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A higher dose of loop diuretics was associated with more rapid skeletal muscle depletion and shorter survival in patients with liver cirrhosis, independent of the severity of disease, Japanese researchers reported.

The findings suggest that these drugs, often used to treat hepatic edema and ascites, are a critical risk factor for sarcopenia. "These results raise the important possibilities that refraining from high-dose loop diuretics for the treatment of hepatic edema and/or ascites may contribute to [preventing] skeletal muscle depletion and to improving the prognosis of patients with liver cirrhosis," wrote Makoto Shiraki, MD, PhD, of Gifu University Graduate School of Medicine in Gifu, and colleagues.

Sarcopenia, observed in of liver cirrhosis patients, has been shown to worsen prognosis. In a previous , the researchers had reported that cirrhosis patients lose skeletal muscle mass at twice the annual rate of healthy people.

In the current retrospective study, published online in , the team evaluated 226 liver cirrhosis patients; median age was 64, and 137 were men. Participants were treated during 2004-2017 at Gifu University Hospital, and separated into two groups by diuretic dose (<20 mg/day and >20 mg/day).

Overall, hepatitis C virus (HCV) infection was the most common cause of cirrhosis (n=105), followed by alcohol (n=64). HCV etiology predominated in the lower-dose group (50%), and alcohol in the higher-dose patients (41%).

CT scans measured skeletal muscle at the level of the third lumbar vertebra, and the relative change in skeletal muscle area per year (ΔSMA) was calculated. The therapeutic dosage of loop diuretics inversely correlated with ΔSMA by both simple (r = –0.27, P<0.0001) and multiple regression analyses (t = –3.07, P = 0.002). During a median follow-up period of 49 months, 82 patients died – 19 in the >20 mg/day group (19/39, 48%) and 63 in the ≤20 mg/day group (63/187, 34%).

Overall survival rates were lower in the >20 mg group than in those in the ≤20 mg group: median 66 versus 97 months (P =0.002).

Multivariate analysis further revealed that higher doses were independently associated with mortality regardless of Child-Pugh class or model for end-stage liver disease score, for a hazard ratio (HR), 1.86 (95% confidence interval 1.03-3.24, P = 0.039). Another independent risk factor that emerged was a change in ΔSMA of at least –3.1% (HR 3.87, 95% CI 2.32-6.60 P<0.0001).

Asked for his perspective, Aldo J. Montano-Loza, MD, PhD, of the University of Alberta in Edmonton, Canada, who was not involved with the study, called the results "interesting," since muscle depletion is a frequent complication of cirrhosis. He cautioned, however, that the study could not determine whether it was the use of loop diuretics per se that contributed to muscle depletion and the poor outcomes or simply reflected more severe liver disease.

"While the data are consistent with the former possibility, which would have implications for pathogenesis and for clinical management, they consist only of observed associations," he told 名媛直播 Today. "External validation of these findings in other cohorts of patients with cirrhosis is warranted."

Long-term use of loop diuretics can induce other adverse events such as hyponatremia and renal impairment, both of which are independent risk factors for mortality in patients with liver cirrhosis, Shiraki and co-authors noted. Loop diuretics impair skeletal myoblast differentiation and exercise-induced muscle hypertrophy, inhibiting by targeting the co-transporter NKCC, which helps deliver sodium, potassium, and chloride into cells.

"The results of the present study showed an urgent need for the strategic change of the treatment of hepatic edema and/or ascites in clinical practice," the researchers wrote.

They concluded that high-dose loop diuretics should be avoided and early add-on therapy with the aquaretic selective vasopressin V2 receptor antagonist tolvaptan (Samsca) should be given to prevent sarcopenia, and called for prospective studies with more patients and longer follow-up.

Study limitations, the team said, included the retrospective and single-center design. And although diet and physical activity have been shown to be associated with skeletal muscle depletion and mortality in liver cirrhosis patients, these data were unavailable in the retrospective analysis. In addition, dose and duration of loop diuretics were decided by individual attending physicians and hence there were significant differences in baseline characteristics between patients on daily doses of >20 mg and those of ≤20 mg, potentially affecting the results.

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