Andrés Cárdenas

Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis

BACKGROUND & AIMSnTolvaptan is a vasopressin V2-receptor antagonist that improves serum sodium concentration by increasing renal solute-free water excretion. Specific data on the safety and efficacy of tolvaptan in patients with cirrhosis and hyponatremia has not been exclusively evaluated.nnnMETHODSnThis sub-analysis of the Study of Ascending Levels of Tolvaptan trials examined cirrhotic patients with hyponatremia who received 15 mg oral tolvaptan (n=63; increased to 30 or 60 mg if needed) or placebo (n=57) once-daily for 30 days. At baseline, 44% had mild hyponatremia (serum sodium 130-134 mmol/L), 56% had marked hyponatremia (serum sodium <130 mmol/L), 85% had cirrhosis due to alcohol and/or hepatitis B/C, and 80% were Child-Pugh class B/C.nnnRESULTSnTolvaptan was effective in raising serum sodium. Average daily area under the curve for serum sodium was significantly greater in the tolvaptan group from baseline to day 4 (p<0.0001) and day 30 (p<0.0001). This superiority was maintained after stratification by baseline hyponatremia (mild and marked), estimated glomerular filtration rate (≤ 60 ml/min and >60 ml/min), or serum creatinine levels (<1.5mg/dl and ≥ 1.5mg/dl). Hyponatremia recurred 7 days after discontinuation of tolvaptan. Mean mental component summary scores of the SF-12 health survey improved from baseline to day 30 in the tolvaptan group but not the placebo group (4.68 vs. 0.08, p=0.02). Major side effects due to tolvaptan were dry mouth and thirst. Gastrointestinal bleeding occurred in 10% and 2% of patients in the tolvaptan and placebo group, respectively (p=0.11). Adverse event rates, withdrawals, and deaths were similar in both groups.nnnCONCLUSIONSnOne month of tolvaptan therapy improved serum sodium levels and patient-reported health status in cirrhotic patients with hyponatremia. Hyponatremia recurred in tolvaptan-treated patients after discontinuation.

Hepatorenal syndrome: a dreaded complication of end-stage liver disease.

Hepatorenal syndrome is the dreaded complication of end-stage liver disease characterized by functional renal failure due to renal vasoconstriction in the absence of underlying kidney pathology. The pathogenesis of hepatorenal syndrome is the result of an extreme underfilling of the arterial circulation secondary to an arterial vasodilation located in the splanchnic circulation. This underfilling triggers a compensatory response with activation of vasoconstrictor systems leading to intense renal vasoconstriction. The diagnosis is based on established diagnostic criteria aimed at excluding nonfunctional causes of renal failure. The prognosis of patients with hepatorenal syndrome is extremely poor especially in those who have a rapidly progressive course. Liver transplantation is the best option in suitable candidates, but it is not always applicable due to the short survival expectancy and donor shortage. Pharmacological therapies based on the use of vasoconstrictor drugs (terlipressin, midodrine, octreotide, or noradrenline) are the most promising in the aim of successfully offering a bridge to liver transplantation. Other treatments such as transjugular intrahepatic portosystemic shunts and albumin dialysis are effective but experience is very limited. Although there is limited information on the prevention of hepatorenal syndrome, intravenous albumin infusion in patients with spontaneous bacterial peritonitis and with oral pentoxifylline in patients with acute alcoholic hepatitis seems to effectively prevent hepatorenal syndrome in these two settings.

Mechanisms of water and sodium retention in cirrhosis and the pathogenesis of ascites

Patients with advanced cirrhosis and portal hypertension often show an abnormal regulation of extracellular fluid volume, resulting in the accumulation of fluid as ascites, pleural effusion or oedema. The mechanisms responsible for ascites formation include alterations in the splanchnic circulation as well as renal functional abnormalities that favour sodium and water retention. Renal abnormalities occur in the setting of a hyperdynamic state characterized by an increase cardiac output, a reduction in total vascular resistance and an activation of neurohormonal vasoactive systems. This circulatory dysfunction, due mainly to intense arterial vasodilation in the splanchnic circulation, is considered to be a primary feature in the pathogenesis of ascites. A major factor involved in the development of splanchnic arterial vasodilation is nitric oxide (NO), a potent vasodilator that is elevated in the splanchnic circulation of patients with cirrhosis. This event decreases effective arterial blood volume and leads to fluid accumulation and renal function abnormalities which are a consequence of the homeostatic activation of vasoconstrictor and antinatriuretic factors triggered to compensate for a relative arterial underfilling. The net effect is avid retention of sodium and water as well as renal vasoconstriction. The mechanisms of sodium and water retention and ascites formation in patients with cirrhosis are discussed in this review.

Comparison of Endoscopic Ultrasonography and Magnetic Resonance Cholangiopancreatography in the Diagnosis of Pancreatobiliary Diseases: A Prospective Study

OBJECTIVES:To compare the diagnostic value of endoscopic ultrasonography (EUS) and magnetic resonance cholangiopancreatography (MRCP) in: (a) patients with a dilated biliary tree unexplained by ultrasonography (US) (group 1), and (b) the diagnosis of choledocholithiasis in patients with nondilated biliary tree (group 2).METHODS:Patients were prospectively evaluated with EUS and MRCP. The gold standard used was surgery or EUS-FNA and ERCP, intraoperative cholangiography, or follow-up when EUS and/or MRCP disclosed or precluded malignancy, respectively. Likelihood ratios (LR) and pretest and post-test probabilities for the diagnosis of malignancy and choledocholithiasis were calculated.RESULTS:A total of 159 patients met one of the inclusion criteria but 24 of them were excluded for different reasons. Thus, 135 patients constitute the study population. The most frequent diagnosis was choledocholithiasis (49% in group 1 and 42% in group 2, P = 0.380) and malignancy was more frequent in group 1 (35% vs 7%, respectively, P < 0.001). When EUS and MRCP diagnosed malignancy, its prevalence in our series (35%) increased up to 98% and 96%, respectively, whereas it decreased to 0% and 2.6% when EUS and MRCP precluded this diagnosis. In patients in group 2, when EUS and MRCP made a positive diagnosis of choledocholithiasis, its prevalence (42%) increased up to 78% and 92%, respectively, whereas it decreased to 6% and 9% when any pathologic finding was ruled out.CONCLUSIONS:EUS and MRCP are extremely useful in diagnosing or excluding malignancy and choledocholithiasis in patients with dilated and nondilated biliary tree. Therefore, they are critical in the approach to the management of these patients.

Hyponatraemia and cirrhosis

Hyponatraemia is a common complication of advanced cirrhosis related to an impairment in the renal capacity for eliminating solute-free water, causing a retention of water that is disproportionate to the retention of sodium, thus leading to a reduction in serum sodium concentration and hypo-osmolality. The main pathogenic factor responsible for hyponatraemia is a non-osmotic hypersecretion of arginine vasopressin (AVP) or antidiuretic hormone from the neurohypophysis, related to circulatory dysfunction. Hyponatraemia in cirrhosis is associated with increased morbidity and mortality. Hyponatraemia is also associated with increased morbidity and impaired short-term survival after transplantation. The current standard of care based on restricting fluids to 1–1.5 L/day is rarely effective. Other approaches, such as albumin infusion and the use of vaptans—which act by specifically antagonizing the effects of AVP on the V2 receptors located in the kidney tubules—have been evaluated for their role in the management of hyponatraemia. The short-term treatment with vaptans is associated with a marked increase in renal solute-free water excretion and improvement of hyponatraemia; however their use in patients with end-stage liver disease is limited by hepatotoxic effects of some of these drugs. Long-term administration of vaptans seems to be effective in maintaining the improvement of serum sodium concentration, but the available information is still limited.

Endoscopic Hemostasis in Acute Esophageal Variceal Bleeding

Acute variceal bleeding (AVB) is a milestone event for patients with portal hypertension. Esophageal varices bleed because of an increase in portal pressure that causes the variceal wall to rupture. AVB in a patient with cirrhosis and portal hypertension is associated with significant morbidity and mortality. The initial management of these patients includes proper resuscitation, antibiotic prophylaxis, pharmacologic therapy with vasoconstrictors, and endoscopic therapy. Intravascular fluid management, timing of endoscopy, and endoscopic technique are key in managing these patients. This article reviews the current endoscopic hemostatic strategies for patients with AVB.

Hemodynamic effects of substance P and its receptor antagonist RP67580 in anesthetized rats with carbon tetrachloride-induced cirrhosis

Objective. Substance P (SP) is a vasodilator that may contribute to systemic and splanchnic vasodilatation in cirrhosis. The aim of this study was to determine the effects of SP (dose –13 pg/kg) and its specific inhibitor, RP67580 (dose – 300 µg/kg) on mean arterial pressure (MAP) and portal pressure (PP) in cirrhotic rats and controls. Material and methods. MAP and PP were measured before and after administering SP and RP67580. Additionally, a small group of cirrhotic rats were pretreated with L-NAME to block the effects of nitric oxide (NO) before measurements. Results. SP produced transient systemic hypotension in both groups. SP caused a significant increase in PP in cirrhotic rats and a decrease in PP in controls. RP67580 reduced the hypotensive effect of SP, but not completely. RP67580 decreased PP in the cirrhotic group but not in controls. In cirrhotic rats pretreated with L-NAME, SP administration caused a significant decrease in MAP but no significant change in PP. Conclusions. Exogenous SP increases PP and decreases MAP in cirrhotic rats. RP687580 decreases PP and reduces SP-induced hypotension in cirrhotic rats. NO blockade abolishes the effect of SP on PP. SP contributes to splanchnic vasodilatation in cirrhosis and this effect may be mediated by NO.

The role of likelihood ratio in clinical diagnosis: Applicability in the setting of spontaneous bacterial peritonitis

Despite imperfect clinical information and uncertainty about clinical course and outcome, the clinicians main task is to make reasonable decisions about patient care. The clinical history and physical examination typically provide information that is useful for making a diagnosis; however, we still rely on laboratory and radiologic tests to confirm a diagnosis in most cases. Understanding the operative characteristic of a test is of key importance because it can change the probability that a patient has a disease before the result of a test is known. This operative characteristic, better known as the likelihood ratio (LR), is a global assessment of the information provided by a test. The LR allows calculating the odds that a patient has a disease after a test is performed. In this article, we explain the meaning of the LR, how it works, and the applicability of this tool in the setting of a challenging scenario in clinical practice, spontaneous bacterial peritonitis.

Mechanisms of Sodium Retention, Ascites Formation, and Renal Dysfunction in Cirrhosis

The mechanisms responsible for ascites formation in liver disease have aroused interest throughout the history of medicine. The Egyptians and Greeks believed that there was a relationship between liver disease and ascites. In 300 bc, Erasitratus of Cappadoccia described ascites as a consequence of “hardness of the liver” or liver disease. Several centuries later, physicians discovered the relationship between advanced liver disease and the development of ascites. Numerous studies addressing this issue have discovered that alterations in systemic and splanchnic circulation, as well as functional renal abnormalities, are the culprit of this dreaded complication of cirrhosis. Renal abnormalities occur in the setting of a hyperdynamic state characterized by an increased cardiac output, a reduction in total vascular resistance and an activation of neurohormonal vasoactive systems. This circulatory dysfunction, a consequence of intense arterial vasodilation in the splanchnic circulation, is considered a primary feature in the pathogenesis of ascites. The main factor responsible for local vasodilation seems to be the overproduction of extra-hepatic nitric oxide (NO). Splanchnic vasodilation by decreasing effective arterial blood volume causes homeostatic activation of vasoconstrictor and antinatriuretic factors triggered to compensate for a relative arterial underfilling. The net effect is avid retention of sodium and water as well as renal vasoconstriction in advanced stages. The mechanisms of ascites formation and sodium and water retention in patients with cirrhosis are discussed in this chapter.

The Not So Good Effects of Nitric Oxide Inhibition with Methylene Blue in Cirrhosis and Ascites

To the Editor: Although acute extrahepatic nitric oxide synthase (NOS) inhibition in experimental cirrhosis may correct systemic vasodilation and renal function in compensated and decompensated cirrhosis, results in humans are still conflicting. We read with interest the article by Kalambokis et al. where patients with cirrhosis and ascites received intravenous methylene blue (MBlue), a nitric oxide (NO) inhibitor, to assess the acute effects on the systemic and renal circulation in decompensated cirrhosis [1]. In the study the authors showed that there was a mild decrease in urinary sodium excretion without any effects on renal or systemic hemodynamics and no improvement in glomerular filtration rate. Based on prior studies it is known that acute extrahepatic NO inhibition in cirrhotic patients with ascites does not induce changes in the circulatory system long enough to reverse the intense sodium and water and renal vasoconstriction they exhibit [2, 3]. Therefore the continuous administration of NO inhibitors could ameliorate these changes and improve sodium and water excretion in cirrhotic patients with ascites [4]. The aim of our study was to evaluate the circulatory and renal effects of continuous NOS inhibition with MBlue, an oxidizing agent that blocks the stimulation of soluble guanylate cyclase (intracellular second messenger of NO). The Institutional Review Board of the Beth Israel Deaconess Medical Center approved the protocol. We examined the systemic hemodynamic, hormonal, and renal effects of continuous NO inhibition in cirrhotic patients with ascites before and