What dietary supplements are recommended for individuals with end-stage liver disease (i.e. cirrhosis)?

Key Practice Points

Intervention

Q: What dietary supplements are recommended for individuals with end-stage liver disease (i.e. cirrhosis)?

Last Updated: 2023-02-15

Key Practice Point #1: Micronutrients

Recommendation

For adults and children with cirrhosis, micronutrient supplementation is recommended to treat deficiencies (confirmed or clinically suspected). However, for malnourished individuals who are starting nutrition support therapy, liberal micronutrient supplementation may be preferable to the cost and delay associated with waiting for confirmation.

Individuals with cirrhosis are at risk of vitamin D deficiency and should be assessed regularly. Supplementation is recommended when serum levels fall below 20 ng/mL.

For individuals with cirrhosis and dysgeusia, vitamin A and zinc supplementation may improve symptoms, and therefore oral intake.

Evidence Summary

Evidence-based clinical practice guidelines from the European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of the Liver (EASL) and a consensus-based position paper from the North American and European Societies for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN and ESPGHAN) recommended micronutrient supplementation to treat deficiencies (confirmed or clinically suspected) for adults and children with cirrhosis. However, the ESPEN guidelines also noted that liberal micronutrient supplementation may be preferable to the cost and delay associated with confirming deficiencies for malnourished adults who are starting nutrition support therapy.

The EASL guidelines recommend regular vitamin D assessment and oral supplementation when serum levels fall below 20 ng/mL. However, a Cochrane review reported an unclear effect of vitamin D supplementation (as vitamin D₃, vitamin D₂, 1,25-dihydroxyvitamin D or 25-dihydroxyvitamin D) on all-cause mortality (15 trials, OR=0.70, 95%CI 0.09 to 5.38), liver-related mortality (one trial, RR=1.62, 95%CI 0.08 to 34.66), and the risk of serious adverse effects (i.e. myocardial infarction, thyroiditis, sustained virological response or cellular rejection in liver transplant recipients).

In a systematic review and meta-analysis of RCTs at high risk of bias, antioxidant supplements were not associated with improved overall mortality (RR 0.84, 95%CI 0.60 to 1.19, I²=0%), liver-related mortality (three trials, RR 0.89, 95%CI 0.39 to 2.05, I²=37%) or morbidity (gastrointestinal bleeding, hepatic encephalopathy, sepsis or cancer) compared to a placebo or no treatment in individuals with liver disease (including cirrhosis).

The ESPEN guidelines also noted that vitamin A and zinc supplementation may improve dysgeusia and, therefore, overall oral intake.

Grade of Evidence C

Remarks

Vitamin deficiencies are common in individuals with cirrhosis, particularly thiamine and vitamin D.

Two evidence-based clinical practice guidelines were published in 2019 on the topic of clinical nutrition in liver disease, one from the European Society for Clinical Nutrition and Metabolism (1) and the other from the European Association for the Study of the Liver (2). Both used an evidence-based system to critically appraise the literature (SIGN for ESPEN and GRADE for EASL) and both were rated as high quality using the AGREE II criteria (3). For adults with cirrhosis, both guidelines recommend micronutrient supplementation to treat deficiencies (confirmed or clinically suspected) based on limited evidence or expert opinion (1,2).
- The ESPEN guidelines made no further recommendations, but qualified that vitamin deficiencies, particularly thiamine and vitamin D, may be common in cirrhosis (1). For individuals with dysgeusia, vitamin A and zinc supplementation may help improve symptoms (and therefore oral intake) and for malnourished individuals starting nutrition support therapy liberal micronutrient supplementation may be preferable to the cost and delay associated with laboratory confirmation of deficiencies.
- The EASL guidelines further recommended regular vitamin D assessment for individuals with cirrhosis (strong recommendation based on moderate quality uncontrolled studies) and oral supplementation to reach serum vitamin D >30 ng/mL when levels fall below 20 ng/mL (strong recommendation based on moderate quality non-RCTs) (2).
In a 2019 joint position paper from the North American and European Societies for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN and ESPGHAN), the authors described nutrition recommendations for children with chronic liver disease (4). For children with cirrhosis, no official recommendations for nutrient supplementation were made, but the authors described the importance of monitoring for micronutrient deficiencies and supplementing, as appropriate.
In a Cochrane review and meta-analysis of 15 RCTs (n=1034) published before January 2017, the authors examined the effect of vitamin D supplementation in individuals with chronic liver disease (chronic hepatitis C, cirrhosis, non-alcoholic fatty liver disease and liver transplant recipients) (5). The baseline vitamin D status of participants was adequate (≥20 ng/mL) in six trials and low in the remaining nine. All vitamin D was administered orally but dosing regimens were varied: ten trials used vitamin D₃ (mean daily dose 2478 IU for eight to 48 weeks), three trials used 1,25-dihydroxyvitamin D (0.25 µg -1.0 µg/day for one month to one year), one trial used vitamin D₂ (50,000 IU, 2-3 times per week for one year) and one trial used 25-hydroxyvitamin D (800 to 2000 IU/day for one year). Due to high imprecision and risk of bias, it was unclear whether vitamin D supplementation was associated with an effect on all-cause mortality (15 trials, OR 0.70, 95%CI 0.09 to 5.38), liver-related mortality (one trial, RR 1.62, 95%CI 0.08 to 34.66) or serious adverse events (i.e. myocardial infarction, thyroiditis, sustained virological response or cellular rejection in liver transplant recipients). No data was available on liver-related morbidity or health-related quality of life. All outcomes were graded as very low quality.
A Cochrane review and meta-analysis of 20 RCTs (n=1225) published before January 2011 concluded that antioxidant supplements (beta-carotene, vitamin A, C, E and selenium) taken by individuals with liver disease (cirrhosis from any etiology, autoimmune, viral or alcohol-related in origin) did not significantly improve the risk of any of the following compared to a placebo or no treatment: mortality (seven trials, RR 0.84, 95%CI 0.60 to 1.19, I²=0%), liver-related mortality (three trials, RR 0.89, 95%CI 0.39 to 2.05, I²=37%), gastrointestinal bleeding (two trials, RR 1.18, 95%CI 0.38 to 3.63, I²=0%), hepatic encephalopathy (one trial, RR=0.90, 95%CI 0.65 to 1.25), sepsis (one trial, RR=0.90, 95%CI, 0.47 to .71) or cancer (one trial, RR 0.36, 95%CI 0.12 to 1.11) (6). Of the five of the trials that reported risk of adverse events, none reported a significant difference between the antioxidant and the control groups, although some outcomes trended towards favouring the placebo, such as increased liver enzyme activity with vitamins A and E and arthralgia and dyspepsia with vitamins A, C, E and selenium. These results are limited by the quality of the included studies, 75% of which were appraised as high risk of bias and at least 50% of which were funded in part by pharmaceutical companies.

Key Practice Point #2: Branched Chain Amino Acids

Recommendation

Oral branched chain amino acids (BCAAs, 0.25 g/kg body weight/day) are recommended for adults with chronic inadequate protein intake and advanced/decompensated cirrhosis or protein intolerance (rare).

In adults, BCAA supplements have been associated with a reduced risk of cirrhosis complications such as ascites, edema and hepatic encephalopathy and an improvement in liver biochemistry. In children, BCAA supplements have been associated with increased weight, fat and fat-free mass.

Evidence Summary

advanced cirrhosis and malnutrition and/or sarcopenia, dose of 0.25 g/kg body weight/day (ESPEN)
decompensated cirrhosis and inadequate nitrogen intake (EASL)
cirrhosis and malnutrition and/or sarcopenia and protein intolerance (rare), dose of 0.25 g/kg body weight/day (ESPEN).
Grade of Evidence B

Two systematic reviews not included in the above guidelines provided further support for BCAA supplementation for individuals with cirrhosis. The first reviewed 40 studies and reported that a BCAA dose of 0.104 to 0.29 g/kg body weight/day could be associated with a small increase in muscle strength, decreased hepatic encephalopathy, a 2.3 x decreased rate of ascites and a 1.8 x decreased rate of edema in adults and an increase in weight, fat and fat-free mass in children. However, no significant effect was described for many clinically important variables, including event-free survival, length of hospital stay and health-related quality of life. The majority of the primary studies were rated as lower quality using the Jadad scale.
Grade of Evidence C

The second review specifically examined the effect of a late night snack on liver function in older adults, but said the snack was BCAA-rich in seven of the eight included studies. Late night snacking was associated with significant improvements in disease state (as measured using the Child-Pugh score, three trials, SMD -0.332, 95%CI -0.660 to -0.004, I²=0%) and the risk of complications (hepatic encephalopathy (two trials, RR 0.46, 95%CI 0.30 to 0.69, I²=0%) and ascites (two trials, RR 0.45, 95%CI 0.23 to 0.87, I²=0%)) as well as improved liver biochemistry, but more research is needed to determine the impact of the BCAAs independent of late night snacking.

Grade of Evidence B

Two evidence-based clinical practice guidelines were published in 2019 on the topic of clinical nutrition in liver disease, one from the European Society for Clinical Nutrition and Metabolism (1) and the other from the European Association for the Study of the Liver (2). Both used an evidence-based system to critically appraise the literature (SIGN for ESPEN and GRADE for EASL) and both were rated as high quality using the AGREE II criteria (3). Both guidelines supported BCAA supplements for adults with advanced cirrhosis and evidence of inadequate protein (1,2):
- The ESPEN guidelines indicate that long-term oral BCAA (0.25 g/kg body weight/day) “should be prescribed” to adults with advanced cirrhosis and malnutrition and/or sarcopenia, based on moderate quality evidence and 89% panel consensus.
- The EASL guidelines indicate the BCAA and leucine-enriched supplements “should be considered” for adults with decompensated cirrhosis and inadequate nitrogen intake (strong recommendation based on low quality non-RCTs).

The ESPEN guidelines also recommend oral BCAA (0.25 g/kg body weight/day) or vegetable protein for the very rare cases of adults with cirrhosis and malnutrition and/or sarcopenia who are protein intolerant (moderate quality evidence and 89% panel consensus).

The authors of a systematic review of 40 randomized controlled, clinical and cohort studies published before March 2018 examined the effect of BCAA supplementation in children and adults with cirrhosis (4). The majority of studies were prospective, focused on an adult population, reported the effect of BCAA in addition to standard medical therapy and were lower quality as scored on the Jadad scale (≤3). Sample size ranged from six to 622. The BCAA supplements were mostly oral with a dose that ranged from 0.104 to 0.29 g/kg body weight/day and substantial variability in the BCAA ratio. Of the studies that described adverse effects, the most common complaints were nausea and lack of palatability.
- In adults (38 studies), BCAA supplementation was associated with a small positive effect on muscle strength (75% of studies), a 2.3 times less rate of ascites (71% of studies), and a 1.8 times less rate of edema (75% of studies). The majority of studies showed no significant effect on weight, fat mass, muscle mass, hepatic encephalopathy, event-free survival, length of hospital stay and health-related quality of life.
- In children (two studies), BCAA supplementation was associated with a significant increase in weight, fat mass and fat-free mass. No effect was described on hepatic encephalopathy or ascites.
In a systematic review and meta-analysis of seven RCTs and one nonRCT (total n=341) published before July 2017, the authors investigated the effect of late night snacks on liver function in individuals with cirrhosis (5). For most studies, the population was older Japanese adults (average age > 60 years) and the intervention was a BCAA-rich 210 kcal oral supplement (“AMINOLEBAN”, 13.5 g protein, 31.05 g carbohydrate, 3.5 g fat) administered between 9 and 10 pm for two weeks to 12 months. Two of the included studies were assessed as low risk of bias using the Cochrane Risk of Bias Tool. The late night, BCAA-rich snack was associated with significantly improved liver biochemistry (e.g. significantly reduced ALT (five trials, SMD -0.320, 95%CI -0.598 to -0.043, I²=77%) and AST (five trials, SMD -0.284, 95%CI -0.553 to -0.014, I²=0%) levels), disease state (as measured using the Child-Pugh score, three trials, SMD -0.332, 95%CI -0.660 to -0.004, I²=0%) and the risk of complications (hepatic encephalopathy (two trials, RR 0.46, 95%CI 0.30 to 0.69, I²=0%) and ascites (two trials, RR 0.45, 95%CI 0.23 to 0.87, I²=0%)). As seven of the eight late night snacks were BCAA-rich, it is unclear whether the above results should be attributed to late night eating, the BCAA content or both.

Contributors

Current Contributors

Lori Warford-Woolgar

Co-Author

Mary Anne Smith

Co-Author

Dawna Royall

Reviewer

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