Papers by Laurence Blendis
Portal Hypertension, 1991
Clinical Biochemistry, 2001
Objective: (i) to characterize the profile of tumor necrosis factor alpha (TNF ␣), interleukin-6 ... more Objective: (i) to characterize the profile of tumor necrosis factor alpha (TNF ␣), interleukin-6 (IL-6), IL 10, Fas-ligand and transforming growth factor beta (TGF ), chronic hepatitis C (HCV) patients with genotype 1; (ii) to determine the influence of triple therapy (TT) with interferon ␣ (IFN ␣) ϩ ribavirin ϩ ursodeoxycholic acid on these cytokines and (iii) to establish the relationship between the proinflammatory cytokines and the outcome of treatment. Design and Methods: 22 patients infected with HCV -genotype 1 a/b and non responsive to IFN-␣ monotherapy were enrolled in the TT. The controls were 49 HCV naïve patients with genotype 1 a/b. Cytokine levels were measured using enzyme-linked immunosorbent assay (ELISA). Results: The baseline TNF ␣ values (pg/mL) in the sustained responders (SRs) (63Ϯ3) were significantly lower than non-responders (NRs) (140Ϯ16) (p Ͻ 0.001). Baseline Fas (ng/mL) levels were also lower in SRs (4.3Ϯ0.2) than NRs (5.4Ϯ0.4) (p Ͻ 0.05). Conclusions: Fas and TNF ␣ may be used as serological markers of inflammation and effectiveness of therapy.
New England Journal of Medicine, 2003
The American Journal of Medicine, 1994
Prostaglandins are cytoprotective agents that have been shown to benefit patients with a variety ... more Prostaglandins are cytoprotective agents that have been shown to benefit patients with a variety of acute and chronic liver diseases. Few data exist on the frequency of adverse effects of prostaglandins in these patients. We retrospectively studied 105 patients with liver disease who were treated with either intravenous (i.v.) or oral prostaglandin E (PGE). Forty-four patients with primary nonfunction after liver transplantation and 36 patients with fulminant hepatic failure received i.v. PGE1 for 4.5 +/- 2.6 and 12.6 +/- 10.9 days, respectively. Twenty-five patients with recurrent hepatitis B viral infection after liver transplantation received oral PGE1 for 105 +/- 94 days or PGE2 for 464 +/- 399 days. Twenty-six of 80 patients (33%) receiving i.v. PGE1 developed gastrointestinal and/or cardiovascular side effects and 8% developed arthritis. Twenty-three of 25 patients (92%) who received high-dose oral PGE1 or PGE2 incurred arthritis and/or gastrointestinal adverse effects. Twenty-five patients received prolonged PGE therapy (oral > 60 days; i.v. > 28 days). Of this group, 23 (92%) developed clubbing and cortical hyperostosis resembling hypertrophic osteoarthropathy. All adverse effects were dose related and resolved with reduction or cessation of therapy. PGE therapy resulted in a wide spectrum of multisystem adverse effects which were reversible with reduction or cessation of therapy. Although the administration of PGE was safe and generally well tolerated, close medical supervision is necessary to avoid serious side effects.
Gut
Background-Preascitic cirrhotic patients receiving 200 mmol of sodium daily for seven days remain... more Background-Preascitic cirrhotic patients receiving 200 mmol of sodium daily for seven days remain in positive sodium balance. Thereafter, sodium handling is unknown. Aim-To assess renal sodium handling in preascitic cirrhosis on a high sodium diet for five weeks. Methods-Sixteen biopsy proven preascitic cirrhotics were assessed at weekly intervals for five weeks on a diet of 200 mmol sodium/day using a daily weight diary and weekly 24 hour urinary sodium estimations. Fasting supine neurohormone levels were measured at baseline and weekly for five weeks while haemodynamics were measured at baseline and at five weeks. Results-The daily diet of 200 mmol of sodium resulted in weight gain and a positive sodium balance for three weeks, associated with significant suppression of plasma renin activity and aldosterone levels, and a significant rise in plasma atrial natriuretic peptide levels (p<0.05). Patients' weights plateaued during week 4, associated with complete sodium balance and significant suppression of plasma noradrenaline levels (p<0.05). This was followed by a negative sodium balance and weight loss, and finally complete sodium balance, again despite a mean net gain of 2.3 (0.3) kg, associated with a return of plasma renin activity and aldosterone levels to within normal ranges. The lack of increase in central blood volume in addition to the persistent increase in plasma atrial natriuretic peptide levels indicated that residual volume expansion, consequent to persistent weight gain, was distributed on the venous side of the circulation. No free fluid was seen on repeat abdominal ultrasound after five weeks. Conclusion-Preascitic cirrhotics have a natriuretic "escape" after three weeks on high sodium dietary intake, associated with elevated plasma atrial natriuretic peptide levels and suppression of the renin-angiotensin-aldosterone system. With continued suppressed sympathetic activity, preascitics re-establish complete sodium balance but with a net weight gain and presumed increased intravascular volume, but without ascites. This further elucidates the compensated sodium retaining abnormality that characterises preascitic cirrhosis.
Gut
Impaired exercise capacity and oxygen consumption are common in cirrhosis. To explore the relatio... more Impaired exercise capacity and oxygen consumption are common in cirrhosis. To explore the relationship between possible myocardial dysfunction and exercise tolerance in cirrhosis. Cardiac responses to exercise, using radionuclide angiography and graded upright cycle ergometry with oxygen consumption, were assessed before and after exercise in 39 cirrhotics patients and compared with 12 age and sex matched healthy volunteers. Baseline cardiac chamber dimensions and wall thickness, ejection fraction, and diastolic function were measured using two dimensional echocardiography is all subjects. Baseline diastolic dysfunction with prolonged isovolumic relaxation times (p=0.02), left atrial enlargement, and left ventricular wall thickening were present in all cirrhotics (p=0.02), despite increased mean ejection fraction. With graded exercise, cirrhotics achieved 71 (4)% (p=0.03) (pre-ascitics) and 46 (3)% (p<0.001) (ascitics) of predicted work loads, respectively, without significant in...
Annals of internal medicine
To assess the effects of transjugular intrahepatic portosystemic shunt (TIPS) on systemic and ren... more To assess the effects of transjugular intrahepatic portosystemic shunt (TIPS) on systemic and renal hemodynamics, neurohumoral factors, and sodium homeostasis in patients with cirrhosis and refractory ascites. Prospective study with 1-year follow-up. Tertiary referral center and university-affiliated hospital. 7 patients with cirrhosis and refractory ascites had metabolic studies done while receiving a 22 mmol/d sodium, 1 L/d fluid diet. TIPS insertion. Urinary sodium excretion, systemic and renal hemodynamics, hormonal profile, and central blood volume were measured before, at day 1 after, and at 1 month after TIPS insertion. Immediately after TIPS insertion, mean corrected sinusoid pressure decreased from 18.2 +/- 2.2 mm Hg to 7.7 +/- 1.3 mm Hg (P < 0.001); mean cardiac output increased from 6.83 +/- 0.68 L/min to 8.62 L/min (P = 0.005); and mean systemic vascular resistance decreased from 1018 +/- 103 dyne.s.cm-5 to 762 +/- 46 dyne.s.cm-5 (P = 0.011). Mean plasma renin activit...
American journal of physiology. Gastrointestinal and liver physiology, 2000
Cellular mechanisms for Na(+) retention in portal hypertension are undefined, but epithelial Na(+... more Cellular mechanisms for Na(+) retention in portal hypertension are undefined, but epithelial Na(+) channels (ENaC) may be involved. Under high-salt diet, ENaC are absent from distal colon of rat but can be induced by mineralocorticoids such as aldosterone. Presence of rat ENaC was determined by amiloride inhibition of (22)Na(+) uptake in surface colonocytes 7 and 14 days after partial portal vein ligation (PVL) or sham surgery. At both times, uptake inhibition was significantly increased in PVL rats. Presence of mRNA transcripts, determined by RT-PCR, demonstrated that channel alpha- and gamma-subunits were similarly expressed in both groups but that beta-subunit mRNA was increased in PVL rats. This confirms that there was induction of rat ENaC and indicates that beta-subunit has a regulatory role. Urinary Na(+) was decreased for 3 days after PVL but was not different at other times, and serum aldosterone levels were elevated at 7 days, at a time when urinary Na(+) output was simila...
The American Journal of Gastroenterology, 2001
Malnutrition is common in patients with decompensated cirrhosis and refractory ascites. The use o... more Malnutrition is common in patients with decompensated cirrhosis and refractory ascites. The use of transjugular intrahepatic portosystemic stent shunt (TIPS) is effective in eliminating ascites. The purpose of this study was to investigate the effect of TIPS and resolution of refractory ascites on the nutritional status of patients with decompensated cirrhosis. Fourteen consecutive patients with refractory ascites and a Pugh score of 9.0+/-0.5 had a TIPS insertion. Biochemical data, resting energy expenditure (REE), total body nitrogen (TBN), body potassium (TBK), body fat (TBF), muscle force (MF), and food intake were recorded before TIPS, and at 3 and 12 months after the procedure. Ten patients completed the study. Baseline values for REE, TBN, TBF, MF, and energy intake were below normal at baseline. There was a significant increase in dry weight, TBN, and REE at 3 and 12 months compared with baseline. TBF improved significantly at 12 months. There was a trend toward an increase in energy intake (p = 0.072). There was no change in protein intake, TBK, MF, and Pugh score. In cirrhotic patients with refractory ascites, resolution of the ascites after TIPS placement resulted in improvement of several nutritional parameters, especially for body composition.
Clinical and investigative medicine. Médecine clinique et experimentale, 1994
Lactulose has been used successfully in the treatment of portal-systemic encephalopathy but its e... more Lactulose has been used successfully in the treatment of portal-systemic encephalopathy but its exact mechanism of action is not known. The aim of this study was to observe the systemic effects of the colonic fermentation of an acute lactulose dose in cirrhotics and normal subjects. Six cirrhotic patients and 6 normal subjects were placed on 2 identical 2-d metabolic diets, 1 of which was supplemented with lactulose (1 g/100 kcals to a maximum of 28 g/d). Lactulose increased colonic fermentation in cirrhotic and normal subjects as evidenced by higher breath hydrogen and serum acetate levels. The increase in serum acetate levels after lactulose compared to control was similar in cirrhotic compared to normal subjects. However, the mean serum acetate concentration in the cirrhotics was significantly greater than that in the control subjects (p = 0.039), indicating increased endogenous production, or decreased peripheral utilization of acetate by the cirrhotic liver, or both. No change ...
The American Journal of Gastroenterology, 2002
Clinics in Liver Disease, 2001
Advances in the understanding of the pathophysiology of sodium retention and ascites formation in... more 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.
The American Journal of Gastroenterology, 2000
For 51 liver allograft recipients, we evaluated whether serum profiles of delta (Bd) and conjugat... more For 51 liver allograft recipients, we evaluated whether serum profiles of delta (Bd) and conjugated bilirubins (Be) could be used to diagnose rejection during the first 30-50 postoperative days, in comparison with histology as the "gold standard." Daily measurements of aspartate aminotransferase, alkaline phosphatase, total bilirubin, Bd, and Bc were made, the last two by liquid chromatography. In 34 patients without any biochemical or histological evidence of rejection, within seven to 10 postoperative days Bd increased to >40-50% of total bilirubin, while Bc decreased to <10%. in patients with severe rejections resulting in death, Bc increased rapidly to >50%, while Bd remained <30%. In 24 histologically proven episodes of rejection in 17 patients there was either a rapid decrease in Bd or its persistence at 30%, plus either a steep increase in Bc, or its remaining at >50% total bilirubin.
Clinical Gastroenterology and Hepatology, 2006
Transplantation, 1989
Primary nonfunction following orthotopic liver transplantation is characterized by rapidly rising... more Primary nonfunction following orthotopic liver transplantation is characterized by rapidly rising serum transaminases, minimal bile production, and severe coagulopathy, which can progress to hypoglycemia, hepatic encephalopathy, and acute renal failure. Untreated it has a mortality of over 80% and to date the only treatment has been retransplantation. As a result of the beneficial effect of Prostaglandin E1 infusion in patients with fulminant hepatic failure, this trial was conducted to determine whether PGE1 would be of value in primary nonfunction. We have encountered 16 cases of primary nonfunction in 94 liver transplants, an incidence of 17%. Initially in the program, there were 6 occurrences of nonfunction that did not receive PGE1; 3 underwent retransplantation (2 survivors), 2 died awaiting another liver, and in one recovery of hepatocellular function occurred with supportive care but the patient died of cytomegalovirus infection. Ten patients received PGE1 within 4-34 hr of transplantation. Within 12 hr of treatment, 8 patients responded with a significant fall in the AST (129 U/hr) whereas, in the untreated group, the AST continued to rise (267 +/- 102 U/hr) at the same rate as prediagnosis (337 +/- 95 U/hr). At the conclusion of the infusion (4-7 days) in the 8 responders, there were significant decreases in AST (4386 +/- 546 U/L to 102 +/- 21 U/L), prothrombin time (22 +/- 2 to 12 +/- .4 sec) and partial thromboplastin time (45 +/- 3-29 +/- 4 sec), and significant increases in coagulation factor V (26 +/- 8 to 95 +/- 12%) and factor VII (10 +/- 5 to 61 +/- 4%). No serious side effects occurred, although 2 patients developed diarrhea, and abdominal cramps. Two patients treated with PGE1 were retransplanted at 10-36 hr and were considered nonresponders. Graft survival was 80% in the PGE1-treated group and 17% in the untreated group (P less than 0.05) and patient survival was 90% and 33%, respectively. This study suggests a potential benefit of PGE1 in the treatment of primary nonfunction.
Transplantation, 1994
While orthotopic liver transplantation (OLT) has become the treatment of choice for most irrevers... more While orthotopic liver transplantation (OLT) has become the treatment of choice for most irreversible end-stage liver diseases, its role in patients with hepatitis B (HBV) infection is controversial. A high risk of reinfection of the transplanted graft, associated with significant morbidity and mortality, has been reported. Although passive and active immunization can delay reappearance of the virus in the allograft, there is not yet an effective therapy for recurrent HBV infection in liver transplant recipients. Between October 1985 and March 25, 1991, 28 OLT in 25 patients with acute and chronic HBV infections were performed. Twelve of the patients were HBV DNA-negative, six were HBV DNA-positive, and seven were not tested prior to transplantation. Only the 19 patients surviving more than 100 days after transplantation were considered to have sufficient duration of follow-up (mean 734 days; range 500-1545) to include in analysis of recurrence. Five (26%) were free of recurrent disease at the time of last follow-up (mean 1031 days, range 526 to 1770 days. Recurrent HBV in the allograft, as defined by positive immunoperoxidase stains of biopsy sections for viral antigens, was detected in 74% (13 male, 1 female; 7 Asian, 7 white) at a mean of 134 days posttransplantation. Histological changes of viral hepatitis, first appearing an average of 157 days (range 95-326) posttransplantation, were evident in 13 of 14 with positive immunostaining. Twelve of the 14 patients were treated, on an open trial basis, with intravenous and oral prostaglandin E (PGE) because of deteriorating clinical condition. Eleven of the twelve responded to PGE with an initial drop in serum transaminases, improvement in coagulopathy and resolution of encephalopathy. One patient failed to respond and died of a myocardial infarction within 9 days of institution of therapy. Three of the eleven patients with an initial response relapsed and died in liver failure as a direct result of recurrent HBV after 13, 16, and 37 days of treatment in association with generalized sepsis. Eight of the 12 patients (67%) had a sustained favorable response to PGE therapy (mean follow-up 737 days, range 403-1545). All patients with a sustained response had accompanying improvement in histology and reduction in viral antigen staining in hepatocytes. Treatment with PGE appeared to be of benefit in recurrent HBV infection of the transplanted liver with an initial response rate of 92% and a sustained response rate of 67%.
Nephron, 1986
Alpha 1-Adrenoreceptor affinity constants (KD) and receptor numbers (Bmax) were determined in the... more Alpha 1-Adrenoreceptor affinity constants (KD) and receptor numbers (Bmax) were determined in the kidneys of 3-day-old bile-duct-ligated (BDL) jaundiced rats using 3H-prazosin. The results were compared to 3-day-old pair-fed and nonpair-fed sham-operated rats as well as nonoperated rats as controls. Abdominal surgery (sham and BDL) resulted in a tendency towards a decrease in KD in all three groups of rats compared to nonoperated controls. The Bmax was also increased in the sham-operated groups compared to the nonoperated controls. In contrast, the tendency for a rise in the Bmax in the BDL group was significantly smaller than the rise seen in the two sham-operated groups. In summary, obstructive jaundice suppresses the normal renal alpha 1-adrenoreceptor response to abdominal surgery in the rat.
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Papers by Laurence Blendis