Systematic Review and Meta-Analysis on the Effects of Lactulose and Rifaximin on Patient-Reported Outcomes in Hepatic Encephalopathy

Moon, Andrew M.; Kim, Hannah P.; Jiang, Yue; Lupu, Gabriel; Bissram, Jennifer; Barritt, A. Sidney; Tapper, Elliot B.

doi:10.14309/ajg.0000000000002008

Cited by 16 publications

(14 citation statements)

References 52 publications

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“…Compared with placebo, lactulose was associated with reduced recurrent overt hepatic encephalopathy (25.5% vs 46.8%) in a meta-analysis of RCTs enrolling 1415 patients with hepatic encephalopathy . In a meta-analysis of 3 clinical trials of 126 participants receiving lactulose, lactulose was associated with an improvement of 6.92 (95% CI, 6.66-7.18) in the Sickness Impact Profile (ranges from 0 [best] to 68 [worst]; clinically important differences are >4) . In a 6-month placebo-controlled, double-blind RCT, rifaximin reduced hospitalization for hepatic encephalopathy from 22.6% to 13.6% among 299 patients with prior hepatic encephalopathy taking lactulose .…”

Section: Discussionmentioning

confidence: 99%

Diagnosis and Management of Cirrhosis and Its Complications

Tapper

Parikh

2023

JAMA

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103

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ImportanceCirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021, the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9 per 100 000 people.ObservationsThe most common causes of cirrhosis in the US, which can overlap, include alcohol use disorder (approximately 45% of all cases of cirrhosis), nonalcoholic fatty liver disease (26%), and hepatitis C (41%). Patients with cirrhosis experience symptoms including muscle cramps (approximately 64% prevalence), pruritus (39%), poor-quality sleep (63%), and sexual dysfunction (53%). Cirrhosis can be diagnosed by liver biopsy but may also be diagnosed noninvasively. Elastography, a noninvasive assessment of liver stiffness measured in kilopascals, can typically confirm cirrhosis at levels of 15 kPa or greater. Approximately 40% of people with cirrhosis are diagnosed when they present with complications such as hepatic encephalopathy or ascites. The median survival time following onset of hepatic encephalopathy and ascites is 0.92 and 1.1 years, respectively. Among people with ascites, the annual incidence of spontaneous bacterial peritonitis is 11% and of hepatorenal syndrome is 8%; the latter is associated with a median survival of less than 2 weeks. Approximately 1% to 4% of patients with cirrhosis develop hepatocellular carcinoma each year, which is associated with a 5-year survival of approximately 20%. In a 3-year randomized clinical trial of 201 patients with portal hypertension, nonselective β-blockers (carvedilol or propranolol) reduced the risk of decompensation or death compared with placebo (16% vs 27%). Compared with sequential initiation, combination aldosterone antagonist and loop diuretics were more likely to resolve ascites (76% vs 56%) with lower rates of hyperkalemia (4% vs 18%). In meta-analyses of randomized trials, lactulose was associated with reduced mortality relative to placebo (8.5% vs 14%) in randomized trials involving 705 patients and reduced risk of recurrent overt hepatic encephalopathy (25.5% vs 46.8%) in randomized trials involving 1415 patients. In a randomized clinical trial of 300 patients, terlipressin improved the rate of reversal of hepatorenal syndrome from 39% to 18%. Trials addressing symptoms of cirrhosis have demonstrated efficacy for hydroxyzine in improving sleep dysfunction, pickle brine and taurine for reducing muscle cramps, and tadalafil for improving sexual dysfunction in men.Conclusions and RelevanceApproximately 2.2 million US adults have cirrhosis. Many symptoms, such as muscle cramps, poor-quality sleep, pruritus, and sexual dysfunction, are common and treatable. First-line therapies include carvedilol or propranolol to prevent variceal bleeding, lactulose for hepatic encephalopathy, combination aldosterone antagonists and loop diuretics for ascites, and terlipressin for hepatorenal syndrome.

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Section: Discussionmentioning

confidence: 99%

Diagnosis and Management of Cirrhosis and Its Complications

Tapper

Parikh

2023

JAMA

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103

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“…Its determinants are complex and related to disease severity, comorbidities, the home environment, medication burden, and symptom burden 1,2,19 . Prior studies have demonstrated that lactulose therapy can improve HRQOL in patients with HE, both overt and covert 6 . In practice, clinicians often initiate lactulose therapy for poor PROs that are linked to HE, such as poor HRQOL, poor sleep, and depressive symptoms.…”

Section: Discussionmentioning

confidence: 99%

Lactulose therapy for patients with cirrhosis, portal hypertension, and poor patient-reported outcomes: The Mi-Kristal trial

et al. 2023

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Background and Aims: Poor patient-reported outcomes (PROs) are common in cirrhosis, including poor sleep and health-related quality of life (HRQOL). HE is a major driver of poor PROs. Many clinicians initiate lactulose therapy to address poor PROs. PRO-triggered therapy, however, has not been studied till date. Methods: We conducted a 28-day randomized trial of crystalline lactulose therapy (20 g BID) compared with no HE-directed therapy in 52 patients with cirrhosis, portal hypertension, no prior HE, and high Work Productivity and Activity Impairment scores (0–10) attributed to cirrhosis. The primary outcome was change in global HRQOL measured with Short Form-8 Health Survey. Secondary outcomes included change in Animal Naming Test score, Work Productivity and Activity Impairment, and sleep quality (scored “very bad” to “very good”). Approach and Results: Overall, 52 patients underwent randomization; 3 subjects withdrew from the crystalline lactulose arm (1 before medication initiation, 1 due to an unrelated condition, and 1 due to high baseline bowel movements). The average age was 60 years, the average Model for Endstage Liver Disease—Sodium score was 10.5, and 56% of the patients had ascites. Baseline bowel movements were 2.3/day, with 35% of the patients having Bristol Stool Scale >4. At 28 days, there was no improvement in HRQOL: patients receiving crystalline lactulose had an 8.1-point (95% CI: 3.7–12.4) increase compared with 6.6 (95% CI: 2.3–10.8) in the control group (p = 0.6). Lactulose was associated with a significantly (p = 0.002) increased Animal Naming Test score (3.7, 95% CI: 2.1–5.4) versus the control group (0.2, 95% CI: −1.7, 1.4). Lactulose users reported more good sleep (92% vs. 52%, p = 0.001) and lower activity impairment (3.0 vs. 4.8, p = 0.02). Conclusions: Lactulose improves sleep and activity impairment in patients with poor PROs. We did not observe any improvement in global HRQOL after 28 days using the Short Form-8 Health Survey instrument.

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“…Sleep disorder in cirrhosis is also a complex topic with multiple contextual nuances, and the field is evolving. For example, lactulose therapy improves sleep for patients with covert hepatic encephalopathy . Following the publication of our Review, we showed that many patients with cirrhosis experienced improved sleep with use of lactulose even if they had not been diagnosed with hepatic encephalopathy …”

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confidence: 82%