Research Letters

Improvement in renal function in hepatorenal syndrome with N-acetylcysteine

Alcohol-associated liver disease is one of the main causes of chronic liver disease. It comprises a clinical-histologic spectrum of presentations, from steatosis, steatohepatitis, to different degrees of fibrosis, including cirrhosis and severe necroinflammatory disease, called alcohol-associated hepatitis. In this focused update, we aim to present specific therapeutic interventions and strategies for the management of alcohol-associated liver disease. Current evidence for management in all spectra of manifestations is derived from general chronic liver disease recommendations, but with a higher emphasis on abstinence and nutritional support. Abstinence should comprise the treatment of alcohol use disorder as well as withdrawal syndrome. Nutritional assessment should also consider the presence of sarcopenia and its clinical manifestation, frailty. The degree of compensation of the disease should be evaluated, and complications, actively sought. The most severe acute form of this disease is alcohol-associated hepatitis, which has high mortality and morbidity. Current treatment is based on corticosteroids that act by reducing immune activation and blocking cytotoxicity and inflammation pathways. Other aspects of treatment include preventing and treating hepatorenal syndrome as well as preventing infections although there is no clear evidence as to the benefit of probiotics and antibiotics in prophylaxis. Novel therapies for alcohol-associated hepatitis include metadoxine, interleukin-22 analogs, and interleukin-1-beta antagonists. Finally, granulocyte colony–stimulating factor, microbiota transplantation, and gut–liver axis modulation have shown promising results. We also discuss palliative care in advanced alcohol-associated liver disease.

Acute-on-chronic liver failure (ACLF) is an entity comprising an acute deterioration of liver function in cirrhotic patients, associated with organ failure(s) and high short-term mortality. We aimed to identify predictive factors for short-term mortality in patients admitted with ACLF that may benefit most from liver transplantation.

Retrospective analysis of patients admitted in ACLF to a tertiary intensive care unit between 2013 and 2017 was performed. The EASL-CLIF acute-on-chronic liver failure in cirrhosis (CANONIC) criteria were used to define ACLF grade. Multivariable analysis using 28-day mortality as an end-point was performed, including severity-of-disease scores and clinical parameters.

Seventy-seven patients were admitted in ACLF over the study period. The commonest aetiology of liver disease was alcohol related 52/77(68%) and the commonest precipitant of ACLF was variceal haemorrhage 38/77(49%). Overall 28-day mortality was 42/77(55%) [ACLF-(grade)1:3/42(7%); ACLF-2:10/42(24%); and, ACLF-3:29/42(69%);p = 0.002]. On multivariable analysis MELD ≥ 26 [odds ratio(OR) = 11.559; 95% confidence interval(CI):2.820–47.382;p = 0.001], ACLF-3 (OR = 3.287; 95%CI:1.047–10.325;p = 0.042) at admission and requirement for renal replacement therapy (OR = 5.348; 95%CI:1.385–20.645;p = 0.015) were independently associated with 28-day mortality.

Patients admitted with ACLF to intensive care have a high mortality rate. Defined early thresholds at admission can identify patients at the highest risk that may benefit most from liver transplantation.

We assessed the nephroprotective effects of montelukast sodium and N-acetylcysteine on secondary renal damage due to unilateral ureteral obstruction in a rat model.

In this study 30 Wistar albino male rats were randomized into 3 groups, including placebo, N-acetylcysteine and montelukast sodium. Three rats served as the control group. The left ureter of the rats was sutured with 4-zero polyglactin sutures. Medications were given 3 days before obstruction and continued for 15 days. Dimercaptosuccinic acid renal scintigraphy was performed before obstruction and on day 15. Rats were sacrificed on day 15 and histopathological examinations were done. We biochemically assessed oxidative stress markers (myeloperoxidase and malondialdehyde), sulfhydryl and total nitrite for lipid peroxidation, oxidative protein damage and antioxidant levels, respectively.

On pathological examination inflammation and tubular epithelial damage in the N-acetylcysteine and montelukast sodium groups were less than in the placebo group (p <0.05). No difference was seen in normal kidneys. Myeloperoxidase, malondialdehyde and total nitrite levels in the N-acetylcysteine group, and myeloperoxidase and malondialdehyde levels in the montelukast sodium group were lower than in the placebo group (p <0.05). No statistical difference was seen in sulfhydryl levels (p >0.05) or among the N-acetylcysteine, montelukast sodium and placebo groups on scintigraphy (p >0.05). No pathological, chemical and scintigraphic differences were seen among the N-acetylcysteine, montelukast sodium and sham treated groups (p >0.05).

N-acetylcysteine and montelukast sodium have a protective effect against obstructive damage of the kidney. However, further investigations are needed.

Renal dysfunction is common in patients with end-stage liver disease (ESLD); it takes on many forms from acute to chronic renal injury and may involve a variety of mechanisms. Hepatorenal syndrome (HRS) is a specific type of hepatorenal disorder (HRD) with a unique pathophysiology. HRS is characterized by splanchnic arterial vasodilatation and decreased effective intravascular volume that leads to renal vasoconstriction and decreased renal blood flow. The incidence of HRS in relation to other forms of HRD is unknown; however, it is estimated that 35% to 40% patients with ESLD and ascites eventually develop the condition. Two subtypes of HRS have been described. Type 1 HRS is rapidly progressive, whereas the renal function in type 2 HRS deteriorates slowly over weeks or months. Type 1 HRS may be precipitated by sepsis or acute alcoholic hepatitis and occasionally develops in patients who already have type 2 HRS. The diagnosis of HRS is based on the exclusion of other causes of renal dysfunction because no specific test is available. The definitive treatment of HRS is liver transplant. As a bridge to liver transplant, medical management with volume expansion and the use of vasoconstrictors is often implemented. A transjugular intrahepatic portosystemic shunt has been attempted in treating HRS, although there is little evidence of its efficacy compared with standard therapy. Renal replacement therapy is often used if the patient is a liver transplant candidate. Artificial liver assist devices are in the research phase.

Le syndrome hépatorénal est une complication sévère de la maladie hépatique au stade terminal. Au cours du syndrome hépatorénal, la vasodilatation splanchnique et périphérique, et donc la réduction du volume artériel efficace, induisent l’activation de molécules vasoconstrictrices rénales, d’où l’insuffisance rénale fonctionnelle. Le diagnostic de syndrome hépatorénal est un diagnostic d’exclusion et n’est retenu qu’après avoir éliminé toutes les autres causes d’insuffisance rénale aiguë (en particulier prérénale). La péritonite bactérienne spontanée est un des facteurs déclenchants, et doit être recherchée chez tout patient ayant une maladie hépatique sévère et une insuffisance rénale aiguë. Sa prise en charge rapide par antibiothérapie parentale et perfusion d’albumine diminue significativement le risque. L’utilisation combinée d’albumine par voie intraveineuse, de vasoconstricteurs splanchniques et périphériques, et/ou d’épuration extrarénale, permet parfois de temporiser jusqu’à la transplantation hépatique (ou combinée foie–rein chez des patients sélectionnés). La transplantation est, en effet, le seul moyen d’améliorer le pronostic à long terme.

Hepatorenal syndrome is a severe complication of end-stage liver disease. The pathophysiological hallmark is severe renal vasoconstriction, resulting from peripheral and splanchnic vasodilation as well as activation of renal vasoconstrictor molecules, which induce the effective arterial volume reduction and the functional renal failure. The diagnosis of hepatorenal syndrome is currently based on the exclusion of other causes of renal failure (especially prerenal). Spontaneous bacterial peritonitis is one of the triggering factors and should be sought in all patients with severe liver disease and acute renal failure. Quickly treating patients with parental antibiotics and albumin infusion significantly decreases the risk. The combined use of intravenous albumin, splanchnic and peripheral vasoconstrictor and/or renal replacement therapy sometimes enables a delay until liver transplantation (or combined liver–kidney in selected patients). Transplantation is in fact the only way to improve the long-term prognosis.

Acute on chronic liver failure (ACLF) is currently recognized as a specific entity characterized by acute deterioration of liver function in the context of compensated or even decompensated, but hitherto stable, cirrhosis. Worsening of liver function and subsequently of other end-organs occurs rapidly and follows a precipitating event that directly or indirectly affects liver function. Available data indicate that ICU mortality for ACLF ranges from 35% to 89% and in-hospital mortality ranges from 43% to 88%. Patient outcome is not simply determined by the severity of liver disease. Indeed, the development and degree of end-stage organ failure represents the main determinant of outcome in ACLF patients. The pathophysiology of ACLF may be approached with the PIRO concept employed for sepsis (Predisposition, Infection/Inflammation, Response, Organ Failure). According to this approach, Predisposition is indicated by the severity of cirrhosis, Injury by nature/severity of the precipitating event(s), and the severity of inflammation and risk of infection express the patient's Response to injury. Finally, the extent of Organ failure is responsible for prognosis of ACLF patients. Current medical therapy involves management of the precipitating event, support end-organs and prevention/treatment of complications, until the eventual recovery of liver function. If medical treatment fails, transplantation is the only option in eligible patients. Characterization of the syndrome, definition of pathophysiological mechanisms, and improvement of patient management, currently call for ample efforts.