Laurence Blendis

Iron-chelation therapy with oral deferiprone in patients with thalassemia major

BACKGROUND To determine whether the orally active iron chelator deferiprone (1,2-dimethyl-3-hydroxy-pyridin-4-one) is efficacious in the treatment of iron overload in patients with thalassemia major, we conducted a prospective trial of deferiprone in 21 patients unable or unwilling to use standard chelation therapy with parenteral deferoxamine. METHODS Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens or magnetic-susceptibility measurements. Detailed clinical and laboratory studies were used to monitor safety and compliance. RESULTS The patients received deferiprone therapy for a mean (+/-SE) of 3.1 +/- 0.3 years. Ten patients in whom previous chelation therapy with deferoxamine had been ineffective had initial hepatic iron concentrations of at least 80 mumol per gram of liver, wet weight -- values associated with complications of iron overload. Hepatic iron concentrations decreased in all 10 patients, from 125.3 +/- 11.5 to 60.3 +/- 9.6 mumol per gram (P < 0.005), with values that were less than 80 mumol per gram in 8 of the 10 patients (P < 0.005). In all 11 patients in whom deferoxamine therapy had previously been effective, deferiprone maintained hepatic iron concentrations below 80 mumol of iron per gram. CONCLUSIONS Oral deferiprone induces sustained decreases in body iron to concentrations compatible with the avoidance of complications from iron overload. The risk of agranulocytosis associated with deferiprone may restrict its administration to patients who are unable or unwilling to use deferoxamine.

Transjugular intrahepatic portosystemic stent shunt : effects on hemodynamics and sodium homeostasis in cirrhosis and refractory ascites

Transjugular intrahepatic portosystemic shunt (TIPS) was recently introduced as an alternative treatment for massive refractory ascites associated with cirrhosis. Preliminary studies from several centers [1-4] have shown encouraging results. Patients have either been reported to improve clinically and to have decreased ascites [1-3] or have been documented as having increased creatinine clearance and urinary sodium excretion [4]. The pathophysiology of sodium retention in cirrhosis is still a controversial topic. The peripheral arterial vasodilatation hypothesis proposes that patients with cirrhosis have systemic arterial vasodilatation, which leads to a reduction in effective arterial blood volume. This reduction, in turn, activates various neurohumoral pressor systems to promote the renal retention of sodium and water [5]. However, the mechanism linking the reduction of sinusoidal portal pressure with natriuresis and diuresis is still unclear. A significant inverse relation between the indices of portal pressure and sodium excretion has been shown [6], and a critical level of sinusoidal portal pressure (8 mm Hg) has been found, below which ascites does not occur [6, 7]. Increased systemic vasodilatation after TIPS insertion [8-10] may lead to changes in renal hemodynamics and renal sodium handling. Changes in neurohumoral profile after the reduction of sinusoidal portal pressure may also be implicated in the mediation of the natriuresis, because positive correlations have been found between portal pressure and circulating antinatriuretic substances, namely, plasma renin activity and norepinephrine [11]. Therefore, our aim was to better define the pathophysiology of sodium retention by determining the following in patients with refractory ascites treated with TIPS: 1) changes in systemic and renal hemodynamics, renal sodium homeostasis, neurohumoral profile, and central blood volume; and 2) the relation among these variables. Methods Approval for the study was granted by the Human Experimentation Committee of the University of Toronto, and all patients gave informed consent. Patients Seven patients (5 men and 2 women) 38 to 75 years of age (mean age, 60 4 years) with biopsy-proven cirrhosis and refractory ascites were studied prospectively from November 1993 to June 1994. Ten patients were referred during that period for assessment of suitability for TIPS insertion, and 3 were rejected (1 was diagnosed with inoperable carcinoma of the rectum, 1 was diagnosed with hairy-cell leukemia, and one had a thrombosed portal vein on Doppler ultrasonography). The cause of cirrhosis was alcohol use in 3 patients and viral hepatitis B virus in 2 patients; cirrhosis was cryptogenic in 2 patients. Baseline clinical and biochemical data and severity of liver disease according to the Pugh classification [12] (Appendix Table 1) are shown in Tables 1 and 2. Five patients were Pugh class B (score, 7 to 9) and 2 were Pugh class C (score, 10). Patients with cirrhosis caused by alcohol use had abstained from alcohol for at least 6 months before being entered into the study. All patients had had ascites for more than 6 months before study entry. Refractoriness was defined as a prolonged history of ascites unresponsive to 400 mg of spironolactone or 30 mg of amiloride plus up to 120 mg of furosemide daily for 2 weeks. Table 1. Changes in Clinical Hematologic Measurements and Liver Function in Patients with Ascites after Insertion of Transjugular Intrahepatic Portosystemic Stent Shunts* Table 2. Changes in Renal Function and Sodium Excretion in Patients with Ascites after Insertion of Transjugular Intrahepatic Portosystemic Stent Shunts* Appendix Table 1. Assessment of Severity of Liver Disease: Pughs Modification of the Child-Turcotte Classification System* Study Protocol After discontinuing therapy with diuretics, all patients were admitted to the Clinical Investigation Unit of Toronto Hospital on a 22 mmol/d sodium, 1 L/d fluid, caffeine-free diet; this diet was maintained before and after TIPS insertion. During a 1-week stabilization period, patients were monitored daily for weight, serum electrolyte concentrations, and 24-hour urinary sodium excretion. None of the patients chosen for the study had renal disease, cardiovascular disease, or sepsis; all had a patent portal vein. Cardiologic assessment included chest radiography, electrocardiography, two-dimensional echocardiography, and examination by a cardiologist. Patients were excluded if they had primary renal disease that was ruled out by a normal serum creatinine level, normal urine on microscopy, and normal kidney size on ultrasonography; they were also excluded if they had spontaneous bacterial peritonitis that was ruled out by at least two negative ascitic-fluid cultures. Patients with other sources of sepsis, including dental sepsis, were excluded. Doppler ultrasonography was done to ascertain the patency of the portal vein. On the morning before TIPS insertion, all patients had blood drawn for the measurement of baseline plasma norepinephrine levels, plasma renin activity, and aldosterone concentrations and for renal hemodynamic and sodium handling studies. Glomerular filtration rate and renal plasma flow were measured using inulin and para-aminohippurate clearances, respectively, and renal vascular resistance was calculated. Lithium clearance was used as an indicator of proximal tubular reabsorption of sodium [13]. On the afternoon before TIPS insertion, central blood volume was measured using radionuclide angiography [14]. Insertion was done on study day 8 while patients were under intravenous sedation in the angiography suite. Cardiac output, as measured by thermodilution, portal vein pressure, and free and wedged hepatic venous pressures, was measured before and 30 minutes after insertion, and the hepatic venous pressure gradient or the corrected sinusoidal pressure was calculated. On the morning after TIPS insertion, Doppler ultrasonography was done to assess the patency of the TIPS; a shunt flow velocity of more than 100 cm/s indicated a widely patent shunt. Ultrasonography was followed by repeated renal hemodynamic studies and measurements of urinary sodium concentrations, hormonal levels, and central blood volume. In patients with a shunt flow velocity of no more than 100 cm/s, an urgent angiographic study of the TIPS was done. Acute thrombosis was lysed with urokinase, and Doppler ultrasonography was repeated. The patients were observed in the Clinical Investigation Unit for an additional 5 days after TIPS insertion; prophylactic lactulose was begun after TIPS insertion. All patients were reviewed in an outpatient clinic 2 weeks after TIPS insertion. One month after insertion, they were rehospitalized for 1 week for repeated measurements of hormonal levels and central blood volume, for Doppler ultrasonography to assess shunt patency, and for renal hemodynamic studies. These tests were done after 5 days of stabilization in the hospital. Techniques Inulin, Para-aminohippurate, and Lithium Clearances The techniques used to measure inulin and para-aminohippurate clearances [15] and lithium clearances [16] have been described previously. We used these clearances as indices of glomerular filtration rate, renal plasma flow, and proximal tubular sodium reabsorption, respectively. Central Blood Volume Measurements The use of radionuclide angiography to measure central blood volume has been described [14]. Quality assurance studies done in our Nuclear Cardiology Laboratory have established the standard error of the estimate of left ventricular ejection fraction calculation to be less than 2% using semi-automated techniques. The standard error of the estimate of ventricular volume calculation is less than 5 mL [17]. Insertion of TIPS Under sterile technique and after the patient had received local anesthesia and moderate intravenous sedation, the left branch of the portal vein was punctured from the anterior abdominal approach using a 22-G needle and ultrasonographic guidance. A Mandril guidewire (Cook, Inc., Bloomington, Indiana) was advanced through the needle into the portal vein and positioned across the confluence of the left and right portal veins. Next, the right internal jugular vein was punctured at the mid-neck under local anesthesia. Using the Seldinger technique, a 10-F sheath was inserted. A double-lumen Swan-Ganz catheter was then introduced through the sheath; right heart pressures were measured and cardiac output was measured by thermodilution. A 9-F Colapinto catheter (Cook, Inc.) was then inserted, and pressure measurements were obtained from the inferior vena cava and from the free and wedged hepatic veins. A transjugular liver biopsy needle (Cook, Inc.) was then inserted through the catheter, and the hepatic parenchyma was punctured under fluoroscopic guidance; the puncture was directed toward the Mandril wire. When blood was aspirated, a small injection of radiographic contrast medium was used to confirm cannulation of the portal vein. The Colapinto catheter was advanced over the needle into the portal vein, and then portal venography was done and portal pressure was measured. A 5-F angioplasty balloon (Cook, Inc.) was used to dilate the intrahepatic tract to 8 mm. A 68-mm Wallstent (Schneider, Inc., Richmond Hill, Ontario, Canada) was then advanced and deployed to lie in the parenchymal tract, extending at least 2 cm into the portal vein. If the stent did not completely traverse the tract to the hepatic vein, a second, overlapping stent was placed. The stent or stents were dilated to between 8 and 9 mm using a high-pressure angioplasty balloon. Portal venography and pressure measurements were repeated. If the portosystemic gradient exceeded 8 mm Hg, the stent or stents were re-dilated to 10 mm. After a resting period of 30 minutes, right heart pressures and cardiac output measurements were repeated. All catheters were then withdrawn and hemostasis w

The hyperdynamic circulation in cirrhosis : an overview

The hyperdynamic circulation begins in the portal venous bed as a consequence of portal hypertension due to the increased resistance to flow from altered hepatic vascular morphology of chronic liver disease. Dilatation of the portal vein is associated with increased blood flow, as well as the opening up or formation of veno-venous shunts and splenomegaly. At the same time, portal hypertension leads to subclinical sodium retention resulting in expansion of all body fluid compartments, including the systemic and central blood volumes. This blood volume expansion is associated with vasorelaxation, as manifested by suppression of the renin--angiotensin--aldosterone system, initially only when the patient is in the supine position. Acute volume depletion in such patients results in normalisation of the hyperdynamic circulation, whilst acute volume expansion results in exaggerated natriuresis. As liver disease progresses and liver function deteriorates, the systemic hyperdynamic circulation becomes more manifest with activation of the renin--angiotensin--aldosterone system. The presence of vasodilatation in the presence of highly elevated levels of circulating vasoconstrictors may be explained by vascular hyporesponsiveness due to increased levels of vasodilators such as nitric oxide, as well as the development of an autonomic neuropathy. However, vasodilatation is not generalised, but confined to certain vascular beds, such as the splanchnic and pulmonary beds. Even here, the status may change with the natural history of the disease, since even portal blood flow may decrease and become reversed with advanced disease. The failure of these changes to reverse following liver transplantation may be due to remodelling and angiogenesis.

Complications after peritoneovenous shunting for ascites

The results and complications in our first 23 consecutive patients receiving the peritoneovenous shunt for intractiable hepatic ascites are presented. A good initial diuretic effect was obtained in 20 of the 23 patients, with reversal of hepatorenal failure in 3 of 5 patients. The postoperative complication rate was high (74 percent). Infection, coagulopathy and complication of the underlying liver disease contributed to a mortality rate of 26 percent. Late complications were related to the primary liver disease. The 6 month survival rate was 58 percent and the 1 hear survival rate 52 percent with five patients followed up for more than 2 years. Because of the significant morbidity and mortality associated with the peritoneovenous shunt, we recommend it only for patients with massive intractable hepatic ascites whose condition is refractory to maximal medical therapy.

The renal sympathetic and renin-angiotensin response to lower body negative pressure in well-compensated cirrhosis

BACKGROUND & AIMS Certain antinatriuretic hormonal systems may be involved in the subclinical sodium handling abnormality in preascitic cirrhosis. The aims of this study were to determine the following in preascitic cirrhosis: (1) basal activity of the renal sympathetic and renin-angiotensin systems and (2) the relationship between the response of these systems to lower body negative pressure and sodium excretion. METHODS Seven preascitic cirrhotic patients and 9 age- and sex-matched controls were studied on a 150 mmol sodium per day diet. Systemic and renal hemodynamics, renal neurohormonal secretion rates, and sodium excretion were assessed before, during increasing levels of, and after lower body negative pressure, each for 30 minutes. RESULTS Both groups responded with a significant decrease in central venous pressure (P < 0.01) that remained higher in the cirrhotics than in the controls throughout the study. Cirrhotics showed significant increases compared with controls in renal renin and angiotensin II secretion rates at -20 mm Hg of lower body negative pressure, which was associated with significant renal sodium retention (96 +/- 17 micromol/min vs. 218 +/- 21 micromol/min at baseline, P < 0.05), but there was no change in renal sympathetic activity. CONCLUSIONS In preascitic cirrhosis, sodium retention occurs in response to lower body negative pressure, which was associated with increased renal renin-angiotensin activity. Stimulation of the intrarenal renin-angiotensin system may be the initial renal pathophysiological change causing sodium retention in cirrhosis.

The mechanism of improved sodium homeostasis of low-dose losartan in pre-ascitic cirrhosis

Renal sodium retention on standing is one aspect of the abnormal renal sodium handling in preascitic, well-compensated patients with cirrhosis. Recently, it has been shown that low doses (7.5 mg) of the angiotensin II (Ang II) receptor antagonist, losartan, can reverse renal sodium retention on high, 200-mmol sodium/d diet in these patients and restore them to sodium balance. Therefore, the effect of 7.5 mg of losartan on sodium excretion, when changing from supine to erect posture for 2 hours, was examined in 10 well-compensated patients with cirrhosis and 9 age- and sex-matched controls on the same sodium diet, under strictly controlled metabolic conditions. In contrast to control subjects, in whom sodium excretion was unaffected, single 7.5-mg doses of losartan again restored the preascitic patients with cirrhosis to sodium balance. In addition, it blunted the fall in erect posture- induced renal sodium excretion by a reduction in proximal and distal tubular reabsorption of sodium. These changes occurred without any significant changes in blood volumes, systemic and renal hemodynamics, or glomerular filtration rate (GFR) and filtered sodium load compared with controls, and despite activation of the systemic renin-angiotensin-aldosterone system, which was still within normal levels. In conclusion, the beneficial natriuretic effects of low-dose losartan on erect posture - induced sodium retention in preascitic cirrhosis supports the suggestion that the pathophysiology of sodium retention in preascites is in part caused by an intrarenal tubular effect of Ang II in that posture.

The Effects of Hypothyroidism on Liver Status of Cirrhotic Patients

We have shown, in animal models as well as in retrospective human study, that some degree of decreased thyroid function is beneficial for subjects with liver damage of various etiologies. Therefore, we herein present the results of a cohort population study. Between 1991 and 1994, 18 patients (12 women and 6 men; mean age, 59 ± 24 years) with both biopsy-proven active cirrhosis (5 hepatitis C virus, 4 hepatitis B virus, 1 immunocompromised host, 2 primary biliary cirrhosis, 1 alcoholic, and 5 cryptogenic; Childs-Pugh criteria: A-8, B-8, C-2) and primary or induced (by either drug or surgery) thyroxine-treated hypothyroidism were prospectively followed. Each patient was examined at least twice yearly and served as their own control. The thyroid of the profiled patients ranged between euthyroidism and subclinical hypothyroidism. Liver function tests were evaluated and compared in states of normal versus increased thyroid-stimulating hormone (TSH) blood levels. A significant improvement in alanine aminotransferase (p < 0.001), alkaline phosphatase (p < 0.0001), albumin (p < 0.001), and bilirubin (p < 0.01) was found in the increased TSH group. Prothrombin time was also found to be significantly better (p < 0.001). We conclude that euthyroid patients with liver cirrhosis might benefit from a controlled hypothyroidism.

Modification of pulmonary metabolism of noradrenaline in experimental obstructive jaundice.

The pulmonary metabolism of noradrenaline (NA) was measured in lungs removed from 3 day sham-operated rats and from rats whose bile ducts had been ligated 3 days earlier (BDL). The pulmonary metabolism of NA as measured by a single clearance of the radio-labelled 14C-amine was significantly increased in lungs excised from BDL rats as compared to that measured in the sham-operated rats. The change in metabolism was associated with an alteration in the pulmonary uptake of NA and not with the activities of the enzymes monoamine oxidase types A and B and catechol-O-methyl transferase. Moreover, it was not correlated with rises in the bilirubin or cholesterol concentrations in the serum of the BDL rats and occurred independent of any changes in pulmonary pressure. In a second series of experiments, the evolution of this abnormality over the period of one to six days postoperative was investigated. In the sham-operated rats, there was no significant change in the pulmonary metabolism of NA even by the sixth day. In contrast, there were time-dependent increases from one to six days in these metabolic processes in BDL rats with the highest values being at six days. In contrast, the serum concentrations of bilirubin and cholesterol and activities of the enzymes, alanine transaminase and alkaline phosphatase all rose to their maximum by the fourth day and thereafter declined. Although serum albumin levels fell significantly in BDL rats they were not significantly different from sham-controls. Thus, change in pulmonary metabolism of NA with obstructive jaundice increases with time from one to six days and it not related to the blood chemical changes of biliary obstruction or hepatic synthetic function.

THE PATHOPHYSIOLOGIC BASIS FOR THE TREATMENT OF CIRRHOTIC ASCITES

Advances in the understanding of the pathophysiology of sodium retention and ascites formation in cirrhosis has helped improve the treatment of ascites in these patients. It is likely that further unraveling of these pathophysiologic changes will lead to the development of novel and better treatment options. For example, the development of aquaretic agents for the management of hyponatremia in cirrhosis may allow more effective use of diuretic therapy. The ultimate challenge is to use the understanding of the pathophysiology to develop new strategies to prevent the development of ascites in cirrhosis.

Streptococcus bovis bacteremia associated with acute cholecystitis.

protein S level remained low, at 17%. Magnetic resonance cholangiography repeated 12 months after initial testing showed partially decreased compression of the common bile duct by venous collaterals (Fig. 2). The patient had portal hypertension, as evidenced by large esophageal varices seen on endoscopy. The portal hypertension was due to portal vein thrombosis, as demonstrated on Doppler and MRI scans, and the thrombosis extended to the splenic and superior mesenteric veins. The ultrasound, MRI, and subsequent clinical course did not suggest associated cirrhosis of the liver. The low protein S level and persistently high factor VIII levels probably predisposed the patient to the thrombosis. Patients with portal vein thrombosis usually present with variceal bleeding, but presentation with deep jaundice is distinctly unusual. Only two of 213 in one series of patients with portal vein thrombosis presented with jaundice. Similarly, only two of 108 patients in our own series of patients with portal vein thrombosis presented with jaundice. The jaundice and the cholangiogram improve after successful shunt surgery. Surgical shunt placement was not an option for this patient because the thrombosis extended to the splenic and superior mesenteric veins, making them unavailable. Endoscopic biliary stenting was deferred owing to the risk of hemobilia. It was considered theoretically possible that if the biliopathy was due to portal hypertension, then reduction of the portal pressure by drugs could ameliorate the biliopathy and jaundice. The jaundice did diminish dramatically with the use of propranolol and nitrate. However, it was not possible to prove that the improvement was associated with reduction in ‘‘portal pressure’’ because the variceal/splenic pulp pressure was not measured and the varices were treated with prophylactic banding. Spontaneous resolution of the biliopathy-induced jaundice is a possibility but has not been documented. Further trials of medical therapy for portal biliopathy appear warranted. A 34-year-old male presenting with deep jaundice due to portal biliopathy is described. Successful medical treatment of portal biliopathy is reported for the first time.