Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15.

BACKGROUND: Hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome (OMIM 238970) is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15. To date, 22 different mutations of the SLC25A15 gene have been described in 49 patients belonging to 31 unrelated families. OBJECTIVE: To further delineate the phenotypic spectrum of HHH syndrome from a description of a genetically homogeneous cohort of patients and identify prognostic factors based on long-term follow-up. METHODS: Sixteen French-Canadian patients were retrospectively and prospectively clinically assessed. RESULTS: Owing to a founder effect, 15 of the 16 patients were homozygous for the F188del mutation in the SLC25A15 gene. The main clinical features at presentation were liver dysfunction (6/16) and neurological disease (9/16), including chronic neurological symptoms (6/9) and acute encephalopathy (3/9). Hyperammonaemia was not constant and usually mild and uncommon after start of treatment. Long-term follow-up showed that variable intellectual impairment and lower limb spasticity often occur, together or separately, with no obvious relationship to age at diagnosis and compliance with treatment. CONCLUSION: We report the largest known cohort to date of patients with HHH syndrome. A similar range of severity occurred in the clinical course and outcome of patients homozygous for delF188 and in the 33 other reported patients compiled from the literature. The poor clinical outcome of some patients with HHH syndrome despite early treatment and repeatedly normal plasma ammonia levels emphasises the need to better understand the pathophysiology and to reconsider the therapeutic goals for HHH.

Transhepatic portal vein stenting for treatment of ruptured duodenopancreatic varices in a patient with chronic pancreatitis.

BACKGROUND: Portal vein obstruction with secondary variceal bleeding in the setting of chronic pancreatitis has not been recognized as frequently as splenic vein occlusion. This condition can be difficult to diagnose and treat. METHODS: A 54-year old man was referred for massive recurrent endoscopy-negative upper-gastrointestinal bleeding. The diagnosis of duodenopancreatic varices was finally made. Direct portography showed a high-grade stenosis of the proximal portal vein that was dilated and stented with a balloon expandable prosthesis. RESULTS: The gradient across the stenosis fell from 9 to 2 mm Hg. Bleeding stopped. After 7 months of follow-up, the patient has experienced no rebleeding, and a Doppler examination is normal. CONCLUSIONS: In patients with chronic pancreatitis and upper gastrointestinal tract bleeding of unknown origin, obstruction of one of the major splanchnic veins must be excluded. Portal vein dilatation and stenting appears to be a safe procedure with good short-term results.

Propranolol disposition in the rat: variation in hepatic extraction with unbound drug fraction.

The plasma protein binding of propranolol has been described as nonrestrictive for its hepatic extraction to explain the observation that propranolol is efficiently removed by the liver, in spite of extensive protein binding. The present study was designed to examine the relationship between propranolol protein binding, metabolism by isolated hepatocytes, and extraction by the isolated perfused rat liver. In isolated hepatocytes, the intrinsic clearance of free drug increased three- to fourfold as albumin and alpha 1-acid glycoprotein (AAG) concentrations increased, suggesting that albumin and AAG facilitate the elimination of propranolol by hepatocytes. In the isolated perfused liver, propranolol extraction was almost complete (E = 0.996) in the absence of albumin and AAG. With 40 g/L of albumin and 2 g/L of AAG in the perfusate, the free fraction of propranolol decreased to 0.031, but extraction remained high (E = 0.960). With 40 g/L of albumin and 10 g/L of AAG in the perfusate, the free fraction further decreased to 0.014 and extraction dropped sharply (E = 0.820). The observed relationship between propranolol extraction and the free fraction of propranolol was in good agreement with that predicted using estimates of intrinsic clearance measured in isolated hepatocytes suspensions. These data indicate that propranolol extraction is sensitive to changes in binding at very low free fraction values and suggest a facilitation of propranolol clearance by albumin and AAG.

[Experience with the transjugular intrahepatic portocaval shunt]. / Expérience avec la dérivation portocave intrahépatique transjugulaire.

Liver transplantation and the intrahepatic shunt have changed the management of variceal hemorrhage and refractory ascites. The purpose of this work is to review the results obtained with intrahepatic shunting. From January 1991 to May 1993, 45 patients underwent a transjugular intrahepatic portosystemic shunt. In 23 patients, liver insufficiency was considered moderate and in 21 severe. Indications for the procedure were: variceal bleeding (23), refractory ascites (19) and portal hypertensive gastritis (3). The portocaval gradient was lowered from 24.2 +/- 5.1 mm Hg to 12.9 +/- 3.9 (-47%). The procedure was effective in 78% of variceal bleeders and in 89% of patients with ascites. Thirty-day mortality was 22%. One-year survival was 39%. Liver failure or severe encephalopathy occurred in 27% of patients. Four patients (9%) presented intra-abdominal bleeding. Four patients developed renal failure. Transjugular intrahepatic portosystemic shunts are effective in lowering portal pressure and controlling complications of portal hypertension. However, important side effects are present and controlled studies are required to evaluate this new treatment.

Intrahepatic pressure measurement: not an accurate reflection of portal vein pressure.

Previous studies have established the reliability of percutaneous portal venous pressure measurement using a Chiba needle, a procedure requiring fluoroscopic guidance. Intrahepatic pressure has been advocated by some as a simple and safe index of portal venous pressure. The aim of this study was to examine the reliability of intrahepatic pressure measurement and its relationship to portal venous pressure. Fifty patients requiring liver biopsy were included: 29 with cirrhosis (n = 20 micronodular, n = 9 macronodular) and 21 with various hepatic disorders but no cirrhosis. The procedure was performed under fluoroscopic guidance, using a Chiba needle connected to a manometer by a saline-filled catheter. Immediately prior to biopsy, each patient underwent measurement of: (i) 3 to 5 separate intrahepatic pressures, the intraparenchymal site being inferred by the lack of blood or bile return; and (ii) portal and hepatic venous pressures, the intravascular position of the needle being ascertained by the reflux of blood and the vessel identified with injection of contrast. Intrahepatic pressure measurements showed great intraindividual variability (variation coefficient up to 115%). Mean intrahepatic pressure (13.19 +/- 8.32 mm Hg) was similar to portal venous pressure (14.43 +/- 6.10 mm Hg) in the noncirrhotics but significantly lower in the cirrhotics (intrahepatic pressure = 18.34 +/- 8.82 mm Hg, portal venous pressure = 22.52 +/- 9.47 mm Hg; p less than 0.01). The difference between these two parameters exceeded 3 mm Hg in 50% of patients (mean = 9 mm Hg, range = 4 to 19 mm Hg), both in cirrhotics and noncirrhotics.(ABSTRACT TRUNCATED AT 250 WORDS)

Clearance by the liver in cirrhosis. I. Relationship between propranolol metabolism in vitro and its extraction by the perfused liver in the rat.

To delineate the factors responsible for impaired clearance in cirrhosis, we examined propranolol disposition in rats with carbon tetrachloride-induced cirrhosis and compared it with that in control animals, rats treated with chlorpromazine (an inhibitor of propranolol metabolism) and rats with acute liver injury. We measured the extraction ratio of propranolol by the isolated perfused liver and related it to estimates of propranolol drug-metabolizing enzyme activity in homogenates of the same livers. In control animals, drug-metabolizing enzyme activity (measured as the ratio Vmax/Km) averaged 5,319 +/- 1,193 ml/min; the extraction ratio in the perfused liver was close to 1.0 (0.97 +/- 0.01). Important decreases of microsomal enzyme activity were observed in rats treated with chlorpromazine (30 +/- 27 ml/min, p < 0.001) and in rats with acute liver injury (724 +/- 401 ml/min, p < 0.001), accounting for the decrease in the hepatic extraction ratio by the perfused liver (0.33 +/- 0.09 and 0.71 +/- 0.04, respectively, p < 0.01). In cirrhotic livers, enzyme activity was not significantly different from that of controls (3,592 +/- 1,857 ml/min) and could not account for the observed decrease in extraction (0.66 +/- 0.14, p < 0.01). The extraction of antipyrine by the isolated perfused liver was also measured as an index of microsomal enzyme activity and related to propranolol extraction. Antipyrine extraction was decreased by 90% in acute liver injury, compared with 33% in cirrhosis, suggesting a much greater reduction of microsomal enzyme activity in the former group.(ABSTRACT TRUNCATED AT 250 WORDS)

Clearance by the liver in cirrhosis. II. Characterization of propranolol uptake with the multiple-indicator dilution technique.

We studied the steady-state hepatic extraction and single-pass hepatic uptake of propranolol in isolated perfused livers from normal rats and compared these values with those of rats with carbon tetrachloride-induced cirrhosis, rats treated with chlorpromazine (an inhibitor of propranolol metabolism) and rats with acute liver injury. The kinetics of propranolol transport in the liver were characterized by means of the multiple-indicator dilution technique, and estimates of cellular influx, efflux and sequestration rate constants were obtained with a computer fit to the model of Goresky. The outflow pattern of propranolol in the hepatic veins was then resolved into throughput material, which had swept past the hepatocytes along with albumin, and returning material, which had entered the cells but returned in the outflow after escaping metabolic sequestration. The steady-state extraction of propranolol was significantly decreased in the three experimental groups compared with that in controls, but the outflow profile differed within each group. In cirrhotic animals, influx was markedly decreased and the sequestration rate constant remained unchanged; most of the propranolol in the outflow consisted of throughput material. In rats treated with chlorpromazine, the sequestration rate constant was decreased, and propranolol in the outflow was mainly returning material. In rats with acute liver injury, both influx and sequestration rate constants were decreased. Indicator dilution curves for nonsequestered tracers showed a decreased transit time for red blood cells and abnormal diffusion of albumin and sucrose into the space of Disse in cirrhotic rats compared with the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Propranolol metabolism by isolated hepatocytes from normal and cirrhotic rat livers: the effect of albumin.

Several recent reports have shown that the hepatic uptake and subsequent elimination of some substrates is faster in the presence of albumin than in its absence, as if some of the substrate bound to albumin was also available for uptake. In the present study, we examined the effect of albumin on the clearance of propranolol by isolated rat hepatocyte suspensions. The clearance of total drug decreased progressively as albumin concentration increased. There was also a progressive decrease in the free fraction of propranolol and the net result was an increase in the clearance of unbound drug (+50% at 40 g/L albumin). This increase was not due to an oncotic pressure effect of albumin, nor to the presence of fatty acids bound to albumin. The clearance of propranolol by isolated hepatocytes from cirrhotic rats was decreased compared with controls (-50%), and albumin also increased propranolol free clearance, albeit to a lesser extent than in control animals. Our results indicate that albumin facilitates the elimination of propranolol by hepatocytes, possibly because of surface-mediated catalysis of the albumin-propranolol complexes.

Value of measurement of mean portal flow velocity by Doppler flowmetry in the diagnosis of portal hypertension.

To establish the sensitivity and specificity of the mean portal flow velocity in the diagnosis of portal hypertension, a population of 304 consecutive cirrhotic patients, in whom 246 abdominal Doppler examinations were performed, was prospectively analysed between June 1988 and December 1990. To avoid equipment-related variability only examinations performed using the same equipment were considered. Further inclusion criteria were the absence of portal vein thrombosis or reversed flow in the portal vessels and the absence of spontaneous, ultrasonographically detectable, portosystemic shunts. The parameter evaluated was mean portal flow velocity calculated directly from the Doppler trace by specific, operator-independent, software. 123 patients satisfied the inclusion criteria. As a control group 60 healthy age- and sex-matched subjects were examined. Mean portal flow velocity was significantly lower in cirrhotic patients than healthy subjects (13.0 +/- 3.2 cm/s vs. 19.6 +/- 2.6 cm/s; p < 0.001). There was also a decrease in mean portal flow velocity in cirrhotics in each Child-Pugh category (13.8 +/- 2.8 cm/s in Child-Pugh A class; 12.1 +/- 3.5 cm/s in Child-Pugh B class and 11.0 +/- 2.4 cm/s in Child-Pugh C class) with a statistically significant difference between each Child-Pugh category and healthy subjects (p < 0.001), between Child-Pugh A and B (p < 0.01) and between Child-Pugh A and C (p < 0.005). The sensitivity and specificity of mean portal flow velocity in the detection of portal hypertension was then analyzed with the receiver operating characteristic curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of propranolol on portosystemic collateral circulation in patients with cirrhosis.

Propranolol has been demonstrated to be effective in lowering portal pressure in cirrhotic patients. This effect is mediated by a reduction of splanchnic arterial inflow and a consequent decrease of portal vein and portocollateral blood flow. Although experimental studies suggest a direct effect of the drug on portocollateral circulation, little information exists about relative flow changes occurring in the portal vein and in collateral veins feeding esophageal varices. This study addressed the problem in 12 cirrhotic patients selected on the basis of feasibility of Doppler flowmetry in both the portal and left gastric veins. Caliber, flow velocity and flow volume in both vessels were measured by Doppler ultrasound before and at 60, 120 and 180 min after an oral dose of 40 mg propranolol, together with heart rate and mean arterial pressure. A significant decrease in heart rate (-17.6% +/- 1.1%, p less than 0.001) and mean arterial pressure (-10.6% +/- 0.9%, p less than 0.005) confirmed effective beta-blockade. Baseline flow velocity was significantly lower in the portal vein than in the left gastric vein (12.4 +/- 0.6 vs. 15.4 +/- 1.5 cm/sec, p less than 0.05). Maximal hemodynamic effect was reached at 120 min after administration of propranolol. The vessel caliber did not change significantly. Flow velocity fell from 12.4 +/- 0.6 to 10.4 +/- 0.7 cm/sec in the portal vein (p less than 0.05) and from 15.4 +/- 1.5 to 11.1 +/- 0.9 cm/sec in the left gastric vein (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Cefotaxime, desacetyl-cefotaxime, and bactericidal activity in spontaneous bacterial peritonitis.

We have prospectively studied 13 episodes of spontaneous bacterial peritonitis (SBP) in 12 patients treated with cefotaxime (CTX) 2 g intravenously every 8 h (mean duration, 5.3 days). Ascitic fluid was inoculated at the bedside. The cultures were done before, during (day 3 after CTX initiation), and 48-72 h (mean, 56 h) after the end of therapy. All SBP episodes were monomicrobial. During treatment, the concentrations of CTX and desacetyl-cefotaxime (d-CTX) in ascitic fluid were high in all 13 SBP episodes, and d-CTX was still present in 6 patients who had residual ascitic bactericidal titer (ABT) activity after the last dose of CTX. ABTs were >/=1:128 during CTX therapy in 12 episodes and were measurable in 7 patients after the last dose. All patients were cured. The present study provides scientific rationale to the clinical studies that suggest treating SBP episodes with lower doses of antibiotics and shorter treatment duration.

Isolated perfused cirrhotic human liver obtained from liver transplant patients: a feasibility study.

Cirrhotic livers obtained from eight patients who underwent orthotopic liver transplantation were perfused through the portal vein and hepatic artery in a closed recycling system for periods ranging from 2 to 7 hr. An average perfusion flow of 451 ml/min was used, with about 80% coming from the portal vein and 20% from the hepatic artery. The livers appeared to remain viable as assessed by gross appearance, stable portal vein and hepatic artery pressures, oxygen consumption and bile production. The extraction ratio of indocyanine green by the perfused livers averaged 0.098 (range = 0.023 to 0.168); that of propranolol averaged 0.445 (range = 0.126 to 0.813). Using the multiple-indicator dilution-curve method, shunts greater than 15 microns in diameter were demonstrated between the portal and hepatic veins in six of eight cases, whereas shunts from the hepatic artery to the hepatic veins were absent. Perfusion of human livers obtained during hepatic transplantation is a fairly simple procedure that will allow researchers to gain new insights into cirrhosis in humans.

Increasing serum creatinine and age reduce the response to hepatitis B vaccine in renal failure patients.

The relationship between diminished response to hepatitis B vaccine in renal failure patients and serum creatinine level, age and other factors is unknown. The immune response of patients with renal failure of varying severity to hepatitis B vaccine was determined in this study. Sixty-eight patients with renal failure of varying severity who were negative for hepatitis B markers received four doses of hepatitis B vaccine, and anti-HBs titers were determined at 0, 1, 2, 3, 6, 8 and 12 months. Maximum anti-HBs titers were seen at 8 months. At this time 86% of patients with creatinine < or = 4 mg/dl but only 37% with creatinine > 4.0 mg/dl had a protective titer of > or = 10 mIU/ml (p < 0.002). Age was inversely related to anti-HBs titer (p = 0.045) and was independent of serum creatinine in predicting antibody response. We conclude that all patients with chronic renal failure should be immunized against hepatitis B as early as possible in the development of their disease, to ensure maximum response, and to minimize the effects of elevated serum creatinine and increasing age.

Inflammatory bowel disease in the Bedouin Arabs of southern Israel: rarity of diagnosis and clinical features.

A prospective epidemiological and clinical study of ulcerative colitis and Crohn's disease was undertaken in the Bedouin Arabs of southern Israel between 1981 and 1990. There were six patients with ulcerative colitis and the prevalence rate in 1990 was calculated to be 9.8/10(5) (95% confidence intervals 3.6-17.4) in the total population, or 6.2/10(5) (0.8-22.5) in men and 13.7/10(5) (3.7-35.0) in women. Two cases of Crohn's disease occurred, both in women; the prevalence rate was 3.2/10(5) (0.4-11.8) in the entire population, and 6.8/10(5) (0.8-17.5) in women. The prevalence rates (age adjusted) in Arabs were significantly lower (p less than 0.01) than the corresponding rates in the local Jewish populations. The Bedouin patients were aged mean (SD) 34.0 (16.4) years at time of diagnosis. The clinical features of both diseases resembled those in the Jewish and other reported populations. It is suggested that the exposure of the Bedouin Arabs to the environmental causative factors of ulcerative colitis and Crohn's disease has hitherto been limited and thereby accounts for the rarity of these diseases in this population.

Haemodynamic adaptation two months after transjugular intrahepatic portosystemic shunt (TIPS) in cirrhotic patients.

BACKGROUND AND AIMS: In portal hypertensive patients, transjugular intrahepatic portosystemic shunt (TIPS) acutely increases cardiac output and exaggerates peripheral vasodilatation. It has been suggested that the worsened hyperdynamic state may progress to high output heart failure. The aim was to evaluate the acute and short-term haemodynamic adaptation to this procedure. METHODS: Systemic, splanchnic, and pulmonary haemodynamics were studied in 15 cirrhotic patients under stable haemodynamic conditions before placement of TIPS, then 15-30 minutes after and two months later. For inclusion in the final analysis, an uneventful post-TIPS at two months follow up and a stable portacaval gradient were required. The following variables were measured or calculated: portacaval gradient; cardiac index (thermodilution); systolic and diastolic mean arterial, atrial, pulmonary arterial, and wedged pulmonary capillary pressures; heart rate; and total peripheral and pulmonary vascular resistances. Blood flow in the shunt was measured using duplex Doppler ultrasound. RESULTS: The portacaval gradient decreased by 56% and remained stable thereafter. Shunt blood flow was unchanged when measured immediately after TIPS and two months later. Immediately after TIPS there was a pronounced increase in cardiac index (+32%; p < 0.05) in association with a decrease in peripheral and pulmonary vascular resistance (-21%; p < 0.05 and -14%; NS). Two months later, whereas the initial rise in cardiac index was attenuated, peripheral vascular resistances remained similar and pulmonary vascular resistances decreased further (-33%; p < 0.05) compared with immediate post-TIPS values. CONCLUSIONS: Hyperdynamic circulation worsened immediately after TIPS, with a progressive adaptation during follow up. The mechanisms of post-TIPS induced haemodynamic changes include an abrupt volume load resulting from splanchnic decompression and an increased delivery of gut derived vasodilators to the systemic circulation. The persistence of decreased peripheral and pulmonary vascular resistances despite the reduction in high cardiac output two months after TIPS suggests that vasodilatation is not solely a compensatory response to a TIPS induced increased preload. Vasodilatory substances shunted away from the liver probably play an important part in this phenomenon.

Improvement of hepatorenal syndrome by transjugular intrahepatic portosystemic shunt.

Hepatorenal syndrome (HRS) is a functional renal failure occurring in advanced liver cirrhosis with ascites. It is due to renal cortical vasoconstriction resulting from complex hemodynamic disturbances related to cirrhosis and portal hypertension. There is no consistently effective therapy except for liver transplantation. We report a case of severe HRS in a patient with advanced liver cirrhosis and portal hypertension. Three sessions of hemodialysis were performed because of severe renal failure (serum urea 83 mg/dl, serum creatinine 6 mg/dl). Creation of an intrahepatic portosystemic shunt reduced the portocaval gradient from 18 to 7 mm Hg. Spectacular improvement of the renal function was observed soon after the procedure, with spontaneous recovery of diuresis and a return of serum urea and creatinine to baseline values. The patient unfortunately died 2 months later from adult respiratory distress syndrome post emergency surgery for a massive bleed related to a duodenal ulcer. Throughout this episode, the renal function remained stable. The postmortem examination showed histologically normal kidneys. We conclude that the intrahepatic portosystemic shunt can improve renal function in cirrhotic patients with HRS; it could be used in patients awaiting liver transplantation to reverse preoperative renal failure.

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.

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.

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.

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.