunt (n = 1), and bile leak treated by a covered stent (n = 1). Median follow-up was 592 days (range 28-2482 days). Rebleeding occurred in 6 patients. In 2 cases rebleeding was observed despite a post-TIPS portacaval gradient lower than 12 mmHg and was controlled by variceal embolization; 1 patient underwent surgical portacaval shunt and never rebled; in 3 patients rebleeding was related to TIPS stenosis and treated with shunt dilatation with addition of a new stent. The cumulative rate of rebleeding was 23% and 31% at 1 and 2 years, respectively. One- and 2-year survival rates were 80% and 76%, respectively. CONCLUSION: The present series demonstrates that bleeding from ectopic varices, a challenging clinical problem, can be managed safely by TIPS placement with low rebleeding and good survival rates.

Relationship between pre-TIPS liver perfusion by the portal vein and the incidence of post-TIPS chronic hepatic encephalopathy.

OBJECTIVE: In the present study we evaluated the predictive value of pretransjugular intrahepatic portosystemic shunt (TIPS) portal perfusion as assessed by Doppler ultrasonography for the onset of chronic encephalopathy after TIPS. METHODS: A total of 231 cirrhotic patients were followed-up prospectively after TIPS placement. The pattern of intrahepatic portal flow was assessed before TIPS. Patients were divided into two groups according to Doppler findings. Group 1 comprised patients with prograde portal flow (n = 200), whereas group 2 comprised those with loss of portal perfusion (hepatofugal or back-and-forth flow or portal vein thrombosis; n = 31). The presence of chronic encephalopathy during a median follow-up of 32 months was prospectively recorded. The prognostic value of the following parameters for the onset of chronic recurrent encephalopathy after TIPS was evaluated: age, presence of encephalopathy before TIPS, alcoholism, Pugh score, and loss of portal perfusion before TIPS. The independent prognostic value of each variable was tested with a multiple logistic regression analysis. RESULTS: The two groups were comparable in terms of age, incidence of prior episodes of hepatic encephalopathy, and portacaval gradient before and after the procedure; however, liver failure was more severe in patients in group 2 (Pugh score: 9.2 +/- 1.9 vs 10.3 +/- 1.7). The 3-yr survival was identical for both groups; 25% of the 200 patients in group 1 developed chronic encephalopathy as compared to 6% of the 31 patients in group 2 (p = 0.03). Multiple logistic regression analysis demonstrated that loss of portal perfusion and age >65 yr were the only independent predictors of the onset of post-TIPS chronic encephalopathy (odds ratios 0.24 and 1.98, respectively). CONCLUSIONS: Cirrhotic patients with loss of portal perfusion before TIPS were protected against post-TIPS chronic hepatic encephalopathy despite a more severe liver dysfunction at baseline. The only other independent predictive factor for the onset of this complication was age.

Transjugular intrahepatic portosystemic shunt (TIPS) versus endoscopic variceal ligation in the prevention of variceal rebleeding in patients with cirrhosis: a randomised trial.

BACKGROUND AND AIMS: The transjugular intrahepatic portosystemic shunt (TIPS) is a new therapeutic modality for variceal bleeding. In this study we compared the two year survival and rebleeding rates in cirrhotic patients treated by either variceal band ligation or TIPS for variceal bleeding. METHODS: Eighty cirrhotic patients (Pugh score 7-12) with variceal bleeding were randomly allocated to TIPS (n=41) or ligation (n=39), 24 hours after control of bleeding. RESULTS: Mean follow up was 581 days in the ligation group and 678 days in the TIPS group. The two year survival rate was 57% in the TIPS group and 56% in the ligation group (NS); the incidence of variceal rebleeding after two years was 18% in the TIPS group and 66% in the ligation group (p<0.001). Uncontrolled rebleeding occurred in 11 patients in the ligation group (eight were rescued by emergency TIPS) but in none of the TIPS group. The incidence of encephalopathy at two years was 47% in the TIPS group and 44% in the ligation group (NS). CONCLUSIONS: TIPS did not increase the two year survival rate compared with variceal band ligation after variceal bleeding in cirrhotic patients with moderate or severe liver failure. It significantly reduced the incidence of variceal rebleeding without increasing the rate of encephalopathy.

Furosemide-induced natriuresis as a test to identify cirrhotic patients with refractory ascites.

The diagnosis of refractory ascites in cirrhotic patients carries a poor prognosis and liver transplantation should always be considered in this situation. Identification of patients who will not respond to diuretic therapy usually requires several weeks of observation during which a trial of diuretics is instituted using stepwise increases in dosage in order to classify ascites as refractory. In the present study we evaluated the effect of a single dose of 80 mg intravenous furosemide on urinary sodium excretion over 8 hours in cirrhotic patients with ascites responsive to diuretic treatment (group 1; n = 14) and patients with refractory ascites (group 2; n = 15). The test was performed after 3 days without diuretics and patients were on a 80 mEq sodium/day diet. Refractory ascites was defined by the absence of response after 3 months of high doses of diuretics (spironolactone 200 mg/d + furosemide 80 mg/d + metolazone 2.5 mg/d) and the need for repeated paracentesis. The two groups had similar degrees of liver and renal dysfunction as assessed by the Pugh score and creatinine clearance. The effects of furosemide on 8-hour natriuresis was much higher in patients with responsive ascites as compared with patients with refractory ascites (125 +/- 46 vs. 30 +/- 16 mEq; mean +/- SD; P <.0001). A natriuresis lower than 50 mEq/8 hours was observed in all group-2 patients as compared with none from group 1. The present study shows that patients with refractory ascites can be identified quickly and accurately by using this simple furosemide-induced natriuresis test, which could be very useful to select patients for liver transplantation.

Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B.

The prognosis of decompensated cirrhosis resulting from chronic hepatitis B is poor, and the benefits of treatment with interferon are outweighed by serious side effects and by the risk of fatal exacerbation of disease activity. Lamivudine rapidly reduces hepatitis B virus (HBV)-DNA in serum to undetectable levels. We have treated 35 patients with chronic hepatitis B and decompensated cirrhosis with lamivudine 100 mg or 150 mg orally once daily. Pretreatment, all were positive for HBV-DNA in serum. Ten had Child-Pugh class B and 25 had Child-Pugh class C liver disease. Seven patients underwent liver transplantation within 6 months of treatment initiation, 5 patients died within 6 months, and 23 patients were treated for at least 6 months (mean = 19 months). In a majority of these 23 cases, there was a slow but marked improvement in liver function, which was most apparent after 9 months of treatment, with a decrease in serum bilirubin from 67 +/- 13 to 30 +/- 4 micromol/L (P <.05, baseline vs. 9 months), an increase in serum albumin from 27 +/- 1 to 34 +/- 1g/L (P <.05), and a decrease in Child-Pugh score from 10.3 +/- 0.4 to 7.5 +/- 0.5 (P <.05). Three patients developed resistance to lamivudine because of a mutation in the YMDD motif, but liver function did not deteriorate. We conclude that inhibition of viral replication with lamivudine results in a significant improvement of liver function in patients with decompensated HBV cirrhosis, but the long-term benefits remain uncertain.

Treatment of chronic bleeding from gastric antral vascular ectasia (GAVE) with estrogen-progesterone in cirrhotic patients: an open pilot study.

OBJECTIVE: Gastric antral vascular ectasia (GAVE) is a rare cause of chronic bleeding in cirrhotic patients. Treatment of GAVE with surgical or nonsurgical portal decompression, beta-blockers, or endoscopic therapy provides disappointing results. In the present study, we evaluated the efficacy of estrogen-progesterone therapy, which has been reported to control chronic bleeding in gastrointestinal vascular malformations, such as Osler-Weber Rendu disease or angiodysplasia, in GAVE-related chronic bleeding. METHODS: Six cirrhotic patients who bled chronically from GAVE were included. Three had alcoholic cirrhosis, two cryptogenic cirrhosis, and one primary biliary cirrhosis. Grade 1 esophageal varices were noted in four patients. Bleeding could not be controlled by beta-blockers, and endoscopic therapy was not considered given the extension of the antral vascular lesions. RESULTS: Before the start of therapy, transfusion requirements averaged 3.5 units/month over a 1.5-11 month period of observation. Patients were then treated with a combination of ethynil estradiol 30 microg and noretisterone 1.5 mg daily. During follow-up (range 3-12 months), bleeding did not recur in four patients; in one patient, treatment with estrogen progesterone decreased the need for transfusions from 4 units/month to 1.4 unit/month; this patient stopped the treatment inadvertently after 6 months and severe anemia recurred with a need for 4 units of blood in the following month; reintroduction of the treatment resulted in an increase of hemoglobin levels without the need for blood transfusions during the following 4 months. In the last patient, a 5-month treatment did not improve chronic bleeding. CONCLUSIONS: The present study suggests that estrogen-progesterone therapy is useful in the treatment of chronic bleeding related to GAVE; however, these findings require confirmation by a controlled trial.

Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction.

BACKGROUND & AIMS: Manganese (Mn) deposition could be responsible for the T(1)-weighted magnetic resonance signal hyperintensities observed in cirrhotic patients. These experiments were designed to assess the regional specificity of the Mn increases as well as their relationship to portal-systemic shunting or hepatobiliary dysfunction. METHODS: Mn concentrations were measured in (1) brain samples from basal ganglia structures (pallidum, putamen, caudate nucleus) and cerebral cortical structures (frontal, occipital cortex) obtained at autopsy from 12 cirrhotic patients who died in hepatic coma and from 12 matched controls; and from (2) brain samples (caudate/putamen, globus pallidus, frontal cortex) from groups (n = 8) of rats either with end-to-side portacaval anastomosis, with biliary cirrhosis, or with fulminant hepatic failure as well as from sham-operated and normal rats. RESULTS: Mn content was significantly increased in frontal cortex (by 38%), occipital cortex (by 55%), pallidum (by 186%), putamen (by 66%), and caudate (by 54%) of cirrhotic patients compared with controls. Brain Mn content did not correlate with patient age, etiology of cirrhosis, or history of chronic hepatic encephalopathy. In cirrhotic and portacaval-shunted rats, Mn content was increased in pallidum (by 27% and 57%, respectively) and in caudate/putamen (by 57% and 67%, respectively) compared with control groups. Mn concentration in pallidum was significantly higher in portacaval-shunted rats than in cirrhotic rats. No significant changes in brain Mn concentrations were observed in rats with acute liver failure. CONCLUSIONS: These findings suggest that brain Mn deposition results both from portal-systemic shunting and from liver dysfunction.

Predictors of clinical response to transjugular intrahepatic portosystemic shunt (TIPS) in cirrhotic patients with refractory ascites.

OBJECTIVE: Transjugular intrahepatic portosystemic shunt (TIPS) is used increasingly as a treatment for refractory ascites. The aim of the present study was to determine the prognostic value of different parameters in predicting a favorable evolution following TIPS in a cohort of 53 cirrhotic patients without organic renal disease and with refractory ascites. METHODS: Patients were classified as good responders if they survived more than 6 months, without severe chronic hepatic encephalopathy and with good control of ascites. The prognostic value for a good outcome was evaluated using age, creatinine clearance, plasma renin activity, plasma aldosterone, and Pugh score. RESULTS: Good control of ascites was obtained in 90%. The cumulative survival rate was 54% at 6 months, 48% at 1 yr, and 39% at 2 yr. The vast majority of patients died of complications of hepatic insufficiency. Severe chronic hepatic encephalopathy developed in 26%. Overall, a good clinical response was observed in 47%. Creatinine clearance was identified as the only pre-TIPS factor to be significantly and independently associated with a good clinical response to TIPS for refractory ascites. A good clinical response was observed in 57% of patients with a creatinine clearance >36 ml/min compared to 9% of those with a clearance <36 ml/min (p < 0.01). This cutoff point in creatinine clearance had a sensitivity of 96% and a specificity of 36%; positive predictive and negative predictive values were 57% and 90%, respectively. CONCLUSIONS: TIPS might be useful for the treatment of refractory ascites in cirrhotic patients without severe renal function impairment. However, the TIPS usefulness still has to be demonstrated compared to large volume paracentesis or Leveen shunt. In patients with poor renal function or with liver failure after TIPS, liver transplantation should be considered.

Gastric antral vascular ectasia in cirrhotic patients: absence of relation with portal hypertension.

BACKGROUND: Portal hypertensive gastropathy and gastric antral vascular ectasia (GAVE) are increasingly recognised as separate entities. The pathogenic role of portal hypertension for the development of GAVE is still controversial. AIMS: To evaluate the effects of portal decompression on chronic bleeding related to GAVE in cirrhotic patients. METHODS: Eight patients with cirrhosis and chronic blood loss related to GAVE were included. GAVE was defined endoscopically and histologically. RESULTS: All patients had severe portal hypertension (mean portocaval gradient (PCG) 26 mm Hg) and chronic low grade bleeding. Seven patients underwent transjugular intrahepatic portosystemic shunt (TIPS) and one had an end to side portacaval shunt. Rebleeding occurred in seven patients. In these, TIPS was found to be occluded after 15 days in one patient; in the other six, the shunt was patent and the PCG was below 12 mm Hg in five. In the responder, PCG was 16 mm Hg. Antrectomy was performed in four non-responders; surgery was uneventful, and they did not rebleed after surgery, but two died 11 and 30 days postoperatively from multiorgan failure. In one patient, TIPS did not control GAVE related bleeding despite a notable decrease in PCG. This patient underwent liver transplantation 14 months after TIPS; two months after transplantation, bleeding had stopped and the endoscopic appearance of the antrum had normalised. CONCLUSIONS: Results suggest that GAVE is not directly related to portal hypertension, but is influenced by the presence of liver dysfunction. Antrectomy is a therapeutic option when chronic bleeding becomes a significant problem but carries a risk of postoperative mortality.

Segment 4 (the quadrate lobe): a barometer of cirrhotic liver disease at US.

PURPOSE: To evaluate the dimensions of segment 4 of the liver in patients with cirrhosis by using ultrasonography (US). MATERIALS AND METHODS: The transverse diameter of segment 4 was measured in 125 control subjects without liver disease and 167 patients with cirrhosis. The size of segment 4 was measured on oblique subcostal US scans obtained between the left wall of the gallbladder (or the main fissure after cholecystectomy) and the ascending or umbilical portion of the left portal vein at the point where it gives rise to the branch to segment 4. RESULTS: In the control subject group, the mean diameter of segment 4 was 43 mm +/- 8 (standard deviation). In the patient group, the mean diameter of segment 4 was 28 mm +/- 9. The cause or severity of cirrhosis had no influence on the size of segment 4. CONCLUSION: A decreased diameter of segment 4 may be a helpful adjunct sign of cirrhosis in the US investigation of chronic liver disease.

Glomerular filtration rate measurement in cirrhotic patients with renal failure.

Assessment of renal function, namely glomerular filtration rate (GFR), by the renal creatinine clearance, may be problematic and less accurate in cirrhotics; however, it is an essential element in the global evaluation of these patients. In order to better characterize misinterpretation of GFR by the renal creatinine clearance, we compared a group of cirrhotic patients with renal failure (n - 30) to a group of chronic renal failure patients (CRF) without liver disease (n - 5). Inulin and PAH clearances were measured during a 4-hour infusion of inulin and PAH; renal creatinine clearance was measured during a 24-hour urine collection and this, simultaneously with inulin and PAH clearance. We observed that in moderate to severe renal failure (renal inulin clearance 30 +/- 10 ml/min), GFR (i. e. renal inulin clearance) in cirrhotic patients was overestimated by the renal creatinine clearance, similarly to CRF patients (ratio 1.8 +/- 0.7 and 1.6 +/- 0.9 respectively); however cirrhotic patients have a lower serum creatinine (186 +/- 97 vs 133 +/- 62 micromol/l respectively). On the other hand, cirrhotic patients with mild renal dysfunction (renal inulin clearance 74 +/- 15 ml/min) had a renal creatinine clearance of 77 +/- 25 ml/min. Systemic inulin clearance overestimated renal inulin clearance, proportionally to the severity of renal dysfunction. We conclude that it is only the degree of renal failure, irrespective of etiology, that explains the overestimation of the glomerular filtration rate by the renal creatinine clearance in cirrhotic patients; hence, there is no specific alteration in the renal excretion of creatinine in cirrhotic patients.

Lack of relationship between preoperative measures of the severity of cirrhosis and short-term survival after liver transplantation.

The purpose of this study was to evaluate the prognostic value of clinical measures of the severity of disease in cirrhotic patients who were candidates for liver transplantation at our institution. The records of the 132 cirrhotic patients who were candidates for a first transplantation between January 1, 1987, and December 31, 1994, were reviewed. One hundred nine patients (82.6%) received grafts, and 23 (17.4%) died while on the waiting list. The variables examined included level of medical urgency at the time of enlistment, date of transplantation, serum creatinine level, variables that constitute the Child-Pugh score and Shaw's risk score (serum bilirubin and albumin, prothrombin time, ascites, encephalopathy, nutritional status, age, and operative blood loss), and 6-month survival status after transplantation. The proportion of patients who died awaiting a graft increased as a function of the Child-Pugh score at enlistment (score 5-6, 0%, n = 6; score 7-9, 7%, n = 54; score 10-11, 18%, n = 33; score 12-15, 33%, n = 39; P = .01). Six-month survival rates after transplantation were similar irrespective of the Child-Pugh score or Shaw's risk score. Stepwise multiple logistic regression models identified the degree of ascites, serum bilirubin, and operative blood loss as significant variables for the prediction of overall mortality 6 months posttransplantation (model chi 2 = 12.8; P = .025; r = 0.32), but the model explained only 10% of the outcomes observed. We concluded that the Child-Pugh score is a valid prognostic index for survival up to the time of transplantation for cirrhotic patients on the waiting list; however, clinical measures of the severity of cirrhosis are poor predictors of 6-month survival after transplantation.

Treatment of refractory ascites using transjugular intrahepatic portosystemic shunt (TIPS): a caution.

Ascites becomes refractory to medical treatment in nearly 10% of cirrhotic patients, who then require repeated large-volume paracentesis. In this prospective study we evaluated the use of transjugular intrahepatic portosystemic shunt (TIPS) in 30 patients with refractory ascites. TIPS was successful in all and resulted in a 54% reduction in portacaval gradient (from 22.8 +/- 0.8 to 10.4 +/- 0.6 mm Hg). Ascites became easily controlled with diuretics in 26 patients following TIPS. Ascites recurrence associated with shunt stenosis was observed during follow-up in eight patients; revision could be undertaken in five of them and resulted in good control of ascites. In responders, a marked decrease in plasma aldosterone and renin activity, a reduction in serum creatinine, and a rise in urinary sodium excretion were observed. Creatinine and inulin clearances improved significantly; PAH clearance remained unchanged. However, new-onset or worsening hepatic encephalopathy was seen in 14 patients. Severe disabling chronic encephalopathy occurred in five patients; it could be reversed successfully by balloon occlusion of the shunt in three. The cumulative survival rate was 41 and 34% at 1 and 2 years, respectively. In summary, TIPS can control refractory ascites in a majority of patients but is associated with a high rate of chronic disabling HE. In addition, the survival rate is poor. Randomized trials are needed to evaluate the exact role of TIPS in the management of refractory ascites. It is unlikely to improve survival but can ameliorate quality of life in nontransplant candidates and be useful as a bridge to transplantation, in particular, to improve denutrition associated with longstanding tense ascites.

Changes in plasma endothelin-1 and Big endothelin-1 induced by transjugular intrahepatic portosystemic shunts in patients with cirrhosis and refractory ascites.

BACKGROUND/AIMS: Endothelin-1 (ET-1) is a potent vasoconstrictor that may be involved in the pathogenesis of splanchnic and renal hemodynamic changes associated with portal hypertension. The aim of this study was to measure the concentration of ET-1 and of its precursor Big endothelin-1 (Big ET-1) in the systemic circulation as well as in the splanchnic and renal venous beds and to evaluate changes after the relief of portal hypertension following transjugular intrahepatic portosystemic shunt placement. METHODS: Plasma concentrations of ET-1 and of Big ET-1 were measured in the vena cava, renal vein, hepatic vein and portal vein in ten patients with cirrhosis and refractory ascites before and 1-2 months after transjugular intrahepatic portosystemic shunt. The porto-caval gradient, creatinine clearance, plasma aldosterone and renin activity, as well as daily urinary sodium excretion were measured at the same time. RESULTS: The plasma concentration of ET-1 and Big ET-1, respectively, in peripheral blood of normal volunteers were 0.28 +/- 03 and 3.95 +/- 0.34 pg/ml; the concentrations of both peptides were higher in patients with cirrhosis, both in vena cava (0.61 +/- 0.14 and 10.01 +/- 1.47 pg/ml), hepatic vein (0.62 +/- 0.13 and 13.93 +/- 1.77 pg/ml), portal vein (1.21 +/- 0.12 and 17.84 +/- 1.98 pg/ml) and renal vein (0.76 +/- 0.12 and 14.21 +/- 1.55 pg/ml). Moreover ET-1 and Big ET-1 concentrations were more elevated in the portal vein than in the vena cava (+98% and +70%) and slightly higher in the renal vein as compared to the vena cava (+25% and +42%). After transjugular intrahepatic portosystemic shunt, a rise in creatinine clearance and urinary sodium excretion (+49%; and +53%) was observed together with a marked reduction in plasma aldosterone and renin activity (-59% and -49%). ET-1 and Big ET-1 concentrations remained unchanged in the vena cava whereas a significant reduction of ET-1 and Big ET-1 occurred both in the portal vein (-43% and -44%) and in the renal vein (-53% and -29%). Portal vein and renal vein concentrations of both peptides became similar to vena cava levels. CONCLUSIONS: Splanchnic and renal hemodynamic changes occurring in patients with cirrhosis and refractory ascites could be related to the production of ET-1 by splanchnic and renal vascular beds. This was abolished by transjugular intrahepatic portosystemic shunt, which could explain the exacerbation of systemic vasodilation and the improvement in renal perfusion observed after the procedure.

Increased blood manganese in cirrhotic patients: relationship to pallidal magnetic resonance signal hyperintensity and neurological symptoms.

Increasing evidence suggests that manganese deposition is responsible for the T1-weighted magnetic resonance imaging (MRI) signal hyperintensity consistently observed in pallidum of cirrhotic patients. However, the relationship between blood manganese and the etiology or severity of liver disease, as well as the neurological symptomatology in these patients, has not been well established. In the present study, blood manganese concentrations were measured by atomic absorption spectrometry together with MRI and neurological evaluation in 57 cirrhotic patients with various etiologies and severity of liver disease. Blood manganese concentrations were elevated in 67% of cirrhotic patients and were significantly higher in patients with previous portacaval anastomoses or transjugular intrahepatic portosystemic shunt (TIPS). Pallidal signal hyperintensity was observed in 88% of patients, and significant correlations were demonstrated between blood manganese and pallidal index (PI) (a measure of pallidal signal hyperintensity), as well as Child-Pugh score. Assessment of extrapyramidal symptoms using the Columbia rating scale revealed a significant incidence of tremor, rigidity, or akinesia in up to 89% of cirrhotic patients. However, there was no significant correlation between blood manganese and extrapyramidal symptoms, although severity of akinesia was significantly greater in Child-Pugh C patients. Extrapyramidal symptoms could result from a toxic effect of manganese on basal ganglia dopaminergic function. These findings further support a role for manganese in the etiology of pallidal MRI signal hyperintensity in patients with chronic liver disease.