By Nicole Leigh Aaronson,MD, Loren Wissner Greene, MD, and Denise Pate, MD
Faculty Peer Reviewed
Introduction:
Whereas there are specially designed diets for patients with hypertension, diabetes, and renal failure, NYU Medical Center, like most medical centers, does not have a specific diet for patients with cirrhosis. In considering what dietary modifications might benefit these patients, it is useful to first examine the nutritional status of the cirrhotic patient. Cirrhosis is a disease characterized by progressive liver injury and hepatocyte death, which eventually produces fibrosis of liver resulting in a loss of hepatic synthetic and detoxification properties. Nutritional compromise is particularly severe in cirrhotic patients. Protein-energy malnutrition (PEM), with low serum albumin and low muscle mass, occurs in 65-90% of cases of advanced cirrhosis. As hepatocytes die and fibrosis progresses, the liver becomes atrophic, hepatic glycogen stores are lost, and peripheral tissues become more resistant to the effects of insulin. The ensuing hyperglucagonemia results in a catabolic state eventually producing anorexia and cachexia.[1] As cirrhotic patients are less able to metabolize glucose efficiently, they increase their use of branched chain amino acids (BCAAs), which become a comparatively more efficient energy source. Furthermore, BCAAs are further depleted from the circulation due to increased uptake by skeletal muscles that use the BCAAs in the synthesis of glutamine, which is produced in order to clear the ammonia that is not cleared by the failing liver.[2]
Because of these alterations in protein metabolism, patients with chronic liver disease, particularly cirrhosis, routinely have decreased BCAAs and increased aromatic amino acids (AAAs) in their circulation.[3] BCAAs include valine, leucine, and isoleucine, while AAAs include phenylalanine, tyrosine, and tryptophan. These altered serum amino acid concentrations are clinically relevant as decreased BCAAs are associated with complications of cirrhosis such as hepatic encephalopathy, worsening cachexia, and increased infection risk. Of note, the serum BCAA concentration is strongly correlated with the serum albumin level. Maintaining a higher serum albumin in patients with cirrhosis is associated with decreased mortality and improved quality of life.[4]
Pathophysiology of Hepatic Encephalopathy
The low level of BCAAs in patients with cirrhosis is hypothesized to be one of multiple factors responsible for development of hepatic encephalopathy. Because of the imbalance between BCAAs and AAAs, AAAs are able to overwhelm the L-system, which preferentially transports neutral amino acids across the blood-brain barrier. AAAs are believed to act as a substrate for the derivation of “false neurotransmitters”, such as tyramime, octopamine, phenethyamine, and phenylethanolamine and actual neurotransmitters, such as serotonin, which themselves result in an increased serum ammonia level. Furthermore, supplementation of BCAAs is thought to facilitate ammonia detoxification by supporting synthesis of glutamine, one of the non-branched chain amino acids, in skeletal muscle and in the brain as well as diminishing the influx of AAAs across the blood-brain barrier.[5] Of note, oral BCAA supplementation is more useful in chronic encephalopathic patients than is parenteral BCAA supplementation in patients with acute encephalopathy. This finding suggests that long-term nutritional modification is of greater benefit than short-term responses to acute mental status changes. [6]
Pathophysiology of Cachexia
As discussed previously, malnutrition progressing to cachexia is another common manifestation of cirrhosis. Malnutrition can be mitigated with BCAA supplementation. Studies show that administration of amino acid formulas enriched with BCAAs can reduce protein loss, support protein synthesis, and improve nutritional status of patients with chronic liver disease. Recent studies in animal models have elucidated the mechanism by which BCAAs act to improve glucose utilization.[7] Leucine has been shown to be the most effective of the BCAAs because it acts via multiple pathways to stimulate protein synthesis. Furthermore, BCAAs metabolites inhibit proteolysis.[8] Patients with cirrhosis have both insulin deficiency and insulin resistance. BCAAs (particularly leucine) help to reverse the catabolic, hyperglucagonemic state of cirrhosis both by stimulating insulin release from the pancreatic β cells and by decreasing insulin resistance allowing for better glucose utilization.[9] Coadministration of BCAAs and glucose has been found to be particularly useful. Recent studies in animal models have shown that BCAAs also induce transcription of the GLUT2 transporter and liver-type glucokinase (L-GK) that allow the liver to uptake and trap glucose.[10] Therefore, BCAA supplementation improves protein-energy malnutrition by improving utilization of glucose, thereby diminishing the drive for proteolysis, inhibiting protein breakdown, and stimulating protein synthesis. The combination of improved protein balance and increased glucose utilization, achieved with BCAA supplementation, also helps to downregulate gluconeogenesis in the kidney which produces 5-28% of the glucose released into the body.[11] The mechanism for this effect on the kidney has not yet been elucidated.
Pathophysiology of Impaired Immune Defense and Hepatic Regeneration
Cirrhotic patients have impaired immune defense, characterized by defective phagocytic activity and impaired intracellular killing activity. One molecular-level study showed that another effect of BCAA supplementation is improvement of phagocytic function of neutrophils and possibly improvement in natural killer T (NKT) cell lymphocyte activity Improvement in NKT activity has been seen but has not been shown to be statistically significant..[12] BCAA supplementation may reduce the risk of infection in patients with advanced cirrhosis not only through improvement in protein-energy malnutrition but also by directly improving the function of the immune cells themselves.
BCAA administration has also been shown to have a positive effect on liver regeneration. This has mostly been studied in cirrhotic patients who underwent partial hepatectomy for cancer resection or liver transplant. A proposed mechanism for improved liver regeneration is the stimulatory effect of BCAAs (particularly leucine) on the secretion of hepatocyte growth factor by hepatic stellate cells.[13] Additionally, BCAAs activate rapamycin signaling pathways which promotes albumin synthesis in the liver as well as protein and glycogen synthesis in muscle tissue.[14] Chemical improvement with BCAA treatment is demonstrated by recovery of serum albumin and lowering of serum bilirubin levels.
Overall Benefit of BCAA Supplementation
The utility of BCAA supplementation has been a topic of debate with many of the studies performed on small groups under an observational framework. Large-scale studies as early as 1989 showed that long-term oral BCAA supplementation was useful in staving off malnutrition and improving survival by preventing end-stage fatal complications of cirrhosis such as hepatic failure and gastrointestinal bleeding.[15] More recently, in 2004, a multicenter, double-blind, randomized controlled trial was performed comparing patients with advanced cirrhosis taking BCAA supplements to those taking equicaloric-equinitrogenous supplements. The odds ratio for progress to liver failure and death for BCAAs versus lactoalbumin was 0.43 (p = 0.039), and the odds ratio for BCAAs versus maltodextrin was 0.51 (p = 0.108). [16] A 2005 multicenter, double-blinded, randomized controlled trial of 646 patients, showed a similar improvement for patients taking 12 grams of oral BCAA supplementation daily. The incidence of death by any cause, development of liver cancer, rupture of esophageal varices, or progression to hepatic failure was decreased in the group that received BCAA supplementation. The hazard ratio for this decrease was 0.67 with a p value of 0.015.[17] Patients receiving BCAA supplementation also have a lower average hospital admission rate, better nutritional status, and better liver function tests.[18] Additionally, when asked to complete a 36-question survey (the short form-36 questionnaire), patients taking BCAA supplementation report improved quality of life. [19] Though length of stay and readmission rates have never been specifically addressed, the authors propose that this should be studied as a quality initiative. In addition to overall survival, BCAAs have been shown to mitigate hepatic encephalopathy, cachexia, and infection rates, complications associated with the progression of hepatic cirrhosis.
Suggestions for implementation for Quality Improvement and further study
While there are many benefits to BCAA supplementation, it is also worthwhile to consider how such dietary modifications can be put in place so that patients can benefit from this research. BCAAs make up 20-25% of the protein content of most foods. Highest levels are found in casein whey protein of dairy products and vegetables, such as corn and mushrooms. Other sources include egg albumin, beans, peanuts and brown rice bran. [20] In addition to BCAAs from diet, oral supplements of BCAAs can be used. Oral supplementation tends to provide a better hepatic supply of BCAAs for patients able to tolerate PO nutrition as compared with IV supplementation, especially when treating symptoms of hepatic encephalopathy. Unfortunately, oral non-dietary BCAA supplements tend to be unpalatable, as they do not dissolve well and require the patient to drink large volumes of water. Side effects occur in 10-15% of patients taking BCAA supplements and include vomiting, bloating, abdominal distention, and diarrhea. Though these side effects tend to be self-limited and resolve as treatment continues, they can be avoided entirely if the BCAAs are supplemented through the diet via dairy products, eggs or vegetables, supplemented by lactose and bean digestive enzymes, if necessary.[21] Coadministration of BCAAs with carnitine and zinc has also been shown to increase ammonia metabolism further reducing the encephalopathic symptoms.[22]
Cirrhotic patients benefit from eating frequent, small meals that prevent long fasts which place the patient in a catabolic state. Correspondingly, the best time for BCAA supplementation is at bedtime to improve the catabolic state during starvation in early morning fasting.[23] Because of their glycogen depletion, cirrhotic patients experience a decrease in glucose oxidation and an increase in protein catabolism after an overnight fast, comparable to the catabolic state seen in healthy patients after 2-3 days of starvation.[24] A late night nutritional snack reduces symptoms of weakness and fatigability, lowers postprandial hyperglycemia, increases skeletal muscle mass,[25] improves nitrogen balance, and increases serum albumin levels.[26] Nocturnal BCAAs even improve serum albumin in cirrhotic patients who show no improvement with daytime BCAAs.[27]
Summary:
Patients with cirrhosis benefit from dietary supplementation with BCAAs. It helps to treat hepatic encephalopathy and protein-energy malnutrition, to prevent infection, and to promote liver regeneration. Increasing foods rich in BCAAs, such as dairy and vegetables, or providing oral supplementation can have a significant positive impact on cirrhotic patients’ health and quality of life. Additionally, limiting AAAs may also benefit these patients. Cirrhosis is a disease that will benefit from dietary control just in the way that many other chronic diseases, such as diabetes and renal insufficiency, currently benefit from nutritional modification. Evidence regarding the benefits of BCAA supplementation have been published since the late 1980s, and more recent randomized controlled trials have supported these prior conclusions in showing that long-term BCAA supplementation improves nutritional status and prevents cirrhotic complications, decreasing mortality and improving prognosis. Although most medical centers have not instituted these dietary modifications for reasons that are largely unclear, increasing BCAA oral intake would be beneficial for cirrhotic patients.
Dr. Aaronson is a third-year medical student at NYU School of Medicine
Dr. Greene is a clinical associate professor of medicine (endocrinology) at NYU Langone Medical Center
Dr. Pate is a 3rd-year resident at NYU Langone Medical Center
Peer reviewed by Michael Poles, section editor, gastroenterology, Clinical Correlations
Image courtesy of Wikimedia Commons.
References:
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[4] H Moriwaki, Y Miwa, M Tajika, et al, “Branched-Chain Amino Acids as a Protein- and Energy-Source in Liver Cirrhosis,” Biochemical and Biophysical Research Communications 313, 2004: 405-407.
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